UST College of Science Department of Biological Sciences 1

Pharmacogenomics of Myofascial Pain Syndrome

An Undergraduate Thesis

Submitted to the

Department of Biological Sciences

College of Science

University of Santo Tomas

In Partial Fulfillment

of the Requirements for the Degree of Bachelor of Science in Biology

Jose Marie V. Lazaga

Marc Llandro C. Fernandez

May 2021

UST College of Science Department of Biological Sciences 2

PANEL APPROVAL SHEET

This undergraduate research manuscript entitled:

Pharmacogenomics of Myofascial Pain Syndrome

prepared and submitted by Jose Marie V. Lazaga and Marc Llandro C. Fernandez, was checked and has complied with the revisions and suggestions requested by panel members after thorough evaluation. This final version of the manuscript is hereby approved and accepted for submission in partial fulfillment of the requirements for the degree of Bachelor of Science in Biology.

Noted by:

Asst. Prof. Marilyn G. Rimando, PhD Research adviser, Bio/MicroSem 602-603

Approved by:

Bio/MicroSem 603 panel member Bio/MicroSem 603 panel member Date: Date:

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DECLARATION OF ORIGINALITY

We hereby affirm that this submission is our own work and that, to the best of our knowledge and belief, it contains no material previously published or written by another person nor material to which a substantial extent has been accepted for award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgement is made in the text.

We also declare that the intellectual content of this undergraduate research is the product of our work, even though we may have received assistance from others on style, presentation, and language expression.

Jose Marie V. Lazaga Marc Llandro C. Fernandez Date: May 6, 2021 Date: May 6, 2021

Asst. Prof. Marilyn G. Rimando, PhD Research adviser Date: May 6, 2021

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ABSTRACT

Myofascial pain syndrome (MPS) is a musculoskeletal pain condition characterised by localized deep pains in the skeletal muscle and fascia, known as trigger points. It is a top contributor to global disability, with a lifetime prevalence of up to 85%, increasing the rate of other health-related concerns. Some of the current pharmacological treatment modalities for MPS and other musculoskeletal pain (MSP)-related conditions show some favourable outcomes in pain. The genetic make-up of patients however may affect drug treatment response. Also, signalling cascades are affected due to the adverse gene-drug- drug-gene interactions. The signalling cascades of G-proteins, such as in cAMP pathway, are also highly linked to MPS and other diseases and conditions, which often present chronic pain complications. A secondary analysis systematic review, using structured mining was conducted to determine the top genes, drugs, and conditions associated with

MPS. The data sets surveyed were sourced from several databases including

Comparative Toxicogenomics Database (CTD) and GeneCards Suite Databases

(GeneCards, MalaCards, PathCards). The purpose of this review is to provide information on the current knowledge on the pharmacogenomics of MPS to direct the focus of future studies to disease-gene-drug associations for better patient treatment and intervention outcomes. Further studies are necessary to better improve the quality of life of patients with MPS, including the minimisation of adverse drug reactions and maximisation of drug efficacy.

Keywords: chronic pain, myofascial pain syndrome, pharmacogenomics

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INTRODUCTION

Chronic pain (Institute of Medicine (IoM), 2011) is amongst the most reported medical conditions in adults (Interagency Pain Research Coordinating Committee (IPRCC),

2016). Approximately 70% to 80% of patients with chronic pain have chronic musculoskeletal pain (MSP) disorder as the underlying diagnosis (James et al., 2018).

Chronic MSP conditions are the top contributors to global disability, increasing the rate of other health-related concerns, including anxiety and depression, and opioid dependence

(Cieza et al., 2020; Gatchel & Schultz, 2014; Groves et al., 1998; Ho et al., 2018; IoM,

2011; Hutson & Ward, 2015; IPRCC, 2016; James et al., 2018; Mills et al., 2019; Smith et al., 2001). Numerous treatment interventions are used in chronic pain management, including pharmacologic treatment modalities, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants (Gatchel & Schultz, 2014; Groves et al., 1998; Ho et al., 2018; Hutson & Ward, 2015), and non-pharmacologic treatment modalities, such as rehabilitation interventions (Gatchel & Schultz, 2014; Kamper et al., 2015).

Myofascial Pain Syndrome

Myofascial pain syndrome (MPS) is one of the common MSP conditions, described as localised deep pains and “complex of sensory, motor, and autonomic symptoms” in the skeletal muscle and fascia, caused by myofascial trigger points (MTrPs) (Friction et al.,

1985; Gatchel & Schultz, 2014; Hutson & Ward, 2015; Kamper et al., 2015; Simons,

1975). Simons (1975) referred to MTrPs as “spots of exquisite tenderness and hyperirritability in muscles or their fascia, localised in taut, palpable bands”. MPS also presents neurologic and otologic associations, including muscle weakness, paraesthesia,

UST College of Science Department of Biological Sciences 6 and hampered vision (Friction et al., 1985; Hutson & Ward, 2015; Simons, 1975). Due to the clinical similarities between MPS and other MSP conditions, most esp. fibromyalgia syndrome (FMS), it is postulated that later stages of MPS result in FMS (Friction et al.,

1985; Gatchel & Schultz, 2014; Hutson & Ward, 2015; Simons, 1975).

Prevalence of MPS

The existing literature regarding the exact prevalence of MPS has been exceedingly rare

(Tantanatip & Chang, 2020). A cross-sectional study conducted by Fleckenstein et al.

(2010) reported that MPS has a lifetime prevalence of up to 85% amongst the general population, primarily affecting sedentary individuals (Vazquez-Delgado et al., 2009) and has a positive age correlation, with peak age prevalence between 59 to 74 years old

(Bergman et al., 2001). There are no reports of significant differences in presentation between males and females. However, it is described that MPS is more prevalent in females than in males (Vazquez-Delgado et al., 2009; Galasso et al., 2020), but the difference was also not of statistical significance (Wolfe et al., 2013). MPS is the leading diagnosis of chronic and persistent localised pain in pain management clinics, with a prevalence of up to 90% (Fleckenstein et al., 2010).

Aetiology and Pathophysiology of MPS

The exact developmental mechanisms of MTrPs are unknown, but it is believed to be initiated by systemic or ergonomic factors, including gross or repetitive muscle trauma and psychological stress (Borg-Stein & Iaccarino, 2014; Gatchel & Schultz, 2014; Hutson

& Ward, 2015; Orhan et al., 2018; Schneider, 1995; Tantanatip & Chang, 2020). Most common factors include fatigue, improper posture, osteoarthritis, and hypothyroidism. An

UST College of Science Department of Biological Sciences 7 increased rate of acetylcholine synthesis, which, in turn, increases the activity of neuromuscular junctions occurs as a physiological response to physical muscle trauma and leads to a cascade of other biochemical responses, such as the release of vasoactive and inflammatory factors (Borg-Stein & Iaccarino, 2014; Hutson & Ward, 2015;

Schneider, 1995; Shah et al., 2008; Tantanatip & Chang, 2020). The results of the trial conducted by Srbely et al. (2010) implied that neurogenic inflammation could facilitate the formation of MTrPs even in the absence of localised muscle injury. Combined evidence

(Smith & Haythornthwaite, 2004) of longitudinal and micro longitudinal studies suggests that sleep disturbance exacerbates MPS.

The main mechanistic hypothesis put forth in describing MPS is central sensitisation

(Hocking, 2013; Hutson & Ward, 2015; Latremoliere & Woolf, 2009; Tantanatip & Chang,

2020), such as hyperalgesia and allodynia, and characterised by a pain persisting for more than three months (Hutson & Ward, 2015; Rivers et al., 2015; Tantanatip & Chang,

2020). However, various hypotheses surrounding chronic MSP conditions are being stipulated. This considers MSP disorders, such as MPS, a biopsychosocial condition, wherein biological, psychological, and social factors significantly affect the belief, behaviour, and cognition towards pain (Orhan et al., 2018).

Diagnosis

Travell and D. G. Simons (1983; … L.S Simons, 1999) proposed the initial set of diagnostic criteria for MPS. The primary diagnostic features of MPS include patterned localised pain, palpable taut band and focal tenderness within it, restricted locomotion in the pain region, and weakness without atrophy. The secondary criteria involve chief pain

UST College of Science Department of Biological Sciences 8 complaints after applied pressure on MTrP nodules, generation of local twitch response upon introduction of snapping palpation and diminishing or relief from pain following muscular treatment. Despite the origination of this diagnostic manual defining clear signs and symptoms, there is yet to be a uniformly accepted diagnostic protocol for the diagnosis of MPS. One of diagnostic challenges is the poor reliability in detecting taut bands (Hutson & Ward, 2015; Myburgh et al., 2008; Simons et al., 1999; Tough et al.,

20017; Travel & Simons, 1983). For a more consistent quantification of the physical properties of TrPs, magnetic resonance elastography can be used (Chen et al., 2008).

However, the diagnosis of MPS is still primarily based on the clinical judgement of the specialists seeing the patients. This clinical assessment involves the identification of trauma, lifestyle, and comorbidity (Galassso et al., 2020; Orhan et al., 2018).

Treatment Modality

Current pharmacologic treatment modalities for MPS and other MSP conditions focus on pain management. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for pain relief by inhibiting COX activity, which, in turn, inhibits the synthesis of prostaglandin, resulting to reduced sensitisation. However, NSAIDs only showed effectiveness as a treatment modality through transdermal route of administration

(Wishart et al., 2017). Tri-cyclic antidepressants (TCA) offers a range of use in pain management, including depression, by serotonin and norepinephrine reuptake inhibition, sodium channel blockade, and muscarinic acetylcholine receptor antagonism. A study

(Hsieh et al., 2010) investigating the efficacy of TCAs in MPS demonstrated therapeutic effects in patients with persistent facial pain and muscle tenderness. Local anaesthetics, such as lidocaine, also show a reduced degree of pain in patients with MSP-related

UST College of Science Department of Biological Sciences 9 conditions. They function as a non-specific sodium channel blocker, inhibiting nerve impulse initiation and conduction.

Gaps in the Pharmacogenomics of Myofascial Pain Syndrome

Pharmacogenomics is a rapidly emerging field that studies how the genome can influence an individual’s response to drugs (Ermak, 2015). The genomic differences between individuals can explain some of the differences in the clinical presentation and prognosis of diseases and the responses of drugs and environmental factors (Collins, 1991). Each patient responds to medications differently, which is why some individuals in a patient population fail to elicit therapeutic responses on drug regimens that are proven efficacious in others. The variations in drug responses can be directly and indirectly attributed to multiple complex causative factors (Meyer et al., 2013; Pirmohamed, 2006), such as genetics, physiology, environment, and lifestyle.

MPS is still poorly understood, and the existing literature regarding its exact pharmacogenomics is exceedingly rare. There are currently no uniformed protocols in the pharmacological treatment of patients with chronic MSP conditions and the patient management is still primarily based on the clinical judgement of the specialists seeing the patients. This can potentially result in compromised quality of patient life and contribute to the increasing global burden of pain disorders (IoM, 2011; IPRCC, 2016). Clinical applications of pharmacogenomics will immensely improve patient management by utilising genomic-wide and systemic-scale approaches to analyse patient conditions and provide personalised care instead of using cell-, tissue-, or organ-specific treatment perspective (Gottlieb, personal communication, March 31, 2021).

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DATA AND METHODS

This study aims to identify the genes and drugs associated with MPS and their gene-drug interactions. It also aims to determine whether a relationship exists between the applicable clinical pharmacogenomics of MPS with other disease conditions (disease- gene-drug associations) and the signalling pathways involved. Further, we sought to understand what other factors affect treatment and interventional outcomes for patients with MPS. Ultimately, we hoped to generate new perspectives from the consolidated data to better understand the clinical pharmacogenomics of MPS and to guide future studies to improve patient quality of life by personalized medicine interventions.

Study Design

This study was designed as a secondary analysis systematic review, using structured mining to synthesise curated and inferred associations from the analyses of filtered structured and semi-structured data sets. The data sets surveyed were sourced from the

Stanford Network Analysis Platform Dataset, Comparative Toxicogenomics Database

(CTD), GeneCards Suite Databases (GeneCards, MalaCards, PathCards), National

Center for Biotechnology Information Database (NCBI), Kyoto Encyclopedia of Genes and Genomes Database (KEGG), Online Mendelian Inheritance in Man Database

(OMIM), and DrugBank Database.

In addition, the identified data sets were extracted, cleaned, and analysed for key values and relevant gene-drug-drug-gene information. The mined data were then interpreted and reported. The generated data are available in Supplementary materials. The top 10 pain-

UST College of Science Department of Biological Sciences 11 relevant genes associated with MPS mined from CTD were selected. The top 10 drugs and the genes associated with MPS generated from CTD and Mala cards were also selected. The top signalling pathways generated from Mala cards were also identified.

Rationale for the Study Design

Given the complex nature of clinical pharmacogenomics, we hypothesised that the use of integrated compendiums to generate comprehensive sets of applicable clinical pharmacogenomic associations of MPS is the most efficient method to conduct this study.

The databases surveyed, primarily CTD and MalaCards, were developed by doctorate- level senior researchers and their data sets are periodically being curated and updated by multiple biocurators and analysed using their respective laboratories or research groups’ analytical programming tools. The generated data in this study were the results of secondary and tertiary data analyses in keeping with the systematic review design.

RESULTS

Gene-determined Association

There are a total of 7,312 identified genes associated with MPS and pain associated diseases, including temporomandibular joint disorder (TMD). The International

Association for Dental Research and International Association for the Study of Pain

(Schiffman et al., 2014) identified myofascial pain as a type of TMD. Of the 7,312 identified genes, 76 genes are associated with myofascial pain, with or without referral; 7,092 genes are associated with TMD; and 144 genes are associated with both. Table 1 shows the top

100 genes associated with MPS, compiled from CTD (Davis et al., 2021) data status as of April 2021.

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Table 1. A list of the top 100 genes associated with MPS, compiled from CTD (Davis et al., 2021) data status as of April 2021. These genes are associated with MPS or its ascendent and have curated associations to the disease or inferred associations via curated chemical interactions. The list includes data from both animal research (inbred strains, knockout mice) and human research (genetic association studies, inference network analyses) derived from OMIM and NCBI.

ACIN1 CRHR1 GRM1 OBSL1 SNAP91 ADGRL1 DBN1 HCRT OLA1 SNCB AFMID DCAF8 HECW2 OSBPL1A SORCS3 AMIGO1 DNM1 HERC1 OTOF SPTBN2 ANKS1B DRD4 HPCAL1 OXTR SSTR2 AP5M1 EGR4 HPCAL4 PAK6 STRIP2 APOLD1 EHMT1 HTR3A PDE10A SYBU ARHGAP29 ELMO1 KCNB1 PEX16 SYT1 ARHGAP9 EPHB6 KCNIP3 PEX5L SYT11 ARHGEF1 ERBIN KCNJ4 PJA2 SYT3 ATP1B2 EYA2 KHDRBS1 PPP5C SYT5 BACH2 FLYWCH1 LDHD PRMT5 TACC1 BAZ1B FNDC5 LIMS2 PTPRB TBC1D14 BCAP31 FUBP1 LY6H RASL11A TRIM3 C1QTNF4 GALNT16 LZTS3 RBM26 TRPC4AP CACNB3 GFRA2 MAPK11 RTN4IP1 TSPYL1 CAMK1G GNB2 MEF2A SEMA4F UBR4 CDK5 GPM6A MFF SEMA7A USP7 CHRM4 GRIK5 NCAN SH3GL1 VAPB CLIP1 GRINA NFE2L1 SLK ZDHHC8

A total of 410 pain-associated genes were identified (Lötsch et al., 2013). Of these, there are a total of 280 identified genes associated with MPS. 6 genes are associated with myofascial pain, with or without referral; 246 genes are associated with TMD; and 23 genes are associated with both. Table 2 shows the list of the 280 pain-relevant genes associated with MPS, compiled from CTD (Davis et al., 2021) data status as of April 2021.

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Table 2. A list of the 280 pain-relevant genes associated with MPS, compiled from CTD

(Davis et al., 2021) data status as of April 2021. These genes are associated with MPS or its ascendent and have curated associations to the disease or inferred associations via curated chemical interactions. The list includes data from both animal research (inbred strains, knockout mice) and human research (genetic association studies, inference network analyses) derived from OMIM and NCBI.

ABCB1 CCL2 EFNB1 GYG1 LPAR1 OXT RGS9 ABCC3 CCR2 EFNB2 HCN2 LXN P2RX4 RPS6KA3 ACHE CCR7 EGR1 HCRT MAP2K1 P2RX7 RUNX1 ACSL6 CD14 ENPP2 HDC MAP2K3 P2RY2 S100B ADCY5 CD4 EPHX2 HRH1 MAP3K8 PCSK2 SCG2 ADCY8 CDK5 ESR1 HRH2 MAP6 PDYN SCN10A ADCYAP1 CDK5R1 FAAH HRH3 MAPK3 PENK SCN1A ADCYAP1R1 CHRM1 FABP3 HTR1A MAPK8 PER1 SCN2B ADM CHRM2 FABP5 HTR1B MAPT PER2 SIGMAR1 ADORA1 CHRNA3 FMR1 HTR2A MGLL PICK1 SLC12A5 ADORA2A CHRNA4 FN1 HTR3A MME PJA2 SLC15A2 ADORA3 CHRNA5 FOS IFNG MMP24 PLCB1 SLC17A6 ADRA2C CHRNA7 FOSB IFNGR1 MMP9 PLCD4 SLC17A7 AGER CHRNB2 FYN IL10 MRGPRE PMP22 SLC17A8 ALOX12 CLOCK GABBR1 IL18 MYD88 POMC SLC1A3 APOE CNR1 GABBR2 IL1A NCAM1 POR SLC6A1 AQP1 CNR2 GABRB3 IL1R1 NFE2L2 PPP1R9B SLC6A2 AQP4 COMT GABRD IL1RAP NFKB1 PRKAR1B SLC6A4 ARRB2 CORO1A GABRG2 IL4 NGFR PRKCA SOD2 ATF3 CRABP2 GAD2 IL6 NLGN2 PRKCB SPP1 ATL1 CRIP2 GAL IL6ST NMU PRKCD SPTLC2 ATP1A2 CSF2RB GAS7 ITPR1 NOS1 PRKCE SSTR4 BACE1 CTSH GFAP KCNC2 NOS2 PRKCG STX1A BAMBI CX3CR1 GFRA2 KCND2 NOS3 PRKG1 SYN2 BBS1 CYBB GJA1 KCNIP3 NPEPPS PRNP TAC1 BDNF CYP19A1 GLRA2 KCNJ3 NPPC PROK2 TACR1 BHLHE22 DAO GNAO1 KCNJ5 NPY PRX TH C4A DBH GNAQ KCNJ6 NPY1R PTGDR THBS4 CACNA1B DICER1 GNAZ KCNJ9 NR2F6 PTGDS TLR2 CACNA1H DLG2 GRIA1 KCNK18 NRG1 PTGES TLR4 CACNA2D1 DLG4 GRIA2 KCNK2 NRN1 PTGS1 TNF CACNB3 DPYSL4 GRIK1 KCNK9 NSF PTGS2 TNFRSF1A CACNG2 DRD1 GRIN1 KCNQ2 NT5E PTN TNFRSF1B CALB1 DRD2 GRIN2A KIF1A NTRK1 PTPN5 TRPA1 CALCA DRD3 GRIN2B KIT NTS PTPRO TRPM3 CAMK2A DTNBP1 GRIN2D KLF7 NTSR1 PTPRZ1 TRPV1 CAMK2D ECE2 GRK5 L1CAM OPRD1 RASD2 TRPV4 CAMK2G EDN1 GRK6 LAMA4 OPRK1 RELN TYRP1 CASP1 EDNRA GRM2 LEP OPRL1 RET UCHL1 CCKBR EDNRB GRM5 LGALS1 OPRM1 RGS4 WNK1

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The top 10 pain-relevant genes associated with myofascial pain, with or without referral, are HRH1, KCNK9, FOS, SLC6A2, IL6, PRKCB, TRPV1, CALCA, TNF, and IL4, respectively. Of these genes, 8 genes are associated with inflammation; 7 with necrosis;

6 with hypertension; 5 with drug-related side effects and adverse reactions, edema, hyperalgesia, and weight loss; and 4 with learning disabilities and memory disorders

(Table 3).

Table 3. A list of the top 10 associated diseases or conditions common amongst the top

10 genes associated with MPS, compiled from CTD (Davis et al., 2021) data status as of

April 2021. These genes are associated with MPS or its ascendent and have curated associations to the disease or inferred associations via curated chemical interactions.

Associated Disease or Associated Gene Condition

Chemical and Drug Induced Liver HRH1, KCNK9, PRKCB, SLC6A2, Injury TRPV1 Drug-Related Side Effects and HRH1, IL6, PRKCB, SLC6A2, TNF Adverse Reactions Edema CALCA, HRH1, IL6, TNF, TRPV1 Hyperalgesia CALCA, FOS, IL6, TNF, TRPV1 CALCA, FOS, IL6, KCNK9, SLC6A2, Hypertension TNF CALCA, HRH1, IL6, KCNK9, PRKCB, Inflammation SLC6A2, TNF, TRPV1 Learning Disabilities HRH1, KCNK9, PRKCB, SLC6A2 Memory Disorders HRH1, KCNK9, PRKCB, SLC6A2 HRH1, IL6, KCNK9, PRKCB, SLC6A2, Necrosis TNF, TRPV1 HRH1, KCNK9, PRKCB, SLC6A2, Weight Loss TRPV1

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Drug-determined Association

The drugs that are associated with MPS with the associated genes compiled from CTD

and MalaCards are shown in Table 4 and Table 5, respectively. The drug-gene

interactions can be found in the Supplements.

Table 4. A list of the drugs associated with MPS, compiled from CTD (Davis et al., 2021)

data status as of April 2021. These genes are associated with MPS or its ascendent and

have curated associations to the disease or inferred associations via curated chemical

interactions.

Associated Drug Associated Gene Number of Associated Associated Dynamics Gene

HRH1, KCNK9, SLC6A2, PRKCB, Therapeutic effects Bupivacaine TRPV1 23 Markers; KCNK9, FOS, CASP9, SLC6A2, mechanisms of IL6, PRKCB 1,493 Cocaine action Markers;

FOS, IL6 mechanisms of 14 Diflunisal action HRH1, KCNK9, FOS, CASP9, Therapeutic effects Lidocaine SCL6A2, SLC22A3 76 Markers; HRH1, FOS, CASP9, SLC6A2, mechanisms of PRKCB, ITGAM 3,215 MDMA action Markers; FOS, CASP9, SLC6A2, SLC22A3, mechanisms of IL6, PRKCB, TRPV1 4,429 Methamphetamine action Markers; HRH1, KCNK9, CASP9, SLC22A3, mechanisms of IL6, SLC22A1, CALCA 136 Ranitidine action

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Table 5. A list of the top 10 drugs associated with MPS via differential diagnosis, compiled

from MalaCards (Rappaport et al., 2017) data status as of April 2021. These drugs are

associated with MPS or its ascendent and have curated associations to the disease or

inferred associations via curated chemical interactions.

Associated Drug Associated Gene Number of Associated Associated Dynamics Gene

Markers;

AR, CCL4 mechanisms of 14 Benzocaine action PTGS2, ICAM1, ABCB11, Therapeutic effects Etoricoxib CYP1A2, CYP3A4 5 Markers; CYP2D6, HTR2B, BDNF, SLC6A4, mechanisms of MAPK1 425 Fluoxetine action

CACNA1D, GABBR1, GABBR2 Therapeutic effects Gabapentin 173 Markers;

HRH1, HRH2, IL18, HRH3, CXCL9 mechanisms of 108 Histamine action Markers;

ACP5, SLC6A3 mechanisms of 9 Modafinil action Markers; CYP2D6, HTR2C, IL10, SLC6A4, mechanisms of STAT3 50 Paroxetine action Markers;

PRL, DRD2 mechanisms of 12 Perphenazine action Polyphenol (Tannic TNF, SIRT1, IL1B, CASP3, IL6 Therapeutic effects acid) 4,123 CYP2D6, HTR2A, OPRD1, Therapeutic effects Tramadol OPRK1, OPRM1 26 Markers; HTR1A, CYP3A4, HTR2A, mechanisms of HTR2C, PTGS2 22 Trazodone action

Disease-determined Association

Furthermore, the top 10 diseases associated with MPS were identified from MalaCards

with the associated genes for the disease as shown in Table 6.

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Table 6. A list of the top 10 associated diseases or conditions with MPS via differential diagnosis, compiled from MalaCards (Rappaport et al., 2017) data status as of April 2021.

These genes are associated with MPS or its ascendent and have the top curated associations to the disease or inferred associations via curated chemical interactions.

Associated Disease or Associated Gene Condition

Bursitis TAC1, LAPTM4A, KNG1, CALCA Complex TAC1, POMC, CALCA Regional Pain Syndrome Facial Neuralgia TAC1, LAPTM4A Fibromyalgia POMC, NGF, CALCA, BDNF Frozen Shoulder LAPTM4A, ASIC3 Glossopharyngeal TAC1, POMC Neuralgia Hypochondriasis POMC, BDNF Pulpitis TRPV1, KNG1 Radiculopathy TAC1, LAPTM4A Sleep Disorder TAC1, POMC, BDNF

Pathway-determined Association

Table 7 shows the top signalling pathways associated with MPS and the genes associated with these signalling pathways.

Table 7. A list of the pathways associated with MPS via differential diagnosis, compiled from MalaCards (Rappaport et al., 2017) data status as of April 2021. These pathways are associated with MPS or its ascendent and have curated associations to the disease or inferred associations via curated chemical interactions.

Associated Pathway Associated Gene

CREB pathway TRPV1, PDGFRB, NGF, EPHB1, BDNF Development endothelin-1/EDNRA signalling pathway TRPV1, NGF, KNG1, ASIC3 G-protein signalling Rac1 pathway PDGFRB, NGF, EPHB1, BDNF G-protein signalling Rap2B pathway PDGFRB, NGF, EPHB1, BDNF

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PI3K/PLC-γ-mediated TRK signalling pathway TRPV1, NGF Sudden infant death syndrome (SIDS) susceptibility pathways TAC1, NGF, BDNF

DISCUSSION

Genetic factors play a role in the presentation of MPS. The genes that are associated with MPS were identified from the CTD and MalaCards databases. The diseases or conditions associated with MPS were also identified. The disease-gene associations of

MPS were determined by curated association to a disease via mechanism-based biomarker or therapeutic linkage or by inferred association via curated chemical interaction. The curated drug compounds associated with MPS were used to identify related genes and conditions. Through this, the top 10 pain-relevant genes associated with myofascial pain, with or without referral, are HRH1, KCNK9, FOS, SLC6A2, IL6,

PRKCB, TRPV1, CALCA, TNF, and IL4, were identified. These genes are curated associations or inferred associations via curated chemical interactions.

Since the fasciae can be found in separate structures within the body, MPS has been associated with various other pain disorders (Hutson & Ward, 2015; Tantanatip &

Change, 2020). Fibromyalgia syndrome (FMS) is one of the top conditions that were identified to be associated with MPS. It is a chronic MSP disorder characterised similarly with MPS but with widespread pain (Chandola & Chakraborty, 2009; Hutson &Ward,

2015; Tantanatip & Change, 2020). It is postulated that later stages of MPS result to FMS

(Simons, 1975; Fricton et al., 1985; Hutson &Ward, 2015; Tantanatip & Change, 2020) whilst some consider MPS as a subtype of FMS (Chandola & Chakraborty, 2009).

Features, such as fatigue, sleep disturbance, paraesthesia, and headache, occur more

UST College of Science Department of Biological Sciences 19 frequently on patients with FMS than on patients with MPS (Chandola & Chakraborty,

2009; Bourgaize et al., 2018). This also makes the clinical diagnosis of MPS a challenge as some pain presentations are caused by injuries or stresses from another localised site because of the body’s interconnected sensory network (referred pain).

TMD is also a pain condition having similar characteristics with MPS but could only be involved in a referred pain pattern (Bordoni et al., 2018) and is primarily manifested in the masticatory muscles (Ward, 2002; Hutson &Ward, 2015; Bordoni et al., 2018). If treatment modalities did not improve the condition, this could be a TMD presentation of cardiac ischemia (Jenzer et al., 2018). MPS is also commonly associated with other conditions, including myofascial pelvic pain, idiopathic neck pain, whiplash-associated disorder, atypical facial pain, glossopharyngeal neuralgia, and depressive disorder.

Current pharmacologic treatment modalities for MPS and other MSP conditions focus on pain management. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for pain relief by inhibiting COX activity, which, in turn, inhibits the synthesis of prostaglandin, resulting to reduced sensitisation. However, NSAIDs only showed effectiveness of a treatment modality through transdermal route of administration (Wishart et al., 2017). Tri-cyclic antidepressants (TCA) offers a range of use in pain management, including depression, by serotonin and norepinephrine reuptake inhibition, sodium channel blockade, and muscarinic acetylcholine receptor antagonism. A study (Hsieh et al., 2010) investigating the efficacy of TCAs in MPS demonstrated therapeutic effects in patients with persistent facial pain and muscle tenderness. Local anaesthetics, such as lidocaine, also show a reduced degree of pain in patients with MSP-related conditions.

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They function as a non-specific sodium channel blocker, inhibiting nerve impulse initiation and conduction.

Genes affect how a patient respond to drug treatment. Bupivacaine is a small molecule drug, widely used as a local or regional anaesthetic agent. Bupivacaine increases the excitation threshold in the nerves, decreases the rising phase of action potential, and slows the impulse propagation by blocking the conduction and generation of nerve impulses. Bupivacaine also binds to the sodium channels to prevent depolarisation by blocking the influx of sodium ions into the neurons. This results in the inability of the nerves to properly function and process pain information. Drug-gene interactions of bupivacaine aid in understanding the treatment course for patients with MPS.

Polymorphisms in the CASP9 gene are associated with increased susceptibility to pain, esp. in the lower back region. The interaction of bupivacaine to the CASP9 genes results in decreased expression of CASP9 protein, which leads to a potential decrease in pain perception. In the presence of KCNK9 gene, bupivacaine inhibits the reaction of sodium ion permeability of excitable membranes. This can result into the formation of ion- selective channel, wherein the increased transport of potassium hyperpolarises the plasma membrane, leading to the inhibition of neuron excitation and decrease in pain sensation. Since KCNK9 and bupivacaine are among the genes and the drugs that has been shown with high association with MPS, this can provide insights on why some patients with MPS might respond differently to bupivacaine, such as when there is a mutation or polymorphism of the KCNK9 gene to these patients. Therefore, treatment decisions for MPS and other MSP conditions can be done by addressing gene-drug associations.

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Jafri (2014) created a schematic diagram, showing the mechanisms of MTrPs and how chosen treatment works. Lidocaine, for example, a local anaesthetic, is described to induce therapeutic pain relief. CALCA and POMC are two of the gene targets of lidocaine, and interaction works with lidocaine inhibiting nerve impulse initiation and conduction, which results into an increased secretion of CALCA and POMC proteins, and, thus, driving analgesic effects. However, drug interaction with other proteins, such as CYP3A5, can result in decreased methylation of lidocaine (Davis et al., 2021), hampering drug metabolism. Psychostimulant and sympathomimetic drugs, like methamphetamine, can induce euphoric effects, which helps in managing pain cognition. They target genes, such as SLC6A4 and TAAR1, and the drug interaction results into increased activity of the proteins, thus regulating serotonergic and dopaminergic signalling pathways.

Another example is diflunisal, a small molecule drug pharmacologically acting as a nonsteroidal anti-inflammatory (NSAI) agent. Most of the mechanisms of action of diflunisal have been associated as an inhibitory drug of prostaglandin synthesis, which separates it from prototypical NSAI drugs (NSAIDs) that function as prostaglandin antagonists. Inhibition of this synthesis suppresses the signalling function of prostaglandins to mediate inflammatory responses. The lack, or absence, of inflammation reduces the pressure on nerves that can be perceived as pain signals by the brain. The interaction of diflunisal with FOS and IL6 genes result in an increase in the FOS and IL6 mRNA expressions. Whilst the increase in these expressions can result into the prognosis of neuropathic and inflammatory pain caused by inflammatory processes, polymorphisms in the genes, most esp. in the IL6 gene, can alter the patient’s perception of pain, resulting

UST College of Science Department of Biological Sciences 22 to both the activation of inflammatory processes and degeneration of nerve processes.

However, this kind of signalling cascade can compromise the quality of life of the patient as the loss of nerve function can also result to the patient’s inability to process information related to temperature, touch, proprioception, and muscle tone, in order of clinical presentation.

The signalling pathway associated with MPS were also identified. The G-protein signalling pathway is a significant drug target in treating pain. This pathway is also highly linked to other diseases and conditions, such as cancer, diabetes, obesity, and cardiovascular diseases. This explains as to why chronic complications, such as cancer pain and diabetic neuropathy, are some of the most common presentation of pain conditions.

Currently, the management of MPS is targeted on alleviating pain with drugs that are also used to treat other pain associated diseases. The effectivity of the drug will also depend on the genotype of the individual and therefore considering disease-gene-drug associations may properly guide selection of the best intervention and management of

MPS.

Further, large association studies are also non-existent to identify the most effective drug treatment for MPS and other MSP conditions. Lack of studies contribute to the increasing concern about inappropriate treatment and poor intervention outcomes, representing a missed opportunity to improve the quality of life of patients. Because MSP disorders are not well understood and have huge lapses in literatures, the controversies underlying

UST College of Science Department of Biological Sciences 23 these conditions shall be addressed with evidence-based medicine to observe uniform protocols in chronic pain management.

Limitations

This study is limited by secondary analysis of data curated by different external research groups, laboratories, and agencies from an almost non-existent literature library associated with the pharmacogenomics of MPS. Consequently, the knowledge of drug- genome interactions is confined by individual drug-gene interactions. Whilst the results of this analysis may serve as a preparation for experimental studies, they cannot be interpreted as an absolute guide for clinical pharmacogenomics and should only be seen as is and not necessarily interconnected. Thus, the results of this review are to be used as a framework for future trials and not as a current clinical treatment protocol.

Implications and Future Directions

Clinical applications of pharmacogenomics will immensely improve the quality of patient care and life as treatments and conditions will be analysed in systems physiology- and genome-wide perspectives. Clinical pharmacogenomics would play a vital role in the search for cure for chronic diseases, such as diabetes and hypertension.

Whilst current treatment modalities for MPS and other MSP-related conditions show some favourable outcomes in pain management, further large association studies are necessary to provide uniform protocols in the diagnosis of MSP conditions and to better ascertain the safety and efficacy of treatment of MPS. Current pharmacological treatment options cannot be observed as a safe long-term regimen for patients with MPS and other

UST College of Science Department of Biological Sciences 24 chronic pains as the gene-drug-drug-gene associations can result into signalling cascades turning awry, which can lead to the quality of life of the patients being compromised. Conducting experimental studies after the identification of biomarkers and signalling pathways highly associated with MPS are intended to continue this review.

Further studies also need to focus on (1) drug optimisation by discovering and evaluating the factors that influence how therapeutic agents work against MPS and other chronic conditions; and (2) molecular therapeutics and targeted and controlled drug delivery by identifying and delivering the most successful compounds and therapies, including the potential use of stem cell therapy. In finding and characterising candidates for therapeutic agents and targets, a paradigm shift could immensely change the way drug discovery is conducted. Rather than focusing on extracting single compounds from medicinal plants and their individual interactions, we can approach its chemical biology and medicinal chemistry by applying clinical pharmacogenomics via the study of large numbers of interacting active compounds to develop and produce new drug treatment candidates.

CONCLUSION

MPS is a chronic MSP condition characterised by localised deep pains in the skeletal muscle and fascia. This review of the current knowledge in the pharmacogenomics of

MPS demonstrates the need for additional evidence in the exact clinical definition of

MPS and its associations. Whilst current treatment modalities for MPS and other MSP- related conditions show some favourable outcomes in pain management, further large association studies are necessary to provide uniform protocols in the diagnosis of MSP conditions and to better ascertain the safety and efficacy of treatment of MPS.

UST College of Science Department of Biological Sciences 25

ACKNOWLEDGEMENT

Prof. Roberta A. Gottlieb, MD (Smidt Heart Institute, Cedars-Sinai Medical Center), for her valuable insights that aided the generation of ideas and perspectives in this manuscript.

AUTHOR CONTRIBUTION

All authors conceived of the presented idea and oversaw overall direction and planning.

J. L. developed the theoretical formalism and performed analysis, and M. G. verified the methodology. M. G. encouraged J. L. to perform the review and supervised the findings of this work. J. L. took the lead in writing the manuscript with input from all authors. All authors discussed the results and contributed to the final version of the manuscript.

UST College of Science Department of Biological Sciences 26

REFERENCES

Bergman, S., Herrström, P., Högström, K., Petersson, I. F., Svensson, B., & Jacobsson,

L. T. (2001). Chronic musculoskeletal pain, prevalence rates, and

sociodemographic associations in a Swedish population study. The Journal of

Rheumatology, 28(6), 1369–1377.

Bordoni, B., Sugumar, K., & Varacallo, M. (2018). Myofascial Pain. StatPearls [Internet].

Borg-Stein, J., & Iaccarino, M. A. (2014). Myofascial pain syndrome treatments.

Physical Medicine and Rehabilitation Clinics of North America, 25(2), 357–374.

https://doi.org/10.1016/j.pmr.2014.01.012

Bourgaize, S., Newton, G., Kumbhare, D., & Srbely, J. (2018). A comparison of the

clinical manifestation and pathophysiology of myofascial pain syndrome and

fibromyalgia: implications for differential diagnosis and management. The Journal

of the Canadian Chiropractic Association, 62(1), 26–41.

Chandola, H. C., & Chakraborty, A. (2009). Fibromyalgia and myofascial pain

syndrome-a dilemma. Indian Journal of Anaesthesia, 53(5), 575–581.

Chang, H. S., Won, E. S., Lee, H. Y., Ham, B. J., Kim, Y. G., & Lee, M. S. (2015). The

association of proopiomelanocortin polymorphisms with the risk of major

depressive disorder and the response to antidepressants via interactions with

stressful life events. Journal of Neural Transmission, 122(1), 59–68.

https://doi.org/10.1007/s00702-014-1333-9

Chen, Q., Basford, J., & An, K. N. (2008). Ability of magnetic resonance elastography to

assess taut bands. Clinical Biomechanics, 23(5), 623–629.

https://doi.org/10.1016/j.clinbiomech.2007.12.002

UST College of Science Department of Biological Sciences 27

Cieza, A., Causey, K., Kamenov, K., Hanson, S. W., Chatterji, S., & Vos, T. (2020).

Global estimates of the need for rehabilitation based on the Global Burden of

Disease study 2019: a systematic analysis for the Global Burden of Disease Study

2019. The Lancet, 396(10267), 2006-2017. https://doi.org/10.1016/s0140-

6736(20)32340-0Institute of Medicine. (2011). Relieving pain in America: a

blueprint for transforming prevention, care, education, and research. The National

Academies Press. https://doi.org/10.17226/13172

Collins, F. S. (1991). Of needles and haystacks: finding human disease genes by

positional cloning. Clinical Research, 39(4), 615-623.

Davis, A. P., Grondin, C. J., Johnson, R. J., Sciaky, D., Wiegers, J., Wiegers, T. C., &

Mattingly, C. J. (2021). Comparative Toxicogenomics Database (CTD): update

2021. Nucleic Acids Research, 49(D1), D1138-D1143.

https://doi.org/10.1093/nar/gkaa891

Ermak, G. (2015). Emerging medical technologies. World Scientific.

Fleckenstein, J., Zaps, D., Rüger, L. J., Lehmeyer, L., Freiberg, F., Lang, P. M., & Irnich,

D. (2010). Discrepancy between prevalence and perceived effectiveness of

treatment methods in myofascial pain syndrome: results of a cross-sectional,

nationwide survey. BMC Musculoskeletal Disorders, 11, 32.

https://doi.org/10.1186/1471-2474-11-32

Fricton, J. R., Kroening, R., Haley, D., & Siegert, R. (1985). Myofascial pain syndrome

of the head and neck: a review of clinical characteristics of 164 patients. Oral

Surgery, Oral Medicine, and Oral Pathology, 60(6), 615–623.

Galasso, A., Urits, I., An, D., Nguyen, D., Borchart, M., Yazdi, C., Manchikanti, L., Kaye,

R. J., Kaye, A. D., Mancuso, K. F., & Viswanath, O. (2020). A comprehensive

UST College of Science Department of Biological Sciences 28

review of the treatment and management of myofascial pain syndrome. Current

Pain and Headache Reports, 24(8), 43. https://doi.org/10.1007/s11916-020-00877-

5

Gatchel, R. J., & Schultz, I. Z. (Eds.). (2014). Handbook of musculoskeletal pain and

disability disorders in the workplace. Springer. https://doi.org/10.1007/978-1-4939-

0612-3

Groves, L., Shellenberger, M. K., & Davis, C. S. (1998). Tizanidine treatment of

spasticity: a meta-analysis of controlled, double-blind, comparative studies with

baclofen and diazepam. Advances in therapy, 15(4), 241-251.

Ho, K. Y., Gwee, K. A., Cheng, Y. K., Yoon, K. H., Hee, H. T., & Omar, A. R. (2018).

Nonsteroidal anti-inflammatory drugs in chronic pain: implications of new data for

clinical practice. Journal of Pain Research, 11, 1937–1948.

https://doi.org/10.2147/jpr.s168188

Hocking, M. J. (2013). Exploring the central modulation hypothesis: do ancient memory

mechanisms underlie the pathophysiology of trigger points. Current Pain and

Headache Reports, 17(7), 347. https://doi.org/10.1007/s11916-013-0347-6

Hsieh, L. F., Hong, C. Z., Chern, S. H., & Chen, C. C. (2010). Efficacy and side effects

of diclofenac patch in treatment of patients with myofascial pain syndrome of the

upper trapezius. Journal of Pain and Symptom Management, 39(1), 116–125.

https://doi.org/10.1016/j.jpainsymman.2009.05.016

Hutson, M., & Ward, A. (Eds.). (2015). Oxford textbook of musculoskeletal medicine.

Oxford University Press. https://doi.org/10.1093/med/9780199674107.001.0001

UST College of Science Department of Biological Sciences 29

Interagency Pain Research Coordinating Committee. (2016). National pain strategy: A

comprehensive population health-level strategy for pain. U.S. Department of

Health and Human Services, National Institutes of Health.

Jafri, M. S. (2014). Mechanisms of myofascial pain. International Scholarly Research

Notices, 2014, 1–16. https://doi.org/10.1155/2014/523924

James, S. L., Abate, D., Abate, K. H., Abay, S., Abbafati, C., Abbasi, N., Abbastabar, H.,

Abd-Allah, F., Abdela, J., Abdelalim, A., Abdollahpour, I., Abdulkader, R. S.,

Abebe, Z., Abera, S. F., Abil, O. Z., Abraha, H. N., Abu-Raddad, L. J., Abu-

Rmeileh, N. M. E, Accrombessi, M. M. K., … Murray, C. L. J. (2018). Global,

regional, and national incidence, prevalence, and years lived with disability for 354

diseases and injuries for 195 countries and territories, 1990–2017: a systematic

analysis for the Global Burden of Disease Study 2017. The Lancet, 392(10159),

1789–1858. https://doi.org/10.1016/s0140-6736(18)32279-7

Jenzer, A. C., Jackson, H., & Berry-Cabán, C. S. (2018). Temporomandibular joint pain

presentation of myocardial ischemia. Journal of Oral and Maxillofacial Surgery,

76(11), 2317.e1–2317.e2. https://doi.org/10.1016/j.joms.2018.06.019

Kamper, S. J., Apeldoorn, A. T., Chiarotto, A., Smeets, R. J. E. M., Ostelo, R. W. J. G.,

Guzman, J., & van Tulder, M. W. (2015). Multidisciplinary biopsychosocial

rehabilitation for chronic low back pain: Cochrane systematic review and meta-

analysis. The BMJ, 350, h444. https://doi.org/10.1136/bmj.h444

Kanehisa, M., Araki, M., Goto, S., Hattori, M., Hirakawa, M., Itoh, M., Katayama, T.,

Kawashima, S., Okuda, S., Tokimatsu, T., & Yamanishi, Y. (2007). KEGG for

linking genomes to life and the environment. Nucleic Acids Research,

36(Database), D480–D484. https://doi.org/10.1093/nar/gkm882

UST College of Science Department of Biological Sciences 30

Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: a generator of pain

hypersensitivity by central neural plasticity. The Journal of Pain, 10(9), 895–926.

https://doi.org/10.1016/j.jpain.2009.06.012

Lötsch, J., Doehring, A., Mogil, J. S., Arndt, T., Geisslinger, G., & Ultsch, A. (2013).

Functional genomics of pain in analgesic drug development and therapy.

Pharmacology and Therapeutics, 139(1), 60–70.

https://doi.org/10.1016/j.pharmthera.2013.04.004

Lucas, N., Macaskill, P., Irwig, L., Moran, R., & Bogduk, N. (2009). Reliability of physical

examination for diagnosis of myofascial trigger points: a systematic review of the

literature. The Clinical Journal of Pain, 25(1), 80–89.

https://doi.org/10.1097/AJP.0b013e31817e13b6

McVinnie D. S. (2013). Obesity and pain. British Journal of Pain, 7(4), 163–170.

https://doi.org/10.1177/2049463713484296

Meyer, U. A., Zanger, U. M., & Schwab, M. (2013). Omics and drug response. Annual

Review of Pharmacology and Toxicology, 53, 475-502.

Mills, S. E. E., Nicolson, K. P., & Smith, B. H. (2019). Chronic pain: a review of its

epidemiology and associated factors in population-based studies. British Journal of

Anaesthesia, 123(2), e273-e283. https://doi.org/10.1016/j.bja.2019.03.023

Myburgh, C., Larsen, A. H., & Hartvigsen, J. (2008). A systematic, critical review of

manual palpation for identifying myofascial trigger points: evidence and clinical

significance. Archives of Physical Medicine and Rehabilitation, 89(6), 1169–1176.

https://doi.org/10.1016/j.apmr.2007.12.033

National Center for Biotechnology Information. (2004). Gene [Internet].

UST College of Science Department of Biological Sciences 31

Orhan, C., Van Looveren, E., Cagnie, B., Mukhtar, N. B., Lenoir, D., & Meeus, M.

(2018). Are pain beliefs, cognitions, and behaviors influenced by race, ethnicity,

and culture in patients with chronic musculoskeletal pain: a systematic review.

Pain Physician, 21(6), 541–558.

Pirmohamed, M. (2006). Genetic factors in the predisposition to drug-induced

hypersensitivity reactions. The AAPS Journal, 8(1), E20-E26.

Rappaport, N., Twik, M., Plaschkes, I., Nudel, R., Iny Stein, T., Levitt, J., Gershoni, M.,

Morrey, C. P., Safran, M., & Lancet, D. (2017). MalaCards: an amalgamated

human disease compendium with diverse clinical and genetic annotation and

structured search. Nucleic Acids Research, 45(D1), D877-D887.

https://doi.org/10.1093/nar/gkw1012

Rivers, W. E., Garrigues, D., Graciosa, J., & Harden, R. N. (2015). Signs and symptoms

of myofascial pain: an international survey of pain management providers and

proposed preliminary set of diagnostic criteria. Pain Medicine, 16(9), 1794–1805.

https://doi.org/10.1111/pme.12780

Schiffman, E., Ohrbach, R., Truelove, E., Look, J., Anderson, G., Goulet, J. P., ... &

Svensson, P. (2014). Diagnostic criteria for temporomandibular disorders

(DC/TMD) for clinical and research applications: recommendations of the

International RDC/TMD Consortium Network and Orofacial Pain Special Interest

Group. Journal of Oral & Facial Pain and Headache, 28(1), 6.

Schneider M. J. (1995). Tender points/fibromyalgia vs. trigger points/myofascial pain

syndrome: a need for clarity in terminology and differential diagnosis. Journal of

Manipulative and Physiological Therapeutics, 18(6), 398–406.

UST College of Science Department of Biological Sciences 32

Shah, J. P., Danoff, J. V., Desai, M. J., Parikh, S., Nakamura, L. Y., Phillips, T. M., &

Gerber, L. H. (2008). Biochemicals associated with pain and inflammation are

elevated in sites near to and remote from active myofascial trigger points. Archives

of Physical Medicine and Rehabilitation, 89(1), 16–23.

https://doi.org/10.1016/j.apmr.2007.10.018

Simons, D. G. (1975). Muscle pain syndromes—Part I. American Journal of Physical

Medicine & Rehabilitation, 54(6), 289-311.

Simons, D. G., Travell, J., & Simons, L. S. (1999). Myofascial pain and dysfunction: the

trigger point manual (Vol. 1). Lippincott Williams & Wilkins.

Smith, B. H., Elliott, A. M., Chambers, W. A., Smith, W. C., Hannaford, P. C., & Penny,

K. (2001). The impact of chronic pain in the community. Family Practice, 18(3),

292–299. https://doi.org/10.1093/fampra/18.3.292

Smith, M. T., & Haythornthwaite, J. A. (2004). How do sleep disturbance and chronic

pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical

trials literature. Sleep Medicine Reviews, 8(2), 119–132.

https://doi.org/10.1016/S1087-0792(03)00044-3

Srbely, J. Z., Dickey, J. P., Lee, D., & Lowerison, M. (2010). Dry needle stimulation of

myofascial trigger points evokes segmental anti-nociceptive effects. Journal of

Rehabilitation Medicine, 42(5), 463–468. https://doi.org/10.2340/16501977-0535

Tantanatip, A., & Chang, K. V. (2020). Myofascial pain syndrome (MPS). StatPearls

[Internet].

Tough, E. A., White, A. R., Richards, S., & Campbell, J. (2007). Variability of criteria

used to diagnose myofascial trigger point pain syndrome--evidence from a review

UST College of Science Department of Biological Sciences 33

of the literature. The Clinical Journal of Pain, 23(3), 278–286.

https://doi.org/10.1097/AJP.0b013e31802fda7c

Travell, J. G., & Simons, D. G. (1983). Myofascial pain and dysfunction: the trigger point

manual (Vol. 2). Lippincott Williams & Wilkins.

Vazquez-Delgado, E., Cascos-Romero, J., & Gay-Escoda, C. (2009). Myofascial pain

syndrome associated with trigger points: a literature review. (I): Epidemiology,

clinical treatment and etiopathogeny. Medicina Oral Patología Oral y Cirugia

Bucal, 14(10), e494–e498. https://doi.org/10.4317/medoral.14.e494

Ward, R. C. (2002). Foundations for osteopathic medicine (2nd Ed.). Lippincott Williams

& Wilkins.

Wishart, D. S., Feunang, Y. D., Guo, A. C., Lo, E. J., Marcu, A., Grant, J. R., Sajed, T.,

Johnson, D., Li, C., Sayeeda, Z., Assempour, N., Iynkkaran, I., Liu, Y.,

Maciejewski, A., Gale, N., Wilson, A., Chin, L., Cummings, R., Le, D., Pon, A.,

Knox, C., & Wilson, M. (2017) DrugBank 5.0: a major update to the DrugBank

database for 2018. Nucleic Acids Research, 46(D1), D1074-D1082.

https://doi.org/10.1093/nar/gkx1037

Wolfe, F., Brähler, E., Hinz, A., & Häuser, W. (2013). Fibromyalgia prevalence, somatic

symptom reporting, and the dimensionality of polysymptomatic distress: results

from a survey of the general population. Arthritis Care & Research, 65(5), 777–

785. https://doi.org/10.1002/acr.2

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SUPPLEMENTS

Supplement 1. A list of the drug-gene interactions of drugs associated with MPS,

compiled from CTD (Davis et al., 2021) data status as of March 2021.

Associated Drug Associated Interaction Gene

Bupivacaine CASP9 Bupivacaine results in decreased expression of CASP9 protein HRH1 HRH1 protein binds to Bupivacaine ITGAM Bupivacaine results in increased expression of ITGAM mRNA 4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine inhibits the reaction [Bupivacaine results in increased expression of ITGAM mRNA] KCNK9 Bupivacaine inhibits the reaction [KCNK9 protein results in increased transport of Potassium] [Bupivacaine co-treated with Tetrodotoxin co-treated with Dexamethasone] results in PRKCB decreased expression of PRKCB mRNA Bupivacaine inhibits the reaction [[Desipramine results in decreased activity of SLC6A2 protein] SLC6A2 which results in decreased abundance of Norepinephrine] TRPV1 Bupivacaine affects the reaction [Capsaicin results in increased activity of TRPV1 protein]

Bupivacaine results in increased activity of TRPV1 protein Cocaine CASP9 SB 203580 inhibits the reaction [Cocaine results in increased activity of CASP9 protein] Cocaine results in increased activity of CASP9 protein

Cocaine results in increased expression of CASP9 protein

Cocaine affects the expression of CASP9 protein Cocaine affects the expression of CASP9 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of CAMK1G FOS mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of CAB39L mRNA FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of SEZ6L mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of SATB1 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of PRKCA mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of NRN1 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of NPTXR mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of NCALD mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of HS3ST2 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of HOMER2 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of DLK2 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of CALR mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of BDNF mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in decreased expression of MAPK11 mRNA]

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FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of SYT2 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of SYNE1 mRNA]

CDK5R1 protein inhibits the reaction [Cocaine affects the expression of FOS mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of SBSN mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of PTPRV mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of PRPF18 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of PPP1R7 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of PBX3 mRNA]

CDK5R1 protein inhibits the reaction [Cocaine results in increased expression of FOS protein] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of NOS3 mRNA] [SCH 23390 binds to and results in decreased activity of DRD1 protein] inhibits the reaction [Cocaine results in increased expression of FOS protein]

Cocaine promotes the reaction [Caffeine results in increased expression of FOS mRNA]

[Cocaine co-treated with Caffeine] results in increased expression of FOS mRNA Cocaine promotes the reaction [[SK&F 81297 co-treated with Quinpirole] results in increased expression of FOS protein]

Alcohols promotes the reaction [Cocaine results in increased expression of FOS protein]

Ethanol promotes the reaction [Cocaine results in increased expression of FOS protein]

Cocaine promotes the reaction [Ethanol results in increased expression of FOS protein] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of NIT2 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of LIN7B mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of KCNT1 mRNA]

[Morphine co-treated with Cocaine] affects the expression of FOS

Cocaine results in increased phosphorylation of FOS protein

RPS6KA3 affects the reaction [Cocaine results in increased phosphorylation of FOS protein]

Reserpine inhibits the reaction [Cocaine results in increased expression of FOS protein] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of LZTS3 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of KDM3A mRNA] cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester inhibits the reaction [Cocaine results in increased expression of FOS protein] prolinedithiocarbamate inhibits the reaction [Cocaine results in increased expression of FOS protein] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of EIF4B mRNA]

GPX1 protein inhibits the reaction [Cocaine results in increased expression of FOS protein]

Cocaine deficiency results in decreased expression of FOS protein FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of MEPCE mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of CTSB mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of CLK1 mRNA]

volinanserin inhibits the reaction [Cocaine results in increased expression of FOS protein]

DRD3 protein inhibits the reaction [Cocaine results in increased expression of FOS protein] [[Cocaine results in increased phosphorylation of and results in increased activity of MAPK1 protein] which results in increased expression of FOS protein] which affects the expression of PDYN protein [[Cocaine results in increased phosphorylation of and results in increased activity of MAPK1 protein] which results in increased expression of FOS protein] which affects the expression of NEO1 protein

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[[Cocaine results in increased phosphorylation of and results in increased activity of MAPK1 protein] which results in increased expression of FOS protein] which affects the expression of SYT7 protein SL 327 inhibits the reaction [[Cocaine results in increased phosphorylation of and results in increased activity of MAPK3 protein] which results in increased expression of FOS protein] SL 327 inhibits the reaction [[Cocaine results in increased phosphorylation of and results in increased activity of MAPK1 protein] which results in increased expression of FOS protein] [Cocaine results in increased phosphorylation of and results in increased activity of MAPK3 protein] which results in increased expression of FOS protein [Cocaine results in increased phosphorylation of and results in increased activity of MAPK1 protein] which results in increased expression of FOS protein

Cocaine promotes the reaction [DRD3 protein results in decreased expression of FOS protein]

Cocaine promotes the reaction [DRD1 protein results in increased expression of FOS protein]

NPPC protein inhibits the reaction [Cocaine results in increased expression of FOS mRNA]

ecopipam inhibits the reaction [Cocaine results in increased expression of FOS protein] [Cocaine co-treated with FOS protein mutant form] results in increased expression of SATB2 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of INA mRNA FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of ZFPM1 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of GPC5 mRNA] [Cocaine co-treated with FOS protein mutant form] results in decreased expression of THRA mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of SYT9 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of SHANK3 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PRKCZ mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PLPP1 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PKNOX2 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PINX1 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PER1 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of PBX2 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of NEXN mRNA

FOS protein mutant form results in decreased susceptibility to Cocaine [Cocaine co-treated with FOS protein mutant form] results in decreased expression of ITPR1 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of FNDC1 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of ENTPD3 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of CORO7 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of CD4 mRNA [Cocaine co-treated with FOS protein mutant form] results in decreased expression of ATPAF1 mRNA

Muscimol inhibits the reaction [Cocaine results in increased expression of FOS protein] [Cocaine co-treated with FOS protein mutant form] results in increased expression of SORCS3 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of TENM4 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of NRIP3 mRNA

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[Cocaine co-treated with FOS protein mutant form] results in increased expression of LARGE1 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of GRIP1 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of ADGRA1 mRNA [Cocaine co-treated with FOS protein mutant form] results in increased expression of CBLN1 mRNA FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of TSPOAP1 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of ATP1B3 mRNA] FOS protein mutant form inhibits the reaction [Cocaine results in increased expression of ATP8B2 mRNA]

Cocaine affects the expression of FOS mRNA

SL 327 inhibits the reaction [Cocaine results in increased activity of FOS protein]

Cocaine results in decreased expression of FOS protein

Cocaine results in increased activity of FOS protein NTRK2 protein affects the reaction [Cocaine affects the expression of FOS protein] Cocaine affects the expression of FOS protein CNR1 mutant form inhibits the reaction [Cocaine results in increased expression of FOS protein] Baclofen inhibits the reaction [Cocaine results in increased expression of FOS protein] N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine inhibits the reaction [Cocaine results in increased expression of FOS protein] Dizocilpine Maleate inhibits the reaction [Cocaine results in increased expression of FOS protein] SCH 23390 inhibits the reaction [Cocaine results in increased expression of FOS protein] SL 327 inhibits the reaction [Cocaine results in increased expression of FOS mRNA] SL 327 inhibits the reaction [Cocaine results in increased expression of FOS protein] N-methyl-3-(bis(4'-fluorophenyl)methoxy)tropane inhibits the reaction [Cocaine results in increased expression of FOS protein] Cocaine inhibits the reaction [[Dopamine co-treated with SLC6A3 protein] results in increased expression of FOS mRNA] Cocaine inhibits the reaction [[Dopamine co-treated with SLC6A3 protein] results in increased expression of FOS protein] [Cocaine co-treated with SLC6A3 protein] results in increased expression of FOS protein Cocaine promotes the reaction [Cocaine results in increased expression of FOS mRNA] Urethane inhibits the reaction [Cocaine results in increased expression of FOS protein] Chloral Hydrate inhibits the reaction [Cocaine results in increased expression of FOS protein] Cocaine results in increased expression of FOS protein Cocaine results in increased expression of FOS mRNA IL6 IL6 protein affects the reaction [Cocaine results in decreased expression of BCL2L1 protein] TNF protein affects the reaction [IL6 protein affects the reaction [Cocaine results in decreased expression of BCL2 protein]] TNF protein affects the reaction [IL6 protein affects the reaction [Cocaine results in decreased expression of BCL2L1 protein]] IL6 protein affects the reaction [Cocaine results in increased expression of BAX protein] IL6 protein affects the reaction [Cocaine results in increased cleavage of CASP3 protein] Cocaine results in decreased expression of IL6 protein Cocaine results in increased expression of IL6 protein Cocaine results in increased expression of IL6 mRNA IL6 protein affects the susceptibility to Cocaine TNF protein affects the reaction [IL6 protein affects the susceptibility to Cocaine] [IL6 protein affects the susceptibility to Cocaine] which affects the expression of TNF mRNA [IL6 protein affects the susceptibility to Cocaine] which affects the expression of TNF protein IL6 protein affects the reaction [Cocaine results in increased phosphorylation of JAK2 protein] IL6 protein affects the reaction [Cocaine results in increased phosphorylation of STAT3 protein] IL6 protein affects the reaction [Cocaine results in increased expression of ADCYAP1 mRNA] IL6 protein affects the reaction [Cocaine results in increased expression of ADCYAP1R1 mRNA] alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide affects the reaction [IL6 protein affects the reaction [Cocaine results in increased phosphorylation of JAK2 protein]]

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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide affects the reaction [IL6 protein affects the reaction [Cocaine results in increased phosphorylation of STAT3 protein]] alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide affects the reaction [IL6 protein affects the reaction [Cocaine results in increased expression of ADCYAP1 mRNA]] IL6 protein affects the reaction [Cocaine results in decreased expression of BCL2 protein] TNF protein affects the reaction [IL6 protein affects the reaction [Cocaine results in increased expression of BAX protein]] TNF protein affects the reaction [IL6 protein affects the reaction [Cocaine results in increased cleavage of CASP3 protein]] alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide affects the reaction [IL6 protein affects the reaction [Cocaine results in increased expression of ADCYAP1R1 mRNA]] PRKCB Cocaine results in increased expression of PRKCB mRNA Cocaine results in decreased expression of PRKCB mRNA SLC6A2 Cocaine results in increased phosphorylation of SLC6A2 protein SLC6A2 protein results in increased susceptibility to Cocaine Cocaine results in increased expression of SLC6A2 protein Cocaine results in decreased activity of SLC6A2 protein SB 203580 inhibits the reaction [Cocaine results in increased expression of SLC6A2 protein] Cocaine inhibits the reaction [SLC6A2 protein results in increased import of Fluorescent Dyes] Cocaine inhibits the reaction [SLC6A2 protein results in increased import of Biogenic Monoamines analog] 2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole inhibits the reaction [Cocaine results in increased expression of and results in increased phosphorylation of SLC6A2 protein] Difflunisal FOS Diflunisal results in increased expression of FOS mRNA IL6 Diflunisal results in increased expression of IL6 mRNA Lidocaine CASP9 Lidocaine results in decreased expression of CASP9 protein FOS Lidocaine inhibits the reaction [Propofol results in increased expression of FOS protein] Lidocaine affects the expression of FOS protein Lidocaine inhibits the reaction [Bee Venoms promotes the reaction [Methamphetamine results in increased expression of FOS protein]] HRH1 [HRH1 protein binds to Lidocaine] which results in increased import of Calcium HRH1 protein binds to Lidocaine IL6 Lidocaine results in decreased expression of IL6 protein Lidocaine inhibits the reaction [TNF protein results in increased expression of [ITGAM protein ITGAM binds to ITGB2 protein]] KCNK9 Lidocaine inhibits the reaction [KCNK9 protein results in increased transport of Potassium] PRKCB Lidocaine results in increased expression of PRKCB protein Dexmedetomidine inhibits the reaction [Lidocaine results in increased expression of PRKCB protein] Lidocaine inhibits the reaction [SLC22A1 protein results in increased uptake of 1-Methyl-4- SLC22A1 phenylpyridinium] Lidocaine inhibits the reaction [SLC22A3 protein results in increased uptake of 1-Methyl-4- SLC22A3 phenylpyridinium] Lidocaine inhibits the reaction [[Desipramine results in decreased activity of SLC6A2 protein] SLC6A2 which results in decreased abundance of Norepinephrine] TRPV1 capsazepine inhibits the reaction [Lidocaine results in increased activity of TRPV1 protein] 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione inhibits the reaction [Lidocaine results in increased activity of TRPV1 protein] oxophenylarsine inhibits the reaction [Lidocaine results in increased activity of TRPV1 protein] Tetradecanoylphorbol Acetate promotes the reaction [Lidocaine results in increased activity of TRPV1 protein] TRPV1 protein affects the reaction [Lidocaine results in increased secretion of CALCA protein] oxophenylarsine inhibits the reaction [Lidocaine promotes the reaction [Capsaicin results in increased activity of TRPV1 protein]] Lidocaine results in increased activity of TRPV1 protein Lidocaine promotes the reaction [TRPV1 protein results in increased abundance of Calcium] Ruthenium Red inhibits the reaction [Lidocaine results in increased activity of TRPV1 protein] N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide inhibits the reaction [Lidocaine results in increased activity of TRPV1 protein] Lidocaine promotes the reaction [Capsaicin results in increased activity of TRPV1 protein] Lidocaine promotes the reaction [Camphor results in increased activity of TRPV1 protein] DDIT3 protein affects the reaction [Methamphetamine results in increased cleavage of CASP9 Methamphetamine CASP9 protein]

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Methamphetamine results in increased expression of and results in increased cleavage of CASP9 protein ATF6 protein affects the reaction [Methamphetamine results in increased cleavage of CASP9 protein] EIF2AK3 protein affects the reaction [Methamphetamine results in increased cleavage of CASP9 protein] ERN1 protein affects the reaction [Methamphetamine results in increased cleavage of CASP9 protein] FOS Methamphetamine results in increased expression of FOS mRNA Idazoxan inhibits the reaction [Bee Venoms promotes the reaction [Methamphetamine results in increased expression of FOS protein]] FOS protein affects the reaction [Methamphetamine results in decreased expression of SLC6A3 protein] Bee Venoms promotes the reaction [Methamphetamine results in increased expression of FOS protein] Methamphetamine results in increased expression of FOS Lidocaine inhibits the reaction [Bee Venoms promotes the reaction [Methamphetamine results in increased expression of FOS protein]] Carbamazepine inhibits the reaction [Methamphetamine results in increased expression of FOS protein] FOS protein affects the susceptibility to Methamphetamine [Methamphetamine co-treated with SCH 23390] results in increased expression of FOS mRNA Oxytocin inhibits the reaction [Methamphetamine results in increased expression of FOS protein] FOS mRNA affects the susceptibility to Methamphetamine Methamphetamine results in increased expression of FOS protein CCK protein alternative form inhibits the reaction [Methamphetamine results in increased IL6 expression of IL6 protein] Methamphetamine results in increased expression of IL6 protein Lactulose inhibits the reaction [Methamphetamine results in increased expression of IL6 protein] [SNCA protein co-treated with Methamphetamine] results in increased expression of IL6 protein CCK protein alternative form inhibits the reaction [Methamphetamine results in increased expression of IL6 mRNA] CCK protein alternative form inhibits the reaction [Methamphetamine results in increased secretion of IL6 protein] Minocycline inhibits the reaction [Methamphetamine results in increased secretion of IL6 protein] Devazepide promotes the reaction [CCK protein alternative form inhibits the reaction [Methamphetamine results in increased secretion of IL6 protein]] IL6 protein affects the reaction [Methamphetamine results in decreased expression of SLC6A3 protein] IL6 protein affects the susceptibility to Methamphetamine Melatonin inhibits the reaction [Methamphetamine results in increased expression of IL6 mRNA] Methamphetamine results in increased expression of IL6 mRNA L 365260 inhibits the reaction [CCK protein alternative form inhibits the reaction [Methamphetamine results in increased secretion of IL6 protein]] margatoxin inhibits the reaction [Methamphetamine results in increased expression of IL6 mRNA] IL6 protein affects the reaction [Methamphetamine affects the expression of SLC6A4 protein] Methamphetamine results in increased secretion of IL6 protein margatoxin inhibits the reaction [Methamphetamine results in increased secretion of IL6 protein] PRKCB Methamphetamine results in decreased expression of PRKCB mRNA Methamphetamine inhibits the reaction [SLC22A3 protein results in increased uptake of 1- SLC22A3 Methyl-4-phenylpyridinium] SLC6A2 protein promotes the reaction [Methamphetamine results in increased activity of SLC6A2 TAAR1 protein] indatraline inhibits the reaction [SLC6A2 protein promotes the reaction [Methamphetamine results in increased activity of TAAR1 protein]] Desipramine inhibits the reaction [SLC6A2 protein promotes the reaction [Methamphetamine results in increased activity of TAAR1 protein]] TRPV1 Methamphetamine results in increased expression of TRPV1 mRNA MDMA FOS N-Methyl-3,4-methylenedioxyamphetamine results in increased expression of FOS mRNA

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HRH1 N-Methyl-3,4-methylenedioxyamphetamine results in increased expression of HRH1 mRNA Caffeine promotes the reaction [N-Methyl-3,4-methylenedioxyamphetamine results in increased ITGAM expression of ITGAM protein] N-Methyl-3,4-methylenedioxyamphetamine results in increased expression of ITGAM protein PRKCB N-Methyl-3,4-methylenedioxyamphetamine results in increased expression of PRKCB mRNA N-Methyl-3,4-methylenedioxyamphetamine inhibits the reaction [SLC6A2 protein results in SLC6A2 increased import of Biogenic Monoamines analog] N-Methyl-3,4-methylenedioxyamphetamine inhibits the reaction [SLC6A2 protein results in increased uptake of Norepinephrine] N-Methyl-3,4-methylenedioxyamphetamine inhibits the reaction [SLC6A2 protein results in increased import of Fluorescent Dyes] SLC6A2 gene SNP affects the susceptibility to N-Methyl-3,4-methylenedioxyamphetamine N-Methyl-3,4-methylenedioxyamphetamine results in decreased activity of SLC6A2 protein N-Methyl-3,4-methylenedioxyamphetamine inhibits the reaction [SLC6A2 protein results in increased uptake of 1-Methyl-4-phenylpyridinium]

Supplement 2. A list of the drug-gene interactions of the top 10 drugs associated with

MPS via differential diagnosis identified from MalaCards (Rappaport et al., 2017),

compiled from CTD (Davis et al., 2021) data status as of April 2021.

Associated Associated Interaction Drug Gene

Gabapentin ABCB1 Gabapentin results in decreased activity of ABCB1 protein CACNA2D1 protein results in increased susceptibility to [Gabapentin affects the activity of [CACNA1D protein co-treated with CACNA1D CACNB3 protein]]

Gabapentin affects the activity of [CACNA1D protein co-treated with CACNB3 protein] Gabapentin affects the reaction [[CACNA1D protein co-treated with CACNB3 protein] results in increased transport of Calcium] CALR [Gabapentin co-treated with Pentylenetetrazole] affects the expression of CALR mRNA CYP1A1 Gabapentin results in decreased expression of CYP1A1 mRNA CYP2E1 Gabapentin results in decreased expression of CYP2E1 mRNA CYP3A23- Gabapentin results in decreased expression of CYP3A23-3A1 mRNA 3A1 F10 Gabapentin results in decreased expression of F10 mRNA CGP 71872 inhibits the reaction [Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form GABBR1 binds to GABBR2 protein]] Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form binds to GABBR2 protein] [Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form binds to GABBR2 protein]] results in increased activity of [KCNJ3 protein binds to KCNJ6 protein] CGP 71872 inhibits the reaction [Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form GABBR2 binds to GABBR2 protein]] Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form binds to GABBR2 protein] [Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form binds to GABBR2 protein]] results in increased activity of [KCNJ3 protein binds to KCNJ6 protein] GSTM1 Gabapentin results in increased expression of GSTM1 mRNA HMOX1 Gabapentin results in increased expression of HMOX1 mRNA HSP90AA1 Gabapentin results in decreased expression of HSP90AA1 mRNA KCNH2 Gabapentin results in decreased activity of KCNH2 protein [Gabapentin binds to and results in increased activity of [GABBR1 protein alternative form binds to GABBR2 protein]] results KCNJ6 in increased activity of [KCNJ3 protein binds to KCNJ6 protein] MDH1 [Gabapentin co-treated with Pentylenetetrazole] affects the expression of MDH1 mRNA NOS2 Gabapentin results in increased expression of NOS2 protein PON1 Gabapentin results in decreased activity of PON1 protein

RPS29 [Gabapentin co-treated with Pentylenetetrazole] affects the expression of RPS29 mRNA

SULT1A1 Gabapentin results in decreased expression of SULT1A1 mRNA Gabapentin inhibits the reaction [Freund's Adjuvant promotes the reaction [Capsaicin results in increased secretion of TAC1 TAC1 protein]]

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TKT Gabapentin results in increased expression of TKT mRNA

TXNRD1 Gabapentin results in increased expression of TXNRD1 mRNA

UBE3A [Gabapentin co-treated with Pentylenetetrazole] affects the expression of UBE3A mRNA Etoricoxib ABCB11 Etoricoxib results in decreased activity of ABCB11 protein

CYP1A2 Etoricoxib results in decreased activity of CYP1A2 protein

CYP3A4 CYP3A4 protein results in increased metabolism of Etoricoxib

ICAM1 Etoricoxib results in decreased expression of ICAM1 mRNA

Etoricoxib results in decreased expression of ICAM1 protein

PTGS2 Etoricoxib inhibits the reaction [Ifosfamide results in increased expression of PTGS2 protein]

Etoricoxib results in decreased activity of PTGS2 protein

Etoricoxib results in decreased activity of PTGS2 protein mutant form

Etoricoxib results in decreased expression of PTGS2 Tramadol BAX Tramadol results in increased expression of BAX protein

BCHE Tramadol results in decreased activity of BCHE protein

CASP3 Tramadol affects the activity of CASP3 protein

Tramadol results in decreased activity of CASP3 protein

CAT Tramadol deficiency inhibits the reaction [Tramadol results in increased expression of CAT mRNA]

Tramadol results in decreased expression of CAT mRNA

CKB Tramadol results in decreased expression of CKB mRNA

CYP2D6 CYP2D6 gene mutant form results in increased chemical synthesis of O-demethyltramadol

CYP2D6 protein results in increased chemical synthesis of O-demethyltramadol [CYP2D6 protein results in increased metabolism of and results in increased activity of Tramadol] which results in increased chemical synthesis of O-demethyltramadol

CYP2D6 affects the susceptibility to Tramadol

CYP2D6 gene mutant form affects the metabolism of Tramadol

CYP2D6 gene mutant form results in increased metabolism of Tramadol

CYP2D6 gene mutant form results in increased susceptibility to Tramadol

CYP2D6 gene polymorphism affects the metabolism of and affects the susceptibility to Tramadol

CYP2D6 gene polymorphism affects the metabolism of Tramadol

CYP2D6 gene polymorphism affects the susceptibility to Tramadol

CYP2D6 gene polymorphism results in decreased susceptibility to Tramadol

CYP2D6 protein affects the methylation of Tramadol

CYP2D6 protein affects the susceptibility to Tramadol

CYP2D6 protein results in decreased methylation of Tramadol

CYP2D6 protein results in increased metabolism of and results in increased activity of Tramadol [CYP2D6 protein results in increased metabolism of and results in increased activity of Tramadol] which results in increased chemical synthesis of O-demethyltramadol

CYP2D6 protein results in increased metabolism of Tramadol

CYP3A4 CYP3A4 protein results in increased metabolism of Tramadol

DRD2 Tramadol results in increased expression of DRD2 protein

DRD3 Tramadol results in increased expression of DRD3 protein

GPT Tramadol results in increased activity of GPT protein

HTR2A Ketanserin inhibits the reaction [Tramadol results in increased activity of HTR2A protein]

Tramadol results in increased activity of HTR2A protein

Tramadol results in increased expression of HTR2A mRNA

OPRK1 Tramadol binds to OPRK1 protein

[Tramadol binds to OPRK1 protein] which results in decreased uptake of Norepinephrine

[Tramadol binds to OPRK1 protein] which results in decreased uptake of Serotonin

OPRM1 Tramadol binds to OPRM1 protein

[Tramadol binds to OPRM1 protein] which results in decreased uptake of Norepinephrine

[Tramadol binds to OPRM1 protein] which results in decreased uptake of Serotonin

PDYN Tramadol results in decreased expression of PDYN mRNA

SLC47A1 Tramadol inhibits the reaction [SLC47A1 protein results in increased uptake of 1-Methyl-4-phenylpyridinium]

SLC47A2 Tramadol inhibits the reaction [SLC47A2 protein results in increased uptake of 1-Methyl-4-phenylpyridinium]

SOD1 Tramadol deficiency inhibits the reaction [Tramadol results in increased expression of SOD1 mRNA]

Tramadol results in decreased expression of SOD1 mRNA

SOD2 Tramadol deficiency inhibits the reaction [Tramadol results in increased expression of SOD2 mRNA]

Tramadol results in decreased expression of SOD2 mRNA [Acetaminophen co-treated with Tramadol] inhibits the reaction [Freund's Adjuvant results in increased expression of TNF TNF protein] Modafinil ACP5 Alendronate inhibits the reaction [Modafinil results in increased expression of ACP5 mRNA]

Modafinil results in increased expression of ACP5 mRNA

Modafinil results in increased expression of ACP5 protein

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ADORA2A Modafinil results in increased activity of ADORA2A protein

ADORA2B Modafinil results in increased activity of ADORA2B protein

COMT COMT gene polymorphism affects the susceptibility to Modafinil

COMT protein affects the susceptibility to Modafinil

FOS Modafinil affects the expression of FOS protein

RUNX2 Alendronate promotes the reaction [Modafinil results in increased expression of RUNX2 mRNA]

Modafinil results in increased expression of RUNX2 mRNA

SLC6A3 Modafinil inhibits the reaction [SLC6A3 protein affects the uptake of Dopamine]

SLC6A3 gene mutant form results in decreased susceptibility to Modafinil

SLC6A3 gene polymorphism affects the susceptibility to Modafinil Trazodone BMP6 Trazodone results in increased expression of BMP6 mRNA

CAT Trazodone affects the activity of CAT protein

CXCL8 Trazodone results in increased expression of CXCL8 mRNA

CYP3A4 CYP3A4 protein affects the metabolism of Trazodone

[SOD2 co-treated with CYP3A4] affects the susceptibility to Trazodone Trazodone inhibits the reaction [CYP3A4 protein results in increased oxidation of and results in increased activity of Haloperidol] Trazodone inhibits the reaction [CYP3A5 protein results in increased oxidation of and results in increased activity of CYP3A5 Haloperidol]

HTR1A etoperidone binds to HTR1A protein

Trazodone binds to HTR1A protein

Trazodone results in decreased expression of HTR1A protein

Trazodone results in increased expression of HTR1A protein

HTR2A Trazodone binds to and results in decreased activity of HTR2A protein

HTR2C Trazodone binds to and results in decreased activity of HTR2C protein

Trazodone binds to HTR2C protein

IL1A Trazodone results in increased expression of IL1A mRNA IL1B Trazodone results in increased expression of IL1B mRNA KCNH2 Trazodone results in decreased activity of KCNH2 protein MET Trazodone results in increased expression of MET mRNA NOS2 Trazodone inhibits the reaction [endotoxin, Escherichia coli results in increased expression of NOS2 protein] Trazodone inhibits the reaction [Lipopolysaccharides results in increased expression of NOS2 protein] PID1 Trazodone results in increased expression of PID1 mRNA PTGS2 Trazodone inhibits the reaction [endotoxin, Escherichia coli results in increased expression of PTGS2 protein] Trazodone inhibits the reaction [Lipopolysaccharides results in increased expression of PTGS2 protein] Trazodone results in increased expression of PTGS2 mRNA SLC22A2 Trazodone inhibits the reaction [SLC22A2 protein results in increased uptake of 4-(4-dimethylaminostyryl)-1-methylpyridinium] SLC7A11 Trazodone results in increased expression of SLC7A11 mRNA SLPI Trazodone results in increased expression of SLPI mRNA SOD2 [SOD2 co-treated with CYP3A4] affects the susceptibility to Trazodone TNFAIP6 Trazodone results in increased expression of TNFAIP6 mRNA 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one inhibits the reaction [[BCR protein mutant form binds to ABL1 protein Histamine ABL1 mutant form] which results in increased chemical synthesis of Histamine] 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide inhibits the reaction [[BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine] [BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine Imatinib Mesylate inhibits the reaction [[BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine] ADCYAP1 ADCYAP1 protein results in increased secretion of Histamine Dinoprostone inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] Galanin inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] IL1B protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] Misoprostol inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] SST protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] TNF protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one inhibits the reaction [Histamine results in increased phosphorylation of AKT1 AKT1 protein] Histamine results in increased phosphorylation of AKT1 protein Pertussis Toxin inhibits the reaction [Histamine results in increased phosphorylation of AKT1 protein] Pyrilamine inhibits the reaction [Histamine results in increased phosphorylation of AKT1 protein] Wortmannin inhibits the reaction [Histamine results in increased phosphorylation of AKT1 protein]

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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one inhibits the reaction [[BCR protein mutant form binds to ABL1 protein BCR mutant form] which results in increased chemical synthesis of Histamine] 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide inhibits the reaction [[BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine] [BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine Imatinib Mesylate inhibits the reaction [[BCR protein mutant form binds to ABL1 protein mutant form] which results in increased chemical synthesis of Histamine] Dinoprostone inhibits the reaction [Flurbiprofen inhibits the reaction [Histamine results in increased secretion of CALCA CALCA protein]] Flurbiprofen inhibits the reaction [Histamine promotes the reaction [[KNG1 protein co-treated with Serotonin] results in increased secretion of CALCA protein]] Flurbiprofen inhibits the reaction [Histamine results in increased secretion of CALCA protein] Flurbiprofen inhibits the reaction [[KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased secretion of CALCA protein] Histamine promotes the reaction [[KNG1 protein co-treated with Serotonin] results in increased secretion of CALCA protein] Histamine results in increased secretion of CALCA protein [KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased secretion of CALCA protein CAMK1 histamine trifluoromethyl-toluidide results in increased phosphorylation of CAMK1 protein CAT Histamine affects the expression of CAT protein CCL2 4-methylhistamine results in decreased expression of CCL2 protein Lipopolysaccharides promotes the reaction [Histamine results in increased expression of CCL2 protein] TNF protein promotes the reaction [Histamine results in increased expression of CCL2 protein] CCND1 [HRH4 protein results in increased susceptibility to Histamine] which results in decreased expression of CCND1 protein CD14 [4-methylhistamine binds to and results in increased activity of HRH2 protein] which affects the expression of CD14 protein Histamine affects the expression of CD14 protein HRH2 protein affects the reaction [Histamine affects the expression of CD14 protein] CD80 4-methylhistamine inhibits the reaction [Lipopolysaccharides results in increased expression of CD80 protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of CD80 protein]] Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of CD80 protein] Ranitidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of CD80 protein]] CDK2 [HRH4 protein results in increased susceptibility to Histamine] which results in decreased expression of CDK2 protein CDKN1A [HRH4 protein results in increased susceptibility to Histamine] which results in increased expression of CDKN1A protein CDKN1B [HRH4 protein results in increased susceptibility to Histamine] which results in increased expression of CDKN1B protein CHRM3 CHRM3 protein affects the reaction [Histamine results in increased secretion of Acids] CHRM3 protein affects the susceptibility to Histamine CREB1 Glycyrrhizic Acid inhibits the reaction [Histamine results in decreased phosphorylation of CREB1 protein] Histamine results in decreased phosphorylation of CREB1 protein prolinedithiocarbamate inhibits the reaction [Histamine results in decreased phosphorylation of CREB1 protein] histamine trifluoromethyl-toluidide results in increased activity of CREB1 protein W 7 inhibits the reaction [histamine trifluoromethyl-toluidide results in increased activity of CREB1 protein] CSF1 Histamine results in decreased expression of CSF1 mRNA CXCL8 CXCL8 protein inhibits the reaction [GAST protein results in increased secretion of Histamine] Cyclosporine inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] Dexamethasone inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] Dexamethasone inhibits the reaction [Histamine results in increased expression of CXCL8 protein] Diphenhydramine inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] Diphenhydramine inhibits the reaction [Histamine results in increased expression of CXCL8 protein] Glycyrrhizic Acid inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] Glycyrrhizic Acid inhibits the reaction [Histamine results in increased secretion of CXCL8 protein] [Histamine co-treated with lipopolysaccharide, E. coli O26-B6] results in decreased expression of CXCL8 mRNA Histamine results in increased activity of [CXCL8 protein binds to RELA protein] Histamine results in increased expression of CXCL8 mRNA Histamine results in increased expression of CXCL8 protein Histamine results in increased secretion of CXCL8 protein L 655238 inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] Leukotriene B4 inhibits the reaction [zileuton inhibits the reaction [Histamine results in increased expression of CXCL8 protein]] Lipopolysaccharides promotes the reaction [Histamine results in increased expression of CXCL8 protein] MK-886 inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] MK-886 inhibits the reaction [Histamine results in increased expression of CXCL8 protein]

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Particulate Matter analog promotes the reaction [Histamine results in increased secretion of CXCL8 protein] prolinedithiocarbamate inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] prolinedithiocarbamate inhibits the reaction [Histamine results in increased secretion of CXCL8 protein] TNF protein promotes the reaction [Histamine results in increased expression of CXCL8 protein] Vehicle Emissions analog promotes the reaction [Histamine results in increased secretion of CXCL8 protein] zileuton inhibits the reaction [Histamine results in increased expression of CXCL8 mRNA] zileuton inhibits the reaction [Histamine results in increased expression of CXCL8 protein] EDN1 EDN1 protein results in decreased activity of [Atropine co-treated with Histamine] EGFR EGFR protein affects the reaction [Histamine results in increased secretion of MMP1 protein] F3 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one inhibits the reaction [Histamine results in increased expression of F3] 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one promotes the reaction [Histamine results in increased expression of F3] Chlorpheniramine inhibits the reaction [Histamine results in increased expression of F3] Diphenhydramine inhibits the reaction [Histamine results in increased expression of F3] [Histamine co-treated with splitomicin] results in increased expression of F3 protein Histamine results in increased activity of F3 protein Histamine results in increased expression of F3 mRNA Histamine results in increased expression of F3 protein pyrazolanthrone inhibits the reaction [Histamine results in increased expression of F3] Pyrilamine inhibits the reaction [Histamine results in increased activity of F3 protein] Pyrilamine inhibits the reaction [Histamine results in increased expression of F3] SB 203580 inhibits the reaction [Histamine results in increased expression of F3] Wortmannin promotes the reaction [Histamine results in increased expression of F3] histamine phosphate results in increased expression of F3 protein FOS Cycloheximide promotes the reaction [Histamine results in increased expression of FOS mRNA] Famotidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased expression of FOS mRNA] [Histamine binds to and results in increased activity of HRH2 protein] which results in increased expression of FOS mRNA Histamine results in increased expression of FOS Histamine results in increased expression of FOS mRNA GAD2 [methylhistaprodifen co-treated with Idazoxan] inhibits the reaction [amitraz affects the expression of GAD2 mRNA] methylhistaprodifen inhibits the reaction [amitraz affects the expression of GAD2 mRNA] GAST alpha-methylhistamine inhibits the reaction [GAST protein modified form results in increased secretion of Histamine] alpha-methylhistamine inhibits the reaction [GAST protein modified form results in increased secretion of Histamine] Chloral Hydrate inhibits the reaction [GAST protein results in increased secretion of Histamine] CXCL8 protein inhibits the reaction [GAST protein results in increased secretion of Histamine] Dinoprostone inhibits the reaction [GAST protein results in increased secretion of Histamine] [fluanisone co-treated with Fentanyl co-treated with Midazolam] inhibits the reaction [GAST protein results in increased secretion of Histamine] Galanin inhibits the reaction [GAST protein results in increased secretion of Histamine] GAST protein affects the abundance of Histamine GAST protein modified form results in increased secretion of Histamine GAST protein results in increased abundance of Histamine GAST protein results in increased secretion of Histamine Histamine affects the activity of GAST protein Impromidine inhibits the reaction [GAST protein modified form results in increased secretion of Histamine] Misoprostol inhibits the reaction [GAST protein results in increased secretion of Histamine] Pentobarbital inhibits the reaction [GAST protein results in increased secretion of Histamine] SST protein inhibits the reaction [GAST protein results in increased secretion of Histamine] TNF protein inhibits the reaction [GAST protein results in increased secretion of Histamine] Urethane inhibits the reaction [GAST protein results in increased secretion of Histamine] GHRL Histamine affects the reaction [GHRL protein results in increased secretion of Acids] GLS [methylhistaprodifen co-treated with Idazoxan] inhibits the reaction [amitraz results in increased expression of GLS mRNA] methylhistaprodifen inhibits the reaction [amitraz results in increased expression of GLS mRNA] HDC alpha-methylhistamine results in decreased expression of HDC mRNA HDC protein results in increased chemical synthesis of Histamine [Troglitazone results in decreased expression of HDC mRNA] which results in decreased secretion of Histamine HRH1 2-(3-trifluoromethylphenyl)histamine binds to and results in increased activity of HRH1 protein 2-methylhistamine binds to and results in increased activity of HRH1 protein 6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide binds to and results in increased activity of HRH1 protein [6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide binds to and results in increased activity of HRH1 protein] which results in increased abundance of Calcium HRH1 protein promotes the reaction [6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide results in increased expression of GUSB protein]

UST College of Science Department of Biological Sciences 45

HRH1 protein promotes the reaction [6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide results in increased expression of IL6 protein] dimethylhistaprodifen binds to and results in decreased activity of HRH1 protein 1-Methyl-3-isobutylxanthine inhibits the reaction [HRH1 protein promotes the reaction [Histamine results in decreased abundance of Cyclic AMP]] Astemizole inhibits the reaction [Histamine results in decreased activity of [KCNQ2 protein co-treated with KCNQ3 protein co- treated with HRH1 protein]] [epinastine binds to and results in decreased activity of HRH1 protein] which affects the susceptibility to Histamine fexofenadine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased abundance of Calcium] fexofenadine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of GUSB protein] Guanosine Triphosphate affects the reaction [Histamine binds to and results in increased activity of HRH1 protein] Guanosine Triphosphate analog affects the reaction [Histamine inhibits the reaction [Pyrilamine binds to HRH1 protein]] Guanosine Triphosphate analog inhibits the reaction [Histamine binds to HRH1 protein] Guanosine Triphosphate inhibits the reaction [Histamine binds to HRH1 protein] Histamine binds to and results in increased activity of HRH1 protein [Histamine binds to and results in increased activity of HRH1 protein] which results in decreased susceptibility to Scopolamine [Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein Histamine binds to HRH1 protein Histamine inhibits the reaction [Pyrilamine binds to HRH1 protein] Histamine results in decreased activity of [KCNQ2 protein co-treated with KCNQ3 protein co-treated with HRH1 protein] Histamine results in increased activity of HRH1 protein [Histamine results in increased activity of HRH1 protein] which affects the transport of Potassium [Histamine results in increased activity of HRH1 protein] which results in increased abundance of Calcium Histamine results in increased expression of HRH1 mRNA HRH1 affects the reaction [Histamine promotes the reaction [TLR2 results in increased expression of PTGS2]] HRH1 protein affects the reaction [Histamine results in increased transport of fluorescein isothiocyanate bovine serum albumin] HRH1 protein affects the susceptibility to Histamine HRH1 protein binds to Histamine [HRH1 protein binds to Histamine] which results in increased import of Calcium HRH1 protein promotes the reaction [Histamine results in decreased abundance of Cyclic AMP] HRH1 protein promotes the reaction [Histamine results in increased export of Calcium] HRH1 protein promotes the reaction [Histamine results in increased expression of GUSB protein] HRH1 protein promotes the reaction [Histamine results in increased expression of IL6 protein] HRH1 protein promotes the reaction [Histamine results in increased metabolism of Phosphatidylinositols] Magnesium inhibits the reaction [Guanosine Triphosphate inhibits the reaction [Histamine binds to HRH1 protein]] Pyrilamine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in decreased susceptibility to Scopolamine] Pyrilamine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein] Quercetin inhibits the reaction [Histamine results in increased expression of HRH1 mRNA] Ro 31-8220 inhibits the reaction [Histamine results in increased expression of HRH1 mRNA] [Tripelennamine binds to and results in decreased activity of HRH1 protein] which affects the susceptibility to Histamine Triprolidine inhibits the reaction [Histamine binds to and results in increased activity of HRH1 protein] [Triprolidine inhibits the reaction [Histamine binds to and results in increased activity of HRH1 protein]] which results in decreased expression of CD40 protein [Triprolidine inhibits the reaction [Histamine binds to and results in increased activity of HRH1 protein]] which results in decreased expression of PTPRC protein Triprolidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein] Triprolidine inhibits the reaction [Histamine results in increased activity of HRH1 protein] Triprolidine inhibits the reaction [[Histamine results in increased activity of HRH1 protein] which results in increased abundance of Calcium] Triprolidine inhibits the reaction [HRH1 protein promotes the reaction [Histamine results in decreased abundance of Cyclic AMP]] Triprolidine inhibits the reaction [HRH1 protein promotes the reaction [Histamine results in increased export of Calcium]] Triprolidine inhibits the reaction [HRH1 protein promotes the reaction [Histamine results in increased metabolism of Phosphatidylinositols]] 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibits the reaction [histamine trifluoromethyl- toluidide results in increased activity of HRH1 protein] histamine trifluoromethyl-toluidide analog results in increased activity of HRH1 protein

UST College of Science Department of Biological Sciences 46

[histamine trifluoromethyl-toluidide analog results in increased activity of HRH1 protein] which affects the transport of Potassium histamine trifluoromethyl-toluidide results in increased activity of HRH1 protein Terfenadine inhibits the reaction [histamine trifluoromethyl-toluidide results in increased activity of HRH1 protein] W 7 inhibits the reaction [histamine trifluoromethyl-toluidide results in increased activity of HRH1 protein] Guanosine Triphosphate affects the reaction [histaprodifen binds to and results in increased activity of HRH1 protein] histaprodifen binds to and results in increased activity of HRH1 protein [histaprodifen binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein Triprolidine inhibits the reaction [histaprodifen results in increased activity of HRH1 protein] Guanosine Triphosphate affects the reaction [methylhistaprodifen binds to and results in increased activity of HRH1 protein] methylhistaprodifen binds to and results in increased activity of HRH1 protein methylhistaprodifen results in increased activity of HRH1 protein Triprolidine inhibits the reaction [methylhistaprodifen results in increased activity of HRH1 protein] HRH2 4-methylhistamine binds to and results in increased activity of HRH2 protein [4-methylhistamine binds to and results in increased activity of HRH2 protein] which affects the expression of CD14 protein aminopotentidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased abundance of Cyclic AMP] Burimamide inhibits the reaction [[Cyclic AMP binds to and results in increased activity of HRH2 protein] which results in increased abundance of Histamine] Burimamide inhibits the reaction [Histamine binds to and results in increased activity of HRH2 protein] [Cimetidine binds to and results in decreased activity of HRH2 protein] results in decreased susceptibility to [Histamine co- treated with [Oxygen deficiency co-treated with Oxygen]] Cimetidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in decreased susceptibility to Scopolamine] Cimetidine inhibits the reaction [HRH2 protein promotes the reaction [Histamine results in increased expression of IL16 protein]] Cyclic AMP promotes the reaction [[Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12A protein] Cyclic AMP promotes the reaction [[Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12B protein] [Famotidine binds to and results in decreased activity of HRH2 protein] which affects the susceptibility to Histamine Famotidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased expression of FOS mRNA] [Histamine affects the activity of HRH2 protein] which affects the secretion of Chlorides Histamine affects the expression of HRH2 protein Histamine affects the localization of HRH2 protein [Histamine affects the localization of HRH2 protein] which affects the degradation of HRH2 protein Histamine binds to and results in increased activity of HRH2 protein [Histamine binds to and results in increased activity of HRH2 protein] which results in decreased expression of IFNG mRNA [Histamine binds to and results in increased activity of HRH2 protein] which results in increased abundance of Cyclic AMP [Histamine binds to and results in increased activity of HRH2 protein] which results in increased expression of FOS mRNA Histamine inhibits the reaction [tiotidine binds to HRH2 protein] Histamine results in increased activity of HRH2 protein [Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12A protein [Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12B protein HRH2 protein affects the reaction [Histamine affects the expression of CD14 protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IFNG protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL2 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL4 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of TNF protein]]

UST College of Science Department of Biological Sciences 47

HRH2 protein affects the reaction [Histamine results in increased expression of IL18 protein] HRH2 protein promotes the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG mRNA]] HRH2 protein promotes the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG protein]] HRH2 protein promotes the reaction [Histamine results in decreased expression of IL12A protein] HRH2 protein promotes the reaction [Histamine results in decreased expression of IL12B protein] HRH2 protein promotes the reaction [[Histamine results in increased abundance of Cyclic AMP] which results in decreased expression of NPPA protein] HRH2 protein promotes the reaction [Histamine results in increased expression of IL16 protein] Ranitidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased abundance of Cyclic AMP] [roxatidine acetate binds to and results in decreased activity of HRH2 protein] which affects the susceptibility to Histamine [thioperamide results in increased abundance of Histamine] which results in increased activity of HRH2 protein [[thioperamide results in increased abundance of Histamine] which results in increased activity of HRH2 protein] which results in decreased susceptibility to Scopolamine tiotidine inhibits the reaction [Histamine binds to and results in increased activity of HRH2 protein] [tiotidine inhibits the reaction [Histamine binds to and results in increased activity of HRH2 protein]] which results in decreased expression of CD40 protein [tiotidine inhibits the reaction [Histamine binds to and results in increased activity of HRH2 protein]] which results in decreased expression of PTPRC protein tiotidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased abundance of Cyclic AMP] zolantidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH2 protein] which results in increased abundance of Cyclic AMP] N-methylhistamine binds to and results in increased activity of HRH2 protein N-methylhistamine inhibits the reaction [tiotidine binds to HRH2 protein] 6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one inhibits the reaction [alpha-methylhistamine promotes the HRH3 reaction [Guanosine Triphosphate binds to HRH3 protein]] alpha-methylhistamine binds to and results in increased activity of HRH3 protein alpha-methylhistamine binds to HRH3 protein alpha-methylhistamine promotes the reaction [Guanosine Triphosphate binds to HRH3 protein] clobenpropit inhibits the reaction [alpha-methylhistamine binds to HRH3 protein] Endocannabinoids inhibits the reaction [alpha-methylhistamine binds to and results in increased activity of HRH3 protein] Histamine H3 Antagonists inhibits the reaction [alpha-methylhistamine binds to HRH3 protein] thioperamide inhibits the reaction [alpha-methylhistamine binds to HRH3 protein] Histamine binds to and results in increased activity of HRH3 protein [Histamine binds to and results in increased activity of HRH3 protein] which results in increased transport of Calcium Histamine promotes the reaction [Guanosine 5'-O-(3-Thiotriphosphate) binds to HRH3 protein] Histamine results in increased activity of HRH3 protein clobenpropit inhibits the reaction [[Methylhistamines binds to and results in increased activity of HRH3 protein] which results in increased transport of Calcium] Methylhistamines binds to and results in increased activity of HRH3 protein [Methylhistamines binds to and results in increased activity of HRH3 protein] which results in increased transport of Calcium 3-fluoro-3-(3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl)-N-(2-methylpropyl)cyclobutanecarboxamide inhibits the reaction [N- methylhistamine binds to HRH3 protein] N-ethyl-3-fluoro-3-(3-fluoro-4-(pyrrolidinylmethyl)phenyl)cyclobutanecarboxamide inhibits the reaction [N-methylhistamine binds to HRH3 protein] N-methylhistamine binds to and results in increased activity of HRH3 protein N-methylhistamine binds to HRH3 protein N,N-dimethylhistamine binds to and results in increased activity of HRH3 protein ICAM1 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein] 4-methylhistamine inhibits the reaction [Lipopolysaccharides results in increased expression of ICAM1 protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of ICAM1 protein]] Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein] Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of ICAM1 protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]]

UST College of Science Department of Biological Sciences 48

Ranitidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of ICAM1 protein]] IFNG 4-methylhistamine affects the expression of IFNG protein 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein] alpha-methylhistamine affects the expression of IFNG protein Cimetidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Histamine affects the expression of IFNG protein [Histamine binds to and results in increased activity of HRH2 protein] which results in decreased expression of IFNG mRNA [Histamine co-treated with Ionomycin co-treated with Tetradecanoylphorbol Acetate] results in increased expression of IFNG mRNA Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein] Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG mRNA] Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG protein] Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IFNG mRNA] Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IFNG protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IFNG protein]] HRH2 protein promotes the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG mRNA]] HRH2 protein promotes the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG protein]] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of IFNG protein]] IL10 4-methylhistamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] Terfenadine inhibits the reaction [Histamine results in increased expression of IL10 protein] IL12A 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] Cyclic AMP promotes the reaction [[Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12A protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] Histamine results in decreased expression of IL12A mRNA Histamine results in decreased expression of IL12A protein [Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12A protein [Histamine results in increased activity of HRH4 protein] which results in decreased expression of IL12A protein Histamine results in increased expression of IL12A protein HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] HRH2 protein promotes the reaction [Histamine results in decreased expression of IL12A protein] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Ranitidine inhibits the reaction [Histamine results in decreased expression of IL12A protein]

UST College of Science Department of Biological Sciences 49

U 0126 inhibits the reaction [[Histamine results in increased activity of HRH4 protein] which results in decreased expression of IL12A protein] IL12B 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] Cyclic AMP promotes the reaction [[Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12B protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] Histamine results in decreased expression of IL12B mRNA Histamine results in decreased expression of IL12B protein [Histamine results in increased activity of HRH2 protein] which results in decreased expression of IL12B protein [Histamine results in increased activity of HRH4 protein] which results in decreased expression of IL12B protein Histamine results in increased expression of IL12B protein HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] HRH2 protein promotes the reaction [Histamine results in decreased expression of IL12B protein] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Ranitidine inhibits the reaction [Histamine results in decreased expression of IL12B protein] U 0126 inhibits the reaction [[Histamine results in increased activity of HRH4 protein] which results in decreased expression of IL12B protein] IL16 alpha-methylhistamine results in increased expression of IL16 protein HRH4 protein promotes the reaction [alpha-methylhistamine results in increased expression of IL16 protein] Cimetidine inhibits the reaction [HRH2 protein promotes the reaction [Histamine results in increased expression of IL16 protein]] Histamine results in increased expression of IL16 protein HRH2 protein promotes the reaction [Histamine results in increased expression of IL16 protein] thioperamide inhibits the reaction [Histamine results in increased expression of IL16 protein] IL18 4-methylhistamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein] 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein] 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein] 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of TNF protein] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein] Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein] Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein] Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]] Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein] Histamine results in increased expression of IL18 protein HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] HRH2 protein affects the reaction [Histamine results in increased expression of IL18 protein] [IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]]

UST College of Science Department of Biological Sciences 50

[IL12A protein binds to IL12B protein] inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide inhibits the reaction [Histamine results in increased expression of IL18 protein] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in decreased expression of IL10 protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of ICAM1 protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of IFNG protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of [IL12A protein binds to IL12B protein]]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased IL1B expression of IL1B protein]] IL1B protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] [Histamine co-treated with Ionomycin co-treated with Tetradecanoylphorbol Acetate] results in decreased expression of IL2 IL2 mRNA Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL2 protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL2 protein]] Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL4 IL4 protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of IL4 protein]] IL4 protein results in increased susceptibility to Histamine IL6 6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide results in increased expression of IL6 protein HRH1 protein promotes the reaction [6-((2-(4-imidazolyl)ethyl)amino)heptanoic acid 4-toluidide results in increased expression of IL6 protein] alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased expression of IL6 protein]] Calcimycin inhibits the reaction [Calcium promotes the reaction [Histamine results in increased expression of IL6 protein]] Calcium promotes the reaction [Histamine results in increased expression of IL6 protein] Diphenhydramine inhibits the reaction [Histamine results in increased expression of IL6 protein] Edetic Acid inhibits the reaction [Calcium promotes the reaction [Histamine results in increased expression of IL6 protein]] fexofenadine inhibits the reaction [Histamine results in increased expression of IL6 protein] Glycyrrhizic Acid inhibits the reaction [Histamine results in increased expression of IL6 mRNA] Glycyrrhizic Acid inhibits the reaction [Histamine results in increased secretion of IL6 protein] Histamine results in increased expression of IL6 mRNA Histamine results in increased expression of IL6 protein Histamine results in increased secretion of IL6 protein HRH1 protein promotes the reaction [Histamine results in increased expression of IL6 protein] Lipopolysaccharides promotes the reaction [Histamine results in increased expression of IL6 protein] prolinedithiocarbamate inhibits the reaction [Histamine results in increased expression of IL6 mRNA] prolinedithiocarbamate inhibits the reaction [Histamine results in increased secretion of IL6 protein] TNF protein promotes the reaction [Histamine results in increased expression of IL6 protein] Astemizole inhibits the reaction [Histamine results in decreased activity of [KCNQ2 protein co-treated with KCNQ3 protein co- KCNQ2 treated with HRH1 protein]] Histamine results in decreased activity of [KCNQ2 protein co-treated with KCNQ3 protein co-treated with HRH1 protein] Dinoprostone promotes the reaction [Histamine promotes the reaction [Serotonin promotes the reaction [KNG1 protein results KNG1 in increased secretion of TAC1 protein]]] Flurbiprofen inhibits the reaction [Histamine promotes the reaction [[KNG1 protein co-treated with Serotonin] results in increased secretion of CALCA protein]] Flurbiprofen inhibits the reaction [[KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased abundance of Dinoprostone] Flurbiprofen inhibits the reaction [[KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased secretion of CALCA protein] Flurbiprofen inhibits the reaction [[Serotonin co-treated with Histamine] promotes the reaction [KNG1 protein results in increased abundance of Dinoprostone]] Histamine promotes the reaction [[KNG1 protein co-treated with Serotonin] results in increased secretion of CALCA protein] Histamine promotes the reaction [Serotonin promotes the reaction [KNG1 protein results in increased secretion of TAC1 protein]] ITGA2 protein results in increased susceptibility to [KNG1 protein modified form co-treated with TAC1 protein modified form co-treated with Serotonin co-treated with Dinoprostone co-treated with Histamine] [KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased abundance of Dinoprostone

UST College of Science Department of Biological Sciences 51

[KNG1 protein co-treated with Serotonin co-treated with Histamine] results in increased secretion of CALCA protein [Serotonin co-treated with Histamine] promotes the reaction [KNG1 protein results in increased abundance of Dinoprostone] LTC4S LTC4S polymorphism results in decreased susceptibility to Histamine MAOB MAOB protein affects the metabolism of tele-methylhistamine MAOB protein results in increased oxidation of tele-methylhistamine MAPK1 Famotidine inhibits the reaction [Histamine results in increased phosphorylation of MAPK1 protein] [Histamine binds to and results in increased activity of HRH4 protein] which results in increased phosphorylation of MAPK1 protein Histamine results in increased phosphorylation of and results in increased activity of MAPK1 protein Histamine results in increased phosphorylation of MAPK1 protein Hydrogen Peroxide promotes the reaction [Histamine results in increased phosphorylation of MAPK1 protein] Pyrilamine inhibits the reaction [Histamine results in increased phosphorylation of and results in increased activity of MAPK1 protein] RTKI cpd inhibits the reaction [Histamine results in increased phosphorylation of MAPK1 protein] MAPK3 Famotidine inhibits the reaction [Histamine results in increased phosphorylation of MAPK3 protein] [Histamine binds to and results in increased activity of HRH4 protein] which results in increased phosphorylation of MAPK3 protein Histamine results in increased phosphorylation of and results in increased activity of MAPK3 protein Histamine results in increased phosphorylation of MAPK3 protein Hydrogen Peroxide promotes the reaction [Histamine results in increased phosphorylation of MAPK3 protein] Pyrilamine inhibits the reaction [Histamine results in increased phosphorylation of and results in increased activity of MAPK3 protein] RTKI cpd inhibits the reaction [Histamine results in increased phosphorylation of MAPK3 protein] MAPK8 Histamine inhibits the reaction [decamethrin results in decreased nitrosation of MAPK8 protein] NFKB1 Histamine affects the localization of NFKB1 protein Histamine promotes the reaction [Lipopolysaccharides affects the localization of NFKB1 protein] Histamine promotes the reaction [TNF protein affects the localization of NFKB1 protein] NFKBIA Glycyrrhizic Acid inhibits the reaction [Histamine results in increased phosphorylation of NFKBIA protein] Histamine results in increased phosphorylation of NFKBIA protein NGF [Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein Pyrilamine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein] Triprolidine inhibits the reaction [[Histamine binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein] [histaprodifen binds to and results in increased activity of HRH1 protein] which results in increased expression of NGF protein alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased NOS2 expression of NOS2 protein]] Deoxyglucose promotes the reaction [STO 609 inhibits the reaction [Histamine results in increased phosphorylation of NOS2 protein]] Histamine results in increased phosphorylation of NOS2 protein NOS2 protein affects the susceptibility to Histamine [PRKAA1 protein co-treated with PRKAA2 protein] affects the reaction [Histamine results in increased phosphorylation of NOS2 protein] STK11 protein promotes the reaction [Histamine results in increased phosphorylation of NOS2 protein] STO 609 inhibits the reaction [Histamine results in increased phosphorylation of NOS2 protein] NOS3 Histamine inhibits the reaction [decamethrin results in decreased expression of NOS3 protein] adenosine-3',5'-cyclic phosphorothioate inhibits the reaction [[Histamine results in increased abundance of Cyclic AMP] which NPPA results in decreased expression of NPPA protein] Cimetidine inhibits the reaction [[Histamine results in increased abundance of Cyclic AMP] which results in decreased expression of NPPA protein] [Histamine results in increased abundance of Cyclic AMP] which results in decreased expression of NPPA protein HRH2 protein promotes the reaction [[Histamine results in increased abundance of Cyclic AMP] which results in decreased expression of NPPA protein] Staurosporine inhibits the reaction [[Histamine results in increased abundance of Cyclic AMP] which results in decreased expression of NPPA protein] PDE4B Cimetidine inhibits the reaction [Histamine results in increased expression of PDE4B mRNA] Histamine results in increased expression of PDE4B mRNA PENK Cycloheximide inhibits the reaction [Histamine results in increased expression of PENK mRNA] Histamine results in increased expression of PENK mRNA PPP3CA Histamine results in increased expression of PPP3CA protein PRKCD epigallocatechin gallate inhibits the reaction [Histamine results in increased phosphorylation of PRKCD protein] Histamine results in increased phosphorylation of and affects the localization of PRKCD protein

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Quercetin inhibits the reaction [Histamine results in increased phosphorylation of and affects the localization of PRKCD protein] [SC 560 binds to and results in decreased activity of PTGS1 protein] promotes the reaction [Histamine results in increased PTGS1 secretion of Acids] alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased PTGS2 expression of PTGS2 protein]] Histamine promotes the reaction [TLR2 results in increased expression of PTGS2] Histamine promotes the reaction [[TLR2 results in increased expression of PTGS2] which results in increased chemical synthesis of Dinoprostone] HRH1 affects the reaction [Histamine promotes the reaction [TLR2 results in increased expression of PTGS2]] alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased RELA expression of RELA protein]] Glycyrrhizic Acid inhibits the reaction [Histamine results in increased phosphorylation of RELA protein] Histamine affects the localization of RELA protein Histamine promotes the reaction [Lipopolysaccharides affects the localization of RELA protein] Histamine promotes the reaction [TNF protein affects the localization of RELA protein] Histamine results in increased activity of [CXCL8 protein binds to RELA protein] Histamine results in increased phosphorylation of RELA protein SLC18A2 Histamine binds to SLC18A2 protein Rabeprazole promotes the reaction [SLC18A2 protein results in increased secretion of Histamine] SLC18A2 protein alternative form affects the transport of Histamine SLC18A2 protein results in increased secretion of Histamine SLC22A3 Corticosterone inhibits the reaction [SLC22A3 protein results in increased transport of Histamine] Estradiol inhibits the reaction [SLC22A3 protein results in increased transport of Histamine] Histamine inhibits the reaction [SLC22A3 protein results in increased uptake of 1-Methyl-4-phenylpyridinium] pseudoisocyanine inhibits the reaction [SLC22A3 protein results in increased transport of Histamine] Serotonin inhibits the reaction [SLC22A3 protein results in increased transport of Histamine] SLC22A3 protein polymorphism affects the uptake of Histamine SLC22A3 protein results in increased transport of Histamine SLC22A3 protein results in increased uptake of Histamine SLC29A4 SLC29A4 protein results in increased uptake of Histamine SLC47A1 Histamine inhibits the reaction [SLC47A1 protein results in increased uptake of 1-Methyl-4-phenylpyridinium] SLC47A2 Histamine inhibits the reaction [SLC47A2 protein results in increased uptake of 1-Methyl-4-phenylpyridinium] SOD1 Histamine affects the expression of SOD1 protein SST SST protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] SST protein inhibits the reaction [GAST protein results in increased secretion of Histamine] STAT6 Histamine results in increased expression of STAT6 protein TAAR1 Histamine results in increased activity of TAAR1 protein [Histamine results in increased activity of TAAR1 protein] which results in increased abundance of Cyclic AMP Dinoprostone promotes the reaction [Histamine promotes the reaction [Serotonin promotes the reaction [KNG1 protein results TAC1 in increased secretion of TAC1 protein]]] Histamine promotes the reaction [Serotonin promotes the reaction [KNG1 protein results in increased secretion of TAC1 protein]] ITGA2 protein results in increased susceptibility to [KNG1 protein modified form co-treated with TAC1 protein modified form co-treated with Serotonin co-treated with Dinoprostone co-treated with Histamine] Nedocromil inhibits the reaction [TAC1 protein results in increased secretion of Histamine] TAC1 protein results in increased secretion of Histamine Theophylline inhibits the reaction [TAC1 protein results in increased secretion of Histamine] TH Cycloheximide inhibits the reaction [Histamine results in increased expression of TH mRNA] Histamine results in increased expression of TH mRNA TLR2 Histamine promotes the reaction [TLR2 results in increased expression of PTGS2] Histamine promotes the reaction [[TLR2 results in increased expression of PTGS2] which results in increased chemical synthesis of Dinoprostone] HRH1 affects the reaction [Histamine promotes the reaction [TLR2 results in increased expression of PTGS2]] TNF 4-methylhistamine inhibits the reaction [IL18 protein results in increased expression of TNF protein] 4-methylhistamine inhibits the reaction [Lipopolysaccharides results in increased expression of TNF protein] alpha-methylhistamine inhibits the reaction [Histamine H3 Antagonists inhibits the reaction [Valproic Acid results in increased expression of TNF protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] Famotidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of TNF protein]] Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein] Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of TNF protein]

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Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of TNF protein] Histamine promotes the reaction [TNF protein affects the localization of NFKB1 protein] Histamine promotes the reaction [TNF protein affects the localization of RELA protein] HRH2 protein affects the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] HRH2 protein affects the reaction [Histamine inhibits the reaction [[Tetradecanoylphorbol Acetate co-treated with Ionomycin] results in increased expression of TNF protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [IL18 protein results in increased expression of TNF protein]] Ranitidine inhibits the reaction [Histamine inhibits the reaction [Lipopolysaccharides results in increased expression of TNF protein]] TNF protein inhibits the reaction [ADCYAP1 protein results in increased secretion of Histamine] TNF protein inhibits the reaction [GAST protein results in increased secretion of Histamine] TNF protein promotes the reaction [Histamine results in increased expression of CCL2 protein] TNF protein promotes the reaction [Histamine results in increased expression of CXCL8 protein] TNF protein promotes the reaction [Histamine results in increased expression of IL6 protein] Benzocaine AR butamben binds to AR protein (Butamben) CCL4 Benzocaine results in increased expression of CCL4 protein [Benzocaine co-treated with Ionomycin co-treated with Tetradecanoylphorbol Acetate] results in decreased expression of IFNG IFNG protein [Benzocaine co-treated with Ionomycin co-treated with Tetradecanoylphorbol Acetate] results in decreased expression of IL10 IL10 protein IL18 Benzocaine results in increased activity of IL18 protein IL1A Benzocaine results in increased activity of IL1A protein [Benzocaine co-treated with Ionomycin co-treated with Tetradecanoylphorbol Acetate] results in decreased expression of IL2 IL2 protein NCOA2 butamben promotes the reaction [NR1I2.L protein binds to NCOA2 protein] NCOA3 butamben promotes the reaction [NR1I2.L protein binds to NCOA3 protein] NR1I2 butamben binds to and results in increased activity of NR1I2 protein NR1I2.L butamben binds to and results in increased activity of NR1I2.L protein butamben promotes the reaction [NR1I2.L protein binds to MED1 protein] butamben promotes the reaction [NR1I2.L protein binds to NCOA1 protein] butamben promotes the reaction [NR1I2.L protein binds to NCOA2 protein] butamben promotes the reaction [NR1I2.L protein binds to NCOA3 protein] NR1I2.S butamben binds to and results in decreased activity of NR1I2.S protein butamben promotes the reaction [NR1I2.S protein binds to MED1 protein] butamben promotes the reaction [NR1I2.S protein binds to NCOA1 protein] Fluoxetine AANAT Fluoxetine results in increased expression of AANAT mRNA ACACA Fluoxetine results in increased expression of ACACA mRNA ACP5 Fluoxetine inhibits the reaction [TNFSF11 protein results in increased expression of ACP5 mRNA] ADAM10 Fluoxetine results in increased expression of ADAM10 mRNA ADARB1 protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased ADARB1 phosphorylation of MAPK1 protein]] ADARB1 protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK3 protein]] ADARB1 protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 mRNA] ADARB1 protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 protein] Fluoxetine results in increased expression of ADARB1 mRNA Fluoxetine results in increased expression of ADARB1 protein HTR2B protein promotes the reaction [Fluoxetine results in increased expression of ADARB1 mRNA] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of ADARB1 protein] ADCY8 Fluoxetine results in decreased expression of ADCY8 mRNA ADORA1 [Fluoxetine co-treated with Caffeine deficiency] results in increased expression of ADORA1 mRNA Fluoxetine inhibits the reaction [[beta-apocarotenoid-14',13'-dioxygenase results in increased activity of ADORA1 protein] promotes the reaction [[KCNJ3 protein co-treated with KCNJ6 protein] results in increased transport of Potassium]] AGO2 Fluoxetine affects the expression of AGO2 mRNA AMPD2 Fluoxetine results in increased expression of AMPD2 mRNA ANO3 Fluoxetine results in decreased expression of ANO3 mRNA AP1S1 Fluoxetine results in decreased expression of AP1S1 mRNA AP2A2 Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2A2 protein] AP2B1 Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2B1 protein] AP2M1 Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2M1 protein] ARC Fluoxetine results in decreased expression of ARC mRNA Fluoxetine results in increased expression of ARC mRNA

UST College of Science Department of Biological Sciences 54

ARL4D Fluoxetine results in increased expression of ARL4D mRNA ARNTL Fluoxetine results in increased expression of ARNTL mRNA ARRB2 ARRB2 protein promotes the reaction [Fluoxetine results in increased expression of CREB1 protein] ARRB2 protein promotes the reaction [Fluoxetine results in increased expression of MAPK3 protein] ARRB2 protein results in increased susceptibility to Fluoxetine Fluoxetine inhibits the reaction [Corticosterone results in decreased expression of ARRB2 mRNA] ASAH1 Fluoxetine results in increased expression of ASAH1 mRNA ASNS Fluoxetine results in increased expression of ASNS mRNA ATP2A2 Fluoxetine results in increased expression of ATP2A2 mRNA AVP Fluoxetine promotes the reaction [Dinoprostone results in increased expression of AVP mRNA] Fluoxetine results in decreased expression of AVP mRNA BAD Fluoxetine results in increased expression of BAD mRNA BAIAP2 Fluoxetine results in decreased expression of BAIAP2 mRNA BCL11B Fluoxetine results in decreased expression of BCL11B mRNA BCL2 BCL2 protein results in decreased susceptibility to Fluoxetine Fluoxetine results in decreased expression of BCL2 mRNA Fluoxetine results in decreased expression of BCL2 protein BCL2L1 Fluoxetine affects the expression of BCL2L1 mRNA Fluoxetine results in decreased expression of BCL2L1 protein Fluoxetine results in increased expression of BCL2L1 mRNA Fluoxetine results in increased expression of BCL2L1 protein BDNF BDNF gene polymorphism affects the susceptibility to Fluoxetine BDNF protein mutant form results in decreased susceptibility to Fluoxetine BDNF protein results in increased susceptibility to Fluoxetine Fluoxetine affects the expression of BDNF mRNA Fluoxetine affects the reaction [sodium arsenate affects the expression of BDNF protein] [Fluoxetine co-treated with Amantadine] results in increased expression of BDNF mRNA [Fluoxetine co-treated with Ketanserin] results in increased expression of BDNF mRNA Fluoxetine inhibits the reaction [Reserpine results in decreased expression of BDNF protein] Fluoxetine results in decreased expression of BDNF mRNA Fluoxetine results in increased expression of BDNF mRNA Fluoxetine results in increased expression of BDNF mRNA alternative form Fluoxetine results in increased expression of BDNF protein BECN1 Fluoxetine results in increased expression of BECN1 protein BET1L Fluoxetine results in increased expression of BET1L mRNA BMPR2 Fluoxetine inhibits the reaction [Monocrotaline results in decreased expression of BMPR2 mRNA] CACNA1H Fluoxetine results in decreased expression of CACNA1H mRNA CAMK4 Fluoxetine results in decreased expression of CAMK4 mRNA Fluoxetine results in increased phosphorylation of and results in increased activity of CAMK4 protein CARTPT Fluoxetine results in decreased expression of CARTPT protein CASP1 Fluoxetine results in increased expression of CASP1 mRNA CASP3 Fluoxetine inhibits the reaction [Monocrotaline results in decreased expression of CASP3 protein] Fluoxetine promotes the reaction [1-Methyl-4-phenylpyridinium results in increased activity of CASP3 protein] Fluoxetine results in increased activity of CASP3 protein Fluoxetine results in increased cleavage of CASP3 protein Palmitic Acid promotes the reaction [Fluoxetine results in increased activity of CASP3 protein] CASP7 Fluoxetine results in increased activity of CASP7 protein Palmitic Acid promotes the reaction [Fluoxetine results in increased activity of CASP7 protein] CASP8 Fluoxetine results in increased activity of CASP8 protein CASP9 Fluoxetine results in increased activity of CASP9 protein CAT Fluoxetine results in decreased activity of CAT protein Fluoxetine results in increased expression of CAT protein [Ibuprofen co-treated with Diclofenac co-treated with Fluoxetine] results in decreased expression of CAT mRNA Resveratrol inhibits the reaction [Fluoxetine results in decreased activity of CAT protein] CCK Fluoxetine results in decreased expression of CCK mRNA CCL2 Fluoxetine results in decreased secretion of CCL2 protein CCL5 Fluoxetine inhibits the reaction [TNF protein results in increased expression of CCL5 protein] CCN3 Fluoxetine results in decreased expression of CCN3 mRNA CCNA2 Fluoxetine results in decreased expression of CCNA2 mRNA Fluoxetine results in decreased expression of CCNA2 protein CCNB1 Fluoxetine results in decreased expression of CCNB1 mRNA CCND1 Fluoxetine results in decreased expression of CCND1 mRNA Fluoxetine results in increased expression of CCND1 mRNA

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Fluoxetine results in increased expression of CCND1 protein N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [Fluoxetine results in increased expression of CCND1 mRNA] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [Fluoxetine results in increased expression of CCND1 protein] CCND3 Fluoxetine results in decreased expression of CCND3 mRNA CCNE1 Fluoxetine affects the expression of CCNE1 mRNA [Fluoxetine results in decreased activity of CKS1B protein] which results in decreased degradation of CCNE1 protein Fluoxetine results in decreased expression of CCNE1 mRNA CCNG2 Fluoxetine results in increased expression of CCNG2 mRNA CDK5 Fluoxetine results in decreased expression of CDK5 mRNA CDKN1A Fluoxetine affects the expression of CDKN1A mRNA [Fluoxetine results in decreased activity of CKS1B protein] which results in decreased degradation of CDKN1A protein Fluoxetine results in increased expression of CDKN1A mRNA CDKN1B Fluoxetine affects the expression of CDKN1B mRNA [Fluoxetine results in decreased activity of CKS1B protein] which results in decreased degradation of CDKN1B protein Fluoxetine results in increased expression of CDKN1B mRNA CDKN2A Fluoxetine results in increased expression of CDKN2A mRNA CDKN2B Fluoxetine results in increased expression of CDKN2B mRNA CES1 Fluoxetine inhibits the reaction [CES1 protein results in increased hydrolysis of 4-nitrophenyl acetate] Fluoxetine inhibits the reaction [CES1 protein results in increased hydrolysis of Methylphenidate] CHRNA5 Fluoxetine results in decreased expression of CHRNA5 mRNA CLOCK Fluoxetine results in increased expression of CLOCK mRNA CNKSR2 Fluoxetine results in decreased expression of CNKSR2 mRNA CNR1 [Fluoxetine affects the susceptibility to Ethanol] which affects the expression of CNR1 mRNA Fluoxetine results in decreased expression of and results in decreased phosphorylation of CNR1 protein Fluoxetine results in decreased expression of CNR1 mRNA CPG21 Fluoxetine results in decreased expression of CPG21 mRNA CREB1 ARRB2 protein promotes the reaction [Fluoxetine results in increased expression of CREB1 protein] Fluoxetine affects the reaction [sodium arsenate affects the expression of CREB1 protein] [Fluoxetine co-treated with Olanzapine] results in decreased phosphorylation of CREB1 protein Fluoxetine results in decreased phosphorylation of and results in decreased activity of CREB1 protein Fluoxetine results in increased expression of CREB1 mRNA Fluoxetine results in increased expression of CREB1 protein Fluoxetine results in increased phosphorylation of and results in increased activity of CREB1 protein Fluoxetine results in increased phosphorylation of and results in increased localization of CREB1 protein Fluoxetine results in increased phosphorylation of CREB1 protein N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [Fluoxetine results in increased phosphorylation of and results in increased activity of CREB1 protein] staurosporine aglycone inhibits the reaction [Fluoxetine results in increased phosphorylation of CREB1 protein] CRH Fluoxetine results in decreased expression of CRH mRNA Fluoxetine results in increased expression of CRH mRNA CRHR1 Fluoxetine results in decreased expression of CRHR1 mRNA Fluoxetine results in increased expression of CRHR1 mRNA CRY1 Fluoxetine affects the expression of CRY1 mRNA CRY2 Fluoxetine results in decreased expression of CRY2 mRNA CSF1R [9,10-Dimethyl-1,2-benzanthracene co-treated with Fluoxetine] affects the expression of CSF1R protein [9,10-Dimethyl-1,2-benzanthracene co-treated with Raloxifene Hydrochloride co-treated with Fluoxetine] affects the expression of CSF1R protein CTNNB1 [Fluoxetine co-treated with Ketanserin] results in increased expression of CTNNB1 mRNA Fluoxetine inhibits the reaction [Monocrotaline results in decreased expression of CTNNB1 protein] CTSK Fluoxetine inhibits the reaction [TNFSF11 protein results in increased expression of CTSK mRNA] CXCL10 Fluoxetine results in decreased secretion of CXCL10 protein CYP11A1 Fluoxetine results in decreased expression of CYP11A1 mRNA Fluoxetine results in increased expression of CYP11A1 mRNA Resveratrol inhibits the reaction [Fluoxetine results in decreased expression of CYP11A1 mRNA] CYP19A1 Fluoxetine results in decreased activity of CYP19A1 protein CYP26B1 Fluoxetine results in decreased expression of CYP26B1 mRNA CYP2C19 CYP2C19 gene polymorphism affects the metabolism of Fluoxetine CYP2C19 protein affects the metabolism of Fluoxetine CYP2C19 protein results in increased metabolism of Fluoxetine Fluoxetine inhibits the reaction [CYP2C19 protein results in increased chemical synthesis of 4-hydroxymephenytoin] Fluoxetine inhibits the reaction [CYP2C19 protein results in increased hydroxylation of Mephenytoin]

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Fluoxetine inhibits the reaction [CYP2C19 protein results in increased metabolism of Mephenytoin] Fluoxetine results in decreased activity of CYP2C19 protein Omeprazole inhibits the reaction [CYP2C19 protein results in increased metabolism of Fluoxetine] CYP2C8 Fluoxetine results in decreased activity of CYP2C8 protein Torsemide inhibits the reaction [Fluoxetine results in decreased activity of CYP2C8 protein] CYP2C9 CYP2C9 affects the metabolism of Fluoxetine [CYP2C9 affects the metabolism of Fluoxetine] which results in increased chemical synthesis of norfluoxetine CYP2C9 gene polymorphism affects the abundance of Fluoxetine CYP2C9 protein affects the abundance of Fluoxetine CYP2C9 protein results in increased metabolism of Fluoxetine [CYP2C9 affects the metabolism of Fluoxetine] which results in increased chemical synthesis of norfluoxetine CYP2D22 CYP2D22 protein results in increased metabolism of Fluoxetine CYP2D6 CYP2D6 affects the metabolism of Fluoxetine [CYP2D6 affects the metabolism of Fluoxetine] which results in increased chemical synthesis of norfluoxetine CYP2D6 gene mutant form results in decreased metabolism of Fluoxetine CYP2D6 gene polymorphism affects the abundance of Fluoxetine CYP2D6 gene polymorphism affects the metabolism of Fluoxetine CYP2D6 protein affects the abundance of Fluoxetine CYP2D6 protein affects the metabolism of Fluoxetine CYP2D6 protein affects the susceptibility to Fluoxetine CYP2D6 protein results in decreased methylation of Fluoxetine CYP2D6 protein results in increased metabolism of Fluoxetine Fluoxetine inhibits the reaction [CYP2D6 protein results in increased metabolism of Tolterodine Tartrate] Fluoxetine results in decreased activity of CYP2D6 protein [Fluoxetine results in decreased activity of CYP2D6 protein] which results in decreased metabolism of Dextromethorphan [CYP2D6 affects the metabolism of Fluoxetine] which results in increased chemical synthesis of norfluoxetine CYP3A4 CYP3A4 protein results in increased metabolism of Fluoxetine Fluoxetine inhibits the reaction [CYP3A4 protein results in increased oxidation of and results in increased activity of Haloperidol] Fluoxetine results in decreased activity of CYP3A4 protein Troleandomycin inhibits the reaction [CYP3A4 protein results in increased metabolism of Fluoxetine] norfluoxetine inhibits the reaction [CYP3A4 protein results in increased oxidation of and results in increased activity of Haloperidol] Fluoxetine inhibits the reaction [CYP3A5 protein results in increased oxidation of and results in increased activity of CYP3A5 Haloperidol] norfluoxetine inhibits the reaction [CYP3A5 protein results in increased oxidation of and results in increased activity of Haloperidol] DBH DBH protein promotes the reaction [Fluoxetine results in increased abundance of Serotonin] DBH protein results in increased susceptibility to Fluoxetine Fluoxetine results in increased expression of DBH mRNA DCLK1 Fluoxetine results in increased expression of DCLK1 mRNA DDN Fluoxetine results in decreased expression of DDN mRNA DEPP1 Fluoxetine results in increased expression of DEPP1 mRNA DGAT1 Fluoxetine results in increased expression of DGAT1 mRNA DICER1 Fluoxetine affects the expression of DICER1 mRNA DIO3 Fluoxetine results in increased activity of DIO3 protein Fluoxetine results in increased expression of DIO3 mRNA SB 203580 inhibits the reaction [Fluoxetine results in increased expression of DIO3 mRNA] U 0126 inhibits the reaction [Fluoxetine results in increased activity of DIO3 protein] U 0126 inhibits the reaction [Fluoxetine results in increased expression of DIO3 mRNA] DRD2 Fluoxetine affects the expression of DRD2 Fluoxetine results in decreased expression of DRD2 mRNA DRD3 DRD3 protein results in increased susceptibility to [Olanzapine co-treated with Fluoxetine] DROSHA Fluoxetine affects the expression of DROSHA mRNA DUSP8 Fluoxetine results in increased expression of DUSP8 mRNA EEF2 Fluoxetine results in increased phosphorylation of EEF2 protein [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNA1 EFNA1 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNA2 EFNA2 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNA3 EFNA3 mRNA

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[Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNA5 EFNA5 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNB1 EFNB1 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in increased expression of EFNB3 EFNB3 mRNA [Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and EGFR results in increased activity of EGFR protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 protein Fluoxetine results in increased phosphorylation of EGFR protein N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide inhibits the reaction [Fluoxetine results in increased phosphorylation of EGFR protein] RTKI cpd inhibits the reaction [Fluoxetine results in increased phosphorylation of EGFR protein] EGR1 [Fluoxetine co-treated with Methylphenidate] results in increased expression of EGR1 mRNA Fluoxetine promotes the reaction [Methylphenidate results in increased expression of EGR1 mRNA] Fluoxetine results in increased expression of EGR1 mRNA EGR3 Fluoxetine results in decreased expression of EGR3 mRNA EGR4 Fluoxetine results in decreased expression of EGR4 mRNA EIF4E Fluoxetine results in increased phosphorylation of EIF4E protein EVI2A Fluoxetine results in increased expression of EVI2A mRNA FAAH [Fluoxetine affects the susceptibility to Ethanol] which affects the expression of FAAH mRNA FABP1 Fluoxetine results in increased expression of FABP1 mRNA FGF2 [Fluoxetine co-treated with Olanzapine] results in increased expression of FGF2 mRNA FHL2 Fluoxetine results in decreased expression of FHL2 mRNA FMOD Fluoxetine results in decreased expression of FMOD mRNA FNDC4 Fluoxetine results in increased expression of FNDC4 mRNA FOS Fluoxetine affects the expression of FOS protein [Fluoxetine co-treated with Methylphenidate] results in increased expression of FOS mRNA [Fluoxetine co-treated with Olanzapine] results in decreased expression of FOS protein Fluoxetine inhibits the reaction [Fenfluramine results in increased expression of FOS protein] Fluoxetine promotes the reaction [Methylphenidate results in increased expression of FOS mRNA] Fluoxetine results in decreased expression of FOS mRNA Fluoxetine results in increased expression of FOS mRNA Fluoxetine results in increased expression of FOS protein N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea inhibits the reaction [Fluoxetine results in increased expression of FOS mRNA] RTKI cpd inhibits the reaction [Fluoxetine results in increased expression of FOS mRNA] SB 206553 inhibits the reaction [Fluoxetine results in increased expression of FOS protein] U 0126 inhibits the reaction [Fluoxetine results in increased expression of FOS mRNA] U 0126 inhibits the reaction [Fluoxetine results in increased expression of FOS protein] FOSB Fluoxetine results in increased expression of FOSB mRNA Fluoxetine results in increased expression of FOSB protein N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea inhibits the reaction [Fluoxetine results in increased expression of FOSB mRNA] RTKI cpd inhibits the reaction [Fluoxetine results in increased expression of FOSB mRNA] RTKI cpd inhibits the reaction [Fluoxetine results in increased expression of FOSB protein] U 0126 inhibits the reaction [Fluoxetine results in increased expression of FOSB mRNA] U 0126 inhibits the reaction [Fluoxetine results in increased expression of FOSB protein] GABRD Fluoxetine results in decreased expression of GABRD mRNA GAD1 Fluoxetine results in increased expression of GAD1 mRNA GAD2 Fluoxetine results in decreased expression of GAD2 mRNA Fluoxetine results in increased expression of GAD2 protein GAL Fluoxetine results in increased expression of GAL mRNA GAP43 Fluoxetine results in decreased expression of GAP43 mRNA GCK Fluoxetine results in increased activity of GCK protein GDNF Fluoxetine results in increased expression of GDNF mRNA U 0126 inhibits the reaction [Fluoxetine results in increased expression of GDNF mRNA] GFAP Fluoxetine results in increased expression of GFAP mRNA

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Fluoxetine results in increased expression of GFAP protein GFAP protein results in increased susceptibility to Fluoxetine GJA1 Fluoxetine results in increased expression of GJA1 protein norfluoxetine results in increased expression of GJA1 mRNA GLO1 GLO1 protein results in increased susceptibility to Fluoxetine GNAI2 Fluoxetine inhibits the reaction [Corticosterone results in decreased expression of GNAI2 mRNA] Fluoxetine results in decreased expression of GNAI2 mRNA GNAQ Fluoxetine results in increased expression of GNAQ mRNA GNAS Fluoxetine results in decreased expression of GNAS mRNA Fluoxetine results in increased expression of GNAS mRNA GNB2 Fluoxetine results in decreased expression of GNB2 mRNA GPATCH4 Fluoxetine results in increased expression of GPATCH4 mRNA GPX3 Fluoxetine results in increased expression of GPX3 mRNA GRAMD3 Fluoxetine results in increased expression of GRAMD3 mRNA GRIA1 Fluoxetine affects the expression of GRIA1 protein Fluoxetine affects the phosphorylation of GRIA1 protein PPP1R1B protein promotes the reaction [Fluoxetine affects the phosphorylation of GRIA1 protein] GRIA2 [Fluoxetine affects the susceptibility to Ethanol] which affects the expression of GRIA2 mRNA Fluoxetine results in increased expression of GRIA2 protein GRIA4 [Fluoxetine affects the susceptibility to Ethanol] which affects the expression of GRIA4 mRNA GRIK2 ADARB1 protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 mRNA] ADARB1 protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 protein] Fluoxetine results in increased expression of GRIK2 mRNA Fluoxetine results in increased expression of GRIK2 protein HTR2B protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 mRNA] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 protein] GRIN2A Fluoxetine results in increased expression of GRIN2A protein GRM3 [Fluoxetine affects the susceptibility to Ethanol] which affects the expression of GRM3 mRNA GSK3B Fluoxetine results in increased expression of GSK3B protein HAPLN2 Fluoxetine results in decreased expression of HAPLN2 mRNA HDAC5 HDAC5 protein results in increased susceptibility to Fluoxetine HES1 Fluoxetine results in increased expression of HES1 mRNA Fluoxetine results in increased expression of HES1 protein HES5 Fluoxetine results in increased expression of HES5 mRNA Fluoxetine results in increased expression of HES5 protein HMGCS1 Fluoxetine results in increased expression of HMGCS1 mRNA HPCAL1 Fluoxetine results in increased expression of HPCAL1 mRNA HRH1 HRH1 protein results in increased susceptibility to [Olanzapine co-treated with Fluoxetine] HSPB8 Fluoxetine results in increased expression of HSPB8 mRNA HTR1A Fluoxetine affects the expression of HTR1A [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of HTR1A mRNA Fluoxetine inhibits the reaction [8-Hydroxy-2-(di-n-propylamino)tetralin binds to and results in increased activity of HTR1A protein] Fluoxetine inhibits the reaction [HTR1A protein results in increased uptake of Serotonin] Fluoxetine inhibits the reaction [IFNA1 protein results in decreased expression of HTR1A mRNA] Fluoxetine inhibits the reaction [IFNA1 protein results in decreased expression of HTR1A protein] Fluoxetine results in decreased expression of HTR1A mRNA Fluoxetine results in increased expression of HTR1A mRNA HTR1A gene polymorphism results in increased susceptibility to Fluoxetine HTR1A promoter polymorphism affects the susceptibility to Fluoxetine HTR1A protein results in increased susceptibility to Fluoxetine N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [HTR1A protein results in increased susceptibility to Fluoxetine] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide promotes the reaction [Fluoxetine inhibits the reaction [HTR1A protein results in increased uptake of Serotonin]] HTR1B Fluoxetine affects the expression of HTR1B mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of HTR1B mRNA Fluoxetine results in decreased expression of HTR1B mRNA Fluoxetine results in increased expression of HTR1B mRNA HTR2A Fluoxetine affects the expression of HTR2A Fluoxetine results in decreased activity of HTR2A protein

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Fluoxetine results in increased expression of HTR2A mRNA HTR2A protein affects the susceptibility to Fluoxetine 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibits the reaction [[Fluoxetine results in HTR2B increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] bisindolylmaleimide I inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] bisindolylmaleimide I inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] Calcium promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] Calcium promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] Fluoxetine binds to and results in increased activity of HTR2B protein [Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK1 protein [[Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK1 protein] which results in increased expression of PLA2G4A protein [Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK3 protein [[Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK3 protein] which results in increased expression of PLA2G4A protein Fluoxetine promotes the reaction [mesulergine binds to HTR2B protein] Fluoxetine results in increased activity of HTR2B protein [Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein [Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein Fluoxetine results in increased expression of and results in increased activity of HTR2B protein [Fluoxetine results in increased expression of and results in increased activity of HTR2B protein] which results in increased metabolism of Glycogen Fluoxetine results in increased expression of HTR2B mRNA HTR2B protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK1 protein]] HTR2B protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK3 protein]] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of ADARB1 mRNA] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of ADARB1 protein] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 mRNA] HTR2B protein promotes the reaction [Fluoxetine results in increased expression of GRIK2 protein] N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] RTKI cpd inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] RTKI cpd inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] HTR2C Fluoxetine binds to and results in decreased activity of HTR2C protein Fluoxetine binds to and results in increased activity of HTR2C protein [Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 protein Fluoxetine binds to HTR2C protein [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of HTR2C mRNA Fluoxetine inhibits the reaction [Serotonin binds to and results in increased activity of HTR2C protein]

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[Fluoxetine results in increased abundance of Serotonin] which results in decreased expression of HTR2C mRNA Fluoxetine results in increased expression of HTR2C mRNA Fluoxetine results in increased expression of HTR2C mRNA alternative form norfluoxetine binds to HTR2C protein [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of HTR4 HTR4 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of HTR7 HTR7 mRNA ICAM5 Fluoxetine results in decreased expression of ICAM5 mRNA IFNG Fluoxetine results in increased expression of IFNG mRNA IGF2 Fluoxetine results in decreased expression of IGF2 mRNA IGFBP2 Fluoxetine results in decreased expression of IGFBP2 mRNA IL10 [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in increased expression of IL10 mRNA Fluoxetine results in increased expression of IL10 mRNA [Lipopolysaccharides co-treated with [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin]] results in increased expression of IL10 mRNA [Lipopolysaccharides co-treated with Fluoxetine] results in increased expression of IL10 mRNA pyrrolidine dithiocarbamic acid inhibits the reaction [[Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in increased expression of IL10 mRNA] pyrrolidine dithiocarbamic acid inhibits the reaction [Fluoxetine results in increased expression of IL10 mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] inhibits the reaction [Lipopolysaccharides results in IL12A increased expression of IL12A mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of IL12A mRNA Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of IL12A mRNA] Fluoxetine results in decreased expression of IL12A mRNA pyrrolidine dithiocarbamic acid inhibits the reaction [Fluoxetine results in decreased expression of IL12A mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] inhibits the reaction [Lipopolysaccharides results in IL1B increased expression of IL1B mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of IL1B mRNA Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of IL1B mRNA] Fluoxetine results in decreased expression of IL1B mRNA Fluoxetine results in increased expression of IL1B mRNA pyrrolidine dithiocarbamic acid inhibits the reaction [[Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of IL1B mRNA] pyrrolidine dithiocarbamic acid inhibits the reaction [Fluoxetine results in decreased expression of IL1B mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] inhibits the reaction [Lipopolysaccharides results in IL6 increased expression of IL6 mRNA] [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of IL6 mRNA Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of IL6 mRNA] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased secretion of IL6 protein] Fluoxetine results in decreased expression of IL6 mRNA Fluoxetine results in increased expression of IL6 mRNA INHBE Fluoxetine results in increased expression of INHBE mRNA INSIG1 Fluoxetine results in increased expression of INSIG1 mRNA ITGAM Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of ITGAM protein] ITPKA Fluoxetine results in decreased expression of ITPKA mRNA JUN Fluoxetine results in decreased expression of JUN mRNA KCNA3 Fluoxetine results in decreased activity of KCNA3 protein KCNA6 Fluoxetine results in decreased expression of KCNA6 mRNA KCNH2 Fluoxetine affects the localization of KCNH2 protein Fluoxetine binds to and results in decreased activity of KCNH2 protein Fluoxetine inhibits the reaction [KCNH2 protein results in increased transport of Potassium] Fluoxetine inhibits the reaction [KCNH2 protein results in increased transport of Thallium] Fluoxetine results in decreased activity of KCNH2 protein KCNH2 protein affects the susceptibility to Fluoxetine KCNH2 protein affects the susceptibility to norfluoxetine norfluoxetine affects the localization of KCNH2 protein norfluoxetine results in decreased activity of KCNH2 protein Fluoxetine inhibits the reaction [[beta-apocarotenoid-14',13'-dioxygenase results in increased activity of ADORA1 protein] KCNJ3 promotes the reaction [[KCNJ3 protein co-treated with KCNJ6 protein] results in increased transport of Potassium]] Fluoxetine inhibits the reaction [[KCNJ3 protein co-treated with KCNJ5 protein] results in increased transport of Potassium] Fluoxetine inhibits the reaction [[KCNJ3 protein co-treated with KCNJ6 protein] results in increased transport of Potassium] KCNJ4 Fluoxetine inhibits the reaction [Methamphetamine results in decreased expression of KCNJ4 mRNA]

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KCNJ5 Fluoxetine inhibits the reaction [[KCNJ3 protein co-treated with KCNJ5 protein] results in increased transport of Potassium] Fluoxetine inhibits the reaction [[beta-apocarotenoid-14',13'-dioxygenase results in increased activity of ADORA1 protein] KCNJ6 promotes the reaction [[KCNJ3 protein co-treated with KCNJ6 protein] results in increased transport of Potassium]] Fluoxetine inhibits the reaction [[KCNJ3 protein co-treated with KCNJ6 protein] results in increased transport of Potassium] Fluoxetine inhibits the reaction [KCNJ6 protein results in increased transport of Potassium] KCNK2 Fluoxetine affects the activity of KCNK2 protein mutant form Fluoxetine inhibits the reaction [Dexamethasone results in increased expression of KCNK2 mRNA] Fluoxetine inhibits the reaction [Dexamethasone results in increased expression of KCNK2 protein] Fluoxetine inhibits the reaction [KCNK2 protein results in increased transport of Potassium] Fluoxetine results in decreased activity of KCNK2 protein Fluoxetine results in decreased expression of KCNK2 mRNA Fluoxetine results in decreased expression of KCNK2 protein Fluoxetine results in decreased susceptibility to KCNK2 protein KCNK2 mRNA affects the susceptibility to Fluoxetine [KCNK2 mRNA co-treated with KCNK10 mRNA] affects the susceptibility to Fluoxetine KLF10 Fluoxetine results in increased expression of KLF10 mRNA L1CAM Fluoxetine results in increased expression of L1CAM protein Ondansetron inhibits the reaction [Fluoxetine results in increased expression of L1CAM protein] LSS Fluoxetine results in decreased expression of LSS mRNA Fluoxetine results in increased expression of LSS mRNA MALAT1 Fluoxetine results in increased expression of MALAT1 mRNA MAOA MAOA gene polymorphism affects the susceptibility to Fluoxetine 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibits the reaction [[Fluoxetine results in MAPK1 increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] ADARB1 protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK1 protein]] bisindolylmaleimide I inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] Calcium promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] [Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK1 protein [[Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK1 protein] which results in increased expression of PLA2G4A protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 protein [Fluoxetine co-treated with Methylphenidate] results in increased expression of MAPK1 mRNA [Fluoxetine co-treated with Methylphenidate] results in increased phosphorylation of MAPK1 protein Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK1 protein] Fluoxetine results in decreased expression of MAPK1 mRNA Fluoxetine results in decreased phosphorylation of MAPK1 protein [Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein Fluoxetine results in increased expression of MAPK1 protein Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK1 protein Fluoxetine results in increased phosphorylation of MAPK1 protein HTR2B protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK1 protein]] N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK1 protein] N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] RTKI cpd inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK1 protein] U 0126 inhibits the reaction [Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK1 protein] MAPK14 Fluoxetine results in increased phosphorylation of MAPK14 protein 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester inhibits the reaction [[Fluoxetine results in MAPK3 increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] ADARB1 protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK3 protein]] ARRB2 protein promotes the reaction [Fluoxetine results in increased expression of MAPK3 protein]

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bisindolylmaleimide I inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] Calcium promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] [Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK3 protein [[Fluoxetine binds to and results in increased activity of HTR2B protein] which results in increased activity of MAPK3 protein] which results in increased expression of PLA2G4A protein [[Fluoxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 protein Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK3 protein] Fluoxetine results in decreased phosphorylation of MAPK3 protein [Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein Fluoxetine results in increased expression of MAPK3 protein Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK3 protein Fluoxetine results in increased phosphorylation of MAPK3 protein HTR2B protein inhibits the reaction [Fluoxetine inhibits the reaction [Excitatory Amino Acid Agents results in increased phosphorylation of MAPK3 protein]] N-(1-methyl-5-indolyl)-N'-(3-methyl-5-isothiazolyl)urea promotes the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide inhibits the reaction [Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK3 protein] N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] RTKI cpd inhibits the reaction [[Fluoxetine results in increased activity of HTR2B protein] which results in increased phosphorylation of MAPK3 protein] U 0126 inhibits the reaction [Fluoxetine results in increased phosphorylation of and results in increased activity of MAPK3 protein] MAPK8 Fluoxetine results in decreased expression of MAPK8 mRNA MBD1 Fluoxetine results in increased expression of MBD1 mRNA Fluoxetine results in increased expression of MBD1 protein MC4R Fluoxetine results in decreased expression of MC4R mRNA Fluoxetine results in decreased expression of MC4R protein MECP2 Fluoxetine results in increased expression of MECP2 mRNA Fluoxetine results in increased expression of MECP2 mRNA alternative form Fluoxetine results in increased expression of MECP2 protein MIF MIF affects the susceptibility to Fluoxetine [9,10-Dimethyl-1,2-benzanthracene co-treated with Raloxifene Hydrochloride co-treated with Fluoxetine] affects the MMP9 expression of MMP9 protein Fluoxetine inhibits the reaction [TNFSF11 protein results in increased expression of MMP9 mRNA] Fluoxetine results in decreased activity of MMP9 protein MTOR [Fluoxetine co-treated with Methylphenidate] results in increased expression of MTOR mRNA [Fluoxetine co-treated with Methylphenidate] results in increased phosphorylation of MTOR protein MYC Fluoxetine results in decreased phosphorylation of MYC protein NCAM1 Fluoxetine results in increased expression of NCAM1 mRNA NEUROD2 Fluoxetine results in decreased expression of NEUROD2 mRNA NF1 Fluoxetine results in decreased expression of NF1 mRNA NFKBIA Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased degradation of NFKBIA protein] Fluoxetine results in increased expression of NFKBIA mRNA NGFR NGFR protein results in increased susceptibility to Fluoxetine NOS2 [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of NOS2 protein Fluoxetine analog inhibits the reaction [Lipopolysaccharides results in increased expression of NOS2 mRNA] Fluoxetine analog inhibits the reaction [[Lipopolysaccharides results in increased expression of NOS2 protein] which results in increased chemical synthesis of Nitric Oxide] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of NOS2 mRNA] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of NOS2 protein] Fluoxetine results in increased expression of NOS2 mRNA NOTCH1 Fluoxetine results in increased expression of NOTCH1 mRNA Fluoxetine results in increased expression of NOTCH1 protein NPAS2 Fluoxetine affects the expression of NPAS2 mRNA NPTX2 Fluoxetine results in increased expression of NPTX2 mRNA NPY Fluoxetine affects the expression of NPY mRNA Fluoxetine results in decreased expression of NPY mRNA

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Fluoxetine results in decreased secretion of NPY mRNA Fluoxetine results in decreased secretion of NPY protein Fluoxetine results in increased expression of NPY mRNA NPY1R Fluoxetine affects the expression of NPY1R mRNA NR3C1 Fluoxetine affects the expression of NR3C1 protein Fluoxetine affects the reaction [sodium arsenate affects the expression of NR3C1 protein] Fluoxetine inhibits the reaction [IFNA1 protein results in decreased expression of NR3C1 mRNA] Fluoxetine inhibits the reaction [IFNA1 protein results in decreased expression of NR3C1 protein] Fluoxetine promotes the reaction [Dexamethasone results in increased activity of NR3C1 protein] Fluoxetine promotes the reaction [Hydrocortisone results in increased activity of NR3C1 protein] Fluoxetine results in decreased expression of NR3C1 mRNA Fluoxetine results in increased expression of NR3C1 mRNA Fluoxetine results in increased expression of NR3C1 protein NR3C1 protein affects the susceptibility to Fluoxetine NR3C2 Fluoxetine affects the reaction [Dexamethasone binds to NR3C2 protein] Fluoxetine results in decreased expression of NR3C2 mRNA Fluoxetine results in increased expression of NR3C2 mRNA Fluoxetine results in increased expression of NR3C2 protein NR4A2 Fluoxetine results in decreased expression of NR4A2 mRNA NR4A3 Fluoxetine results in decreased expression of NR4A3 mRNA NRGN Fluoxetine results in decreased expression of NRGN mRNA NRN1 Fluoxetine results in increased expression of NRN1 mRNA NTRK2 Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2A2 protein] Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2B1 protein] Fluoxetine inhibits the reaction [NTRK2 protein binds to AP2M1 protein] Fluoxetine results in increased expression of NTRK2 mRNA Fluoxetine results in increased expression of NTRK2 mRNA alternative form Fluoxetine results in increased phosphorylation of and results in increased activity of NTRK2 protein Fluoxetine results in increased phosphorylation of NTRK2 protein NUPR1 Fluoxetine results in increased expression of NUPR1 mRNA OPRM1 Fluoxetine inhibits the reaction [Methamphetamine results in decreased expression of OPRM1 mRNA] Fluoxetine inhibits the reaction [Methamphetamine results in decreased expression of OPRM1 protein] Fluoxetine results in increased expression of OPRM1 protein OTX2 Fluoxetine affects the expression of OTX2 mRNA OXT Fluoxetine results in decreased expression of OXT mRNA Fluoxetine affects the reaction [vasotocin, (beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)-O-methyl-Tyr(2)- OXTR Thr(4)-Orn(8)-Tyr(9)-NH2 binds to OXTR protein] OXTR Fluoxetine results in increased expression of OXTR protein P4HB Fluoxetine results in increased expression of P4HB mRNA PDE4A Fluoxetine results in increased expression of PDE4A mRNA PDE4B Fluoxetine affects the expression of PDE4B mRNA Fluoxetine results in decreased expression of PDE4B protein Fluoxetine results in increased expression of PDE4B mRNA PDE4D Fluoxetine affects the expression of PDE4D mRNA alternative form PDYN Fluoxetine affects the expression of PDYN protein Fluoxetine results in decreased expression of PDYN mRNA PENK Fluoxetine results in decreased expression of PENK mRNA PER1 Fluoxetine results in decreased expression of PER1 mRNA PER2 Fluoxetine affects the expression of PER2 mRNA PLCB1 Fluoxetine results in decreased expression of PLCB1 mRNA Fluoxetine results in decreased expression of PLCB1 protein PLEC Fluoxetine results in decreased expression of PLEC mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of PLXNA3 PLXNA3 mRNA [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of PLXND1 PLXND1 mRNA PMCH Fluoxetine results in decreased expression of PMCH mRNA POMC Fluoxetine results in decreased expression of POMC mRNA Fluoxetine results in increased expression of POMC mRNA Fluoxetine results in increased expression of POMC protein POU5F1 Fluoxetine affects the expression of POU5F1 mRNA PPARG Fluoxetine inhibits the reaction [Serotonin results in increased localization of PPARG protein] PPP1R1B Fluoxetine affects the phosphorylation of PPP1R1B protein

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Fluoxetine results in increased expression of PPP1R1B mRNA Fluoxetine results in increased expression of PPP1R1B protein PPP1R1B protein promotes the reaction [Fluoxetine affects the phosphorylation of GRIA1 protein] PPP1R1B protein results in increased susceptibility to Fluoxetine PRKCG Fluoxetine results in decreased expression of PRKCG mRNA PRKG1 Fluoxetine inhibits the reaction [Monocrotaline results in decreased expression of PRKG1 protein] PRL Fluoxetine results in increased expression of PRL protein [Olanzapine co-treated with Fluoxetine] results in increased expression of PRL protein PRSS23 Fluoxetine results in decreased expression of PRSS23 mRNA PTGDS Fluoxetine results in decreased expression of PTGDS mRNA PTGS2 Fluoxetine results in decreased expression of PTGS2 mRNA Fluoxetine results in decreased expression of PTGS2 protein PTK2B Fluoxetine results in decreased expression of PTK2B mRNA RELA [Amitriptyline co-treated with Fluoxetine co-treated with Mianserin] results in decreased expression of RELA mRNA Fluoxetine inhibits the reaction [Lipopolysaccharides affects the localization of RELA protein] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased phosphorylation of RELA protein] Fluoxetine results in decreased expression of RELA mRNA Fluoxetine results in increased activity of RELA protein RELN Fluoxetine results in increased expression of RELN mRNA RGS3 Fluoxetine results in increased expression of RGS3 mRNA RPRML Fluoxetine results in decreased expression of RPRML mRNA S100B Fluoxetine results in increased expression of S100B mRNA Fluoxetine results in increased expression of S100B protein S100B protein results in increased susceptibility to Fluoxetine SAMD4A Fluoxetine results in decreased expression of SAMD4A mRNA SGK1 Fluoxetine results in increased expression of SGK1 mRNA SLC13A4 Fluoxetine results in decreased expression of SLC13A4 mRNA SLC17A7 Fluoxetine results in decreased expression of SLC17A7 mRNA Fluoxetine results in increased expression of SLC17A7 mRNA Fluoxetine results in increased expression of SLC17A7 protein SLC22A2 Fluoxetine inhibits the reaction [SLC22A2 protein results in increased uptake of 4-(4-dimethylaminostyryl)-1-methylpyridinium] SLC2A3 Fluoxetine results in decreased expression of SLC2A3 mRNA SLC30A3 Fluoxetine results in decreased expression of SLC30A3 mRNA SLC32A1 Fluoxetine results in decreased expression of SLC32A1 protein SLC6A15 [Fluoxetine co-treated with Caffeine] results in decreased expression of SLC6A15 mRNA SLC6A2 Fluoxetine inhibits the reaction [SLC6A2 protein results in increased import of Biogenic Monoamines analog] Fluoxetine inhibits the reaction [SLC6A2 protein results in increased import of Fluorescent Dyes] Amphetamine inhibits the reaction [nisoxetine binds to SLC6A2 protein] nisoxetine results in decreased activity of SLC6A2 protein Norepinephrine inhibits the reaction [nisoxetine binds to SLC6A2 protein] SLC6A3 Fluoxetine affects the expression of SLC6A3 Fluoxetine inhibits the reaction [SLC6A3 protein results in increased import of Biogenic Monoamines analog] Fluoxetine inhibits the reaction [SLC6A3 protein results in increased import of Fluorescent Dyes] Fluoxetine inhibits the reaction [SLC6A3 protein results in increased uptake of Dopamine] SLC6A3 mutant form affects the reaction [Fluoxetine affects the abundance of Dopamine] SLC6A3 protein affects the susceptibility to Fluoxetine SLC6A4 [Estradiol co-treated with Fluoxetine] results in increased expression of SLC6A4 mRNA Fluoxetine affects the expression of SLC6A4 protein Fluoxetine binds to and results in decreased activity of SLC6A4 protein [Fluoxetine co-treated with Venlafaxine Hydrochloride co-treated with Carbamazepine] results in decreased expression of SLC6A4 mRNA Fluoxetine inhibits the reaction [SLC6A4 protein results in increased import of Biogenic Monoamines analog] Fluoxetine inhibits the reaction [SLC6A4 protein results in increased import of Fluorescent Dyes] Fluoxetine results in decreased activity of SLC6A4 protein Fluoxetine results in decreased expression of SLC6A4 Fluoxetine results in decreased expression of SLC6A4 mRNA [Fluoxetine results in decreased expression of SLC6A4 mRNA] which results in decreased abundance of Serotonin Fluoxetine results in decreased expression of SLC6A4 protein Fluoxetine results in decreased localization of SLC6A4 protein Fluoxetine results in increased expression of SLC6A4 mRNA Org 34850 promotes the reaction [Fluoxetine results in decreased expression of SLC6A4 protein] SLC6A4 affects the susceptibility to Fluoxetine SLC6A4 gene polymorphism results in decreased susceptibility to Fluoxetine

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SLC6A4 gene polymorphism results in increased susceptibility to Fluoxetine SLC6A4 protein affects the susceptibility to Fluoxetine SLC6A4 protein results in increased susceptibility to Fluoxetine nisoxetine binds to and results in decreased activity of SLC6A4 protein SLC7A11 Fluoxetine results in increased expression of SLC7A11 mRNA SMAD1 Fluoxetine inhibits the reaction [Monocrotaline results in decreased expression of SMAD1 mRNA] SMAD1 Fluoxetine inhibits the reaction [Monocrotaline results in decreased phosphorylation of SMAD1 protein] SMPD1 Fluoxetine results in decreased activity of SMPD1 protein Fluoxetine results in decreased expression of and results in decreased activity of SMPD1 protein [Fluoxetine results in decreased expression of and results in decreased activity of SMPD1 protein] which results in decreased abundance of Ceramides SMPD1 protein results in increased susceptibility to Fluoxetine SND1 Fluoxetine results in increased expression of SND1 mRNA SOD1 Fluoxetine results in increased expression of SOD1 protein SOX2 Fluoxetine affects the expression of SOX2 mRNA SP5 Fluoxetine affects the expression of SP5 mRNA SPRY2 Fluoxetine affects the expression of SPRY2 mRNA SQLE Fluoxetine results in decreased expression of SQLE mRNA SQSTM1 Fluoxetine results in decreased expression of SQSTM1 mRNA SRSF5 Fluoxetine affects the expression of SRSF5 mRNA STC1 Fluoxetine results in increased expression of STC1 mRNA STS Fluoxetine results in decreased expression of STS mRNA STXBP1 Fluoxetine results in increased expression of STXBP1 mRNA SYN1 Fluoxetine results in increased expression of SYN1 mRNA SYP Fluoxetine results in decreased expression of SYP mRNA SYP Fluoxetine results in increased expression of SYP mRNA TAGLN Fluoxetine results in decreased expression of TAGLN mRNA TH Fluoxetine affects the expression of TH Fluoxetine results in decreased expression of TH mRNA Fluoxetine results in increased expression of TH mRNA [9,10-Dimethyl-1,2-benzanthracene co-treated with Raloxifene Hydrochloride co-treated with Fluoxetine] affects the TIMP1 expression of TIMP1 protein TNF Fluoxetine inhibits the reaction [lipopolysaccharide, E coli O55-B5 results in increased expression of TNF protein] Fluoxetine inhibits the reaction [lipopolysaccharide, Escherichia coli O111 B4 results in increased expression of TNF protein] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased expression of TNF mRNA] Fluoxetine inhibits the reaction [Lipopolysaccharides results in increased secretion of TNF protein] Fluoxetine inhibits the reaction [Reserpine results in increased expression of TNF protein] Fluoxetine inhibits the reaction [TNF protein results in increased expression of CCL5 protein] Fluoxetine promotes the reaction [caryophyllene inhibits the reaction [lipopolysaccharide, E coli O55-B5 results in increased expression of TNF protein]] Fluoxetine results in decreased activity of TNF protein Fluoxetine results in increased expression of TNF mRNA TP53 Fluoxetine results in increased expression of TP53 mRNA TPH2 [Estradiol co-treated with Fluoxetine] results in increased expression of TPH2 mRNA Fluoxetine affects the expression of TPH2 mRNA Fluoxetine results in decreased expression of TPH2 mRNA Fluoxetine results in increased expression of TPH2 mRNA TPH2 protein affects the susceptibility to Fluoxetine TPH2 results in increased susceptibility to Fluoxetine TPM1 Fluoxetine results in decreased expression of TPM1 mRNA TRP53 Fluoxetine results in increased expression of TRP53 mRNA TSSK2 Fluoxetine results in decreased expression of TSSK2 mRNA TTR Fluoxetine results in increased expression of TTR mRNA TUBB3 Fluoxetine results in decreased expression of TUBB3 mRNA [9,10-Dimethyl-1,2-benzanthracene co-treated with Raloxifene Hydrochloride co-treated with Fluoxetine] affects the VEGFA expression of VEGFA protein Fluoxetine results in increased expression of VEGFA mRNA VGF Fluoxetine results in increased expression of VGF mRNA VLDLR Fluoxetine results in increased expression of VLDLR mRNA Fluoxetine results in increased expression of VLDLR protein WFS1 Fluoxetine results in decreased expression of WFS1 mRNA YWHAE Fluoxetine affects the expression of YWHAE mRNA YWHAH Fluoxetine affects the expression of YWHAH mRNA

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YWHAZ Fluoxetine results in increased expression of YWHAZ mRNA Fluoxetine results in increased expression of YWHAZ protein Paroxetine ABCB1 ABCB1 protein results in increased export of Paroxetine APP [Paroxetine binds to APP 5' UTR] which results in decreased secretion of APP protein modified form AR Paroxetine binds to and results in decreased activity of AR protein ARC Paroxetine results in increased expression of ARC mRNA BDNF Paroxetine results in increased expression of BDNF mRNA Paroxetine results in increased expression of BDNF protein CASP3 Paroxetine results in increased activity of and results in increased cleavage of CASP3 protein Paroxetine results in increased activity of CASP3 protein CASP8 Paroxetine results in increased activity of CASP8 protein CASP9 Paroxetine results in increased activity of CASP9 protein CYP19A1 Paroxetine results in decreased activity of CYP19A1 protein CYP2B6 Paroxetine inhibits the reaction [CYP2B6 protein results in increased chemical synthesis of hydroxybupropion] Paroxetine inhibits the reaction [CYP2B6 protein results in increased metabolism of Bupropion] Paroxetine results in decreased activity of CYP2B6 protein CYP2D6 gene mutant form results in decreased metabolism of Paroxetine CYP2D6 gene mutant form results in increased susceptibility to Paroxetine CYP2D6 protein affects the metabolism of Paroxetine CYP2D6 protein results in increased metabolism of Paroxetine Paroxetine inhibits the reaction [CYP2D6 gene mutant form results in decreased susceptibility to Debrisoquin] Paroxetine inhibits the reaction [CYP2D6 gene mutant form results in decreased susceptibility to Nortriptyline] Paroxetine inhibits the reaction [CYP2D6 gene mutant form results in increased abundance of 10-hydroxynortriptyline] Paroxetine inhibits the reaction [CYP2D6 gene mutant form results in increased abundance of Debrisoquin metabolite] Paroxetine inhibits the reaction [CYP2D6 protein results in increased chemical synthesis of Dextrorphan] Paroxetine inhibits the reaction [CYP2D6 protein results in increased metabolism of Dextromethorphan] Paroxetine inhibits the reaction [CYP2D6 protein results in increased oxidation of dimemorfan] Paroxetine results in decreased activity of CYP2D6 protein [Paroxetine results in decreased activity of CYP2D6 protein] which results in decreased abundance of 4-hydroxy-N- desmethyltamoxifen [Paroxetine results in decreased activity of CYP2D6 protein] which results in decreased degradation of Metoprolol [Paroxetine results in decreased activity of CYP2D6 protein] which results in decreased metabolism of Dextromethorphan [Paroxetine results in decreased activity of CYP2D6 protein] which results in increased susceptibility to Metoprolol DBH DBH protein results in increased susceptibility to Paroxetine DDAH1 Paroxetine inhibits the reaction [Manganese deficiency results in decreased expression of DDAH1 protein] [Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and EGFR results in increased activity of EGFR protein [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 protein [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 protein GRK2 Paroxetine results in decreased activity of GRK2 protein GRK5 Paroxetine results in decreased activity of GRK5 protein HCRTR2 Paroxetine results in increased expression of HCRTR2 mRNA HRH1 Paroxetine results in increased expression of HRH1 mRNA HTR1B Paroxetine results in decreased expression of HTR1B mRNA HTR2A HTR2A gene polymorphism affects the susceptibility to Paroxetine HTR2C Paroxetine binds to and results in increased activity of HTR2C protein [Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 protein [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 protein IL10 LY 215840 inhibits the reaction [Paroxetine results in increased expression of IL10 mRNA] LY 215840 inhibits the reaction [Paroxetine results in increased expression of IL10 protein] Paroxetine results in increased expression of IL10 mRNA Paroxetine results in increased expression of IL10 protein IL17A LY 215840 inhibits the reaction [Paroxetine results in decreased expression of IL17A protein]

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Paroxetine results in decreased expression of IL17A protein IL1B Paroxetine affects the expression of IL1B protein INS Paroxetine affects the reaction [INS protein affects the phosphorylation of IRS1 protein] pyrazolanthrone inhibits the reaction [Paroxetine affects the reaction [INS protein affects the phosphorylation of IRS1 protein]] IRS1 Paroxetine affects the reaction [INS protein affects the phosphorylation of IRS1 protein] Paroxetine results in decreased activity of IRS1 protein pyrazolanthrone inhibits the reaction [Paroxetine affects the reaction [INS protein affects the phosphorylation of IRS1 protein]] JAK2 LY 215840 promotes the reaction [Paroxetine results in increased expression of JAK2 mRNA] Paroxetine results in increased expression of JAK2 mRNA KCNJ3 Paroxetine results in decreased activity of [KCNJ3 protein binds to KCNJ6 protein] KCNJ5 Paroxetine results in decreased activity of [KCNJ6 protein binds to KCNJ5 protein] KCNJ6 Paroxetine results in decreased activity of [KCNJ3 protein binds to KCNJ6 protein] Paroxetine results in decreased activity of [KCNJ6 protein binds to KCNJ5 protein] Paroxetine results in decreased activity of [KCNJ6 protein binds to KCNJ6 protein] [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK1 MAPK1 protein [[Paroxetine binds to and results in increased activity of HTR2C protein] which results in increased phosphorylation of and results in increased activity of EGFR protein] which results in increased phosphorylation of and results in increased activity of MAPK3 MAPK3 protein MAPK8 Paroxetine results in increased activity of MAPK8 protein pyrazolanthrone inhibits the reaction [Paroxetine results in increased phosphorylation of and results in increased activity of MAPK8 protein] PF4 Paroxetine results in decreased expression of PF4 protein PPBP Paroxetine results in decreased expression of PPBP protein PTGS2 Paroxetine results in decreased expression of PTGS2 mRNA Paroxetine results in decreased expression of PTGS2 protein SLC22A2 Paroxetine inhibits the reaction [SLC22A2 protein results in increased uptake of 4-(4-dimethylaminostyryl)-1-methylpyridinium] SLC6A15 Paroxetine inhibits the reaction [Corticosterone results in decreased expression of SLC6A15 mRNA] SLC6A4 Paroxetine affects the expression of SLC6A4 mRNA Paroxetine binds to and results in decreased activity of SLC6A4 protein Paroxetine results in decreased expression of SLC6A4 mRNA SOD2 Paroxetine inhibits the reaction [Manganese deficiency results in increased expression of SOD2 protein] STAT3 LY 215840 promotes the reaction [Paroxetine results in increased expression of STAT3 mRNA] Paroxetine results in decreased expression of STAT3 mRNA Paroxetine results in decreased expression of STAT3 protein Paroxetine results in increased expression of STAT3 mRNA TFAP2A Paroxetine results in increased expression of TFAP2A protein TNF LY 215840 inhibits the reaction [Paroxetine results in decreased expression of TNF protein] Paroxetine results in decreased expression of TNF protein Paroxetine results in decreased secretion of TNF protein VEGFA Paroxetine results in increased expression of VEGFA mRNA VGF Paroxetine results in increased expression of VGF mRNA

Supplement 3. A list of the top associated diseases or conditions common amongst the

top 12 genes associated with MPS, in rank, compiled from CTD (Davis et al., 2021) data

status as of March 2021.

Associated Gene Associated Disease or Condition Inference Score Number of Associated With Associated (IS =) Studies Exposure Studies (n=54,824)

HRH1 Necrosis 150.09 337

(IS = 17.07; n = 2) Chemical and Drug Induced Liver Injury 133.35 1,033

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Inflammation Y 133.21 266

Weight Loss 123.25 194

Memory Disorders Y 115.96 216

Learning Disabilities Y 114.70 130

Edema 112.88 115 Drug-Related Side Effects and Adverse Reactions 109.33 294

Prenatal Exposure Delayed Effects Y 106.65 332

Hypertension Y 106.32 279

KCNK9 Prenatal Exposure Delayed Effects Y 62.37 216

(IS = 12.99; n = 1) Weight Loss 54.49 51

Necrosis 52.43 80

Inflammation Y 45.76 88

Learning Disabilities 45.53 40

Chemical and Drug-Induced Liver Injury 41.46 251

Memory Disorders 40.59 52

Hypertension Y 38.03 44

FOS Necrosis 841.63 860

(IS = 11.94; n = 2) Chemical and Drug-Induced Liver Injury Y 717.18 1,820

Inflammation Y 596.34 719

Weight Loss 553.12 491

Kidney Diseases Y 500.91 965

Hypertension Y 498.81 1,697

Memory Disorders Y 489.59 452

Edema 485.43 437

Prenatal Exposure Delayed Effects Y 451.44 878

Learning Disabilities Y 422.71 282

Nerve Degeneration 401.60 332

CASP9 Necrosis 884.32 898

(IS = 11.41; n = 2) Chemical and Drug-Induced Liver Injury Y 821.62 1,907

Weight Loss 647.72 552

Inflammation Y 615.12 699

Kidney Diseases Y 538.77 941

Edema 408.29 389

Prenatal Exposure Delayed Effects Y 379.91 794 Drug-Related Side Effects and Adverse Reactions 371.36 551

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Memory Disorders Y 367.83 375

Nerve Degeneration 362.78 344

SLC6A2 Prenatal Exposure Delayed Effects Y 157.28 398

(IS = 10.95; n = 1) Memory Disorders Y 130.58 186

Chemical and Drug-Induced Liver Injury 129.31 507

Necrosis 129.09 200

Learning Disabilities Y 123.73 113

Nerve Degeneration 120.69 102

Weight Loss 118.25 146

Inflammation Y 114.68 131

SLC22A3 Chemical and Drug-Induced Liver Injury 161.67 860

(IS = 10.43; n = 2) Necrosis 155.70 311

Hypertension Y 143.60 931

Weight Loss 141.51 198

Inflammation Y 123.90 198

Prenatal Exposure Delayed Effects Y 122.14 327 Drug-Related Side Effects and Adverse Reactions 107.86 247

IL6 Chemical and Drug-Induced Liver Injury Y 1,199.53 2,214

(IS = 10.07; n = 2) Inflammation Y 1,065.15 838

Necrosis 1,051.27 947

Weight Loss 832.56 597

Edema 729.39 505

Kidney Diseases Y 695.82 1,059

Hypertension Y 514.26 1,804

Memory Disorders Y 502.08 465 Drug-Related Side Effects and Adverse Reactions 481.64 705

SLC22A1 Chemical and Drug-Induced Liver Injury Y 358.21 1,270

(IS = 10.05; n = 2) Necrosis 277.54 424

Weight Loss 247.21 329

Kidney Diseases Y 231.17 585

Prenatal Exposure Delayed Effects Y 211.07 415

Inflammation Y 204.12 347

Hypertension Y 192.35 1,078

Edema 179.24 179 Drug-Related Side Effects and Adverse Reactions 162.12 294

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PRKCB Necrosis 337.82 564

(IS = 9.97; n = 1) Chemical and Drug-Induced Liver Injury Y 267.65 1,223

Inflammation Y 267.60 413

Weight Loss 254.38 375

Prenatal Exposure Delayed Effects Y 207.92 599

Memory Disorders Y 178.33 235

Kidney Diseases Y 178.31 585

Learning Disabilities Y 176.73 147 Drug-Related Side Effects and Adverse Reactions 173.71 332

Nerve Degeneration 172.47 191

TRPV1 Necrosis 207.55 269

(IS = 9.81; n = 1) Edema 203.21 225

Inflammation Y 190.51 393

Weight Loss 153.56 242

Nerve Degeneration 135.04 103

Chemical and Drug-Induced Liver Injury 131.09 486

Hypertension Y 112.41 422

Prenatal Exposure Delayed Effects Y 107.32 329

Memory Disorders 106.78 145

ITGAM Inflammation Y 336.77 454

(IS = 9.70; n = 1) Necrosis 335.78 536

Chemical and Drug-Induced Liver Injury Y 269.29 1,148

Memory Disorders 217.01 198

Weight Loss 214.25 300

Kidney Diseases Y 213.13 429

Nerve Degeneration 210.70 195

Prenatal Exposure Delayed Effects Y 192.08 425 Drug-Related Side Effects and Adverse Reactions 191.42 169

Learning Disabilities Y 184.66 123

Edema 163.77 169

CALCA Necrosis 231.76 416

(IS = 9.68; n = 2) Inflammation Y 211.08 367

Chemical and Drug-Induced Liver Injury 189.92 994

Weight Loss 178.39 292

Hypertension Y 172.54 784

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Edema 170.50 185

Kidney Diseases Y 168.91 426

Prenatal Exposure Delayed Effects Y 144.97 426 Drug-Related Side Effects and Adverse Reactions 139.84 199

Supplement 4. A list of the associated drugs curated to identify the inferred top 12 genes associated with MPS, in rank, compiled from CTD (Davis et al., 2021) data status as of

March 2021.

Associated Associated Drug Associated Evidence Number of Gene Associated Study (n=348)

HRH1 Bupivacaine Therapeutic effects 1 (IS = 17.07; n = 2) Lidocaine Therapeutic effects 2 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 1 Markers; mechanisms of Ranitidine action 1 KCNK9 Bupivacaine Therapeutic effects 1 (IS = 12.99; n = 1) Lidocaine Therapeutic effects 1 Markers; mechanisms of FOS Cocaine action 179 (IS = 11.94; n Markers; mechanisms of = 2) Diflunisal action 1 Lidocaine Therapeutic effects 3 Markers; mechanisms of Methamphetamine action 16 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 5 Markers; mechanisms of Ranitidine action 1 Markers; mechanisms of CASP9 Cocaine action 12 (IS = 11.41; n = 2) Lidocaine Therapeutic effects 1 Markers; mechanisms of Methamphetamine action 9 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 1 Markers; mechanisms of Ranitidine action 1 SLC6A2 Bupivacaine Therapeutic effects 1 (IS = 10.95; n Markers; mechanisms of = 1) Cocaine action 10 Lidocaine Therapeutic effects 1 Markers; mechanisms of Methamphetamine action 3 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 6 SLC22A3 Lidocaine Therapeutic effects 1 (IS = 10.43; n Markers; mechanisms of = 2) Methamphetamine action 1 Markers; mechanisms of Ranitidine action 3

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Markers; mechanisms of IL6 Cocaine action 24 (IS = 10.07; n Markers; mechanisms of = 2) Diflunisal action 1 Lidocaine Therapeutic effects 1 Markers; mechanisms of Methamphetamine action 14 Markers; mechanisms of Ranitidine action 7 SLC22A1 Lidocaine Therapeutic effects 1 (IS = 10.05; n Markers; mechanisms of = 2) Ranitidine action 4 PRKCB Bupivacaine Therapeutic effects 1 (IS = 9.97; n = Markers; mechanisms of 1) Cocaine action 2 Lidocaine Therapeutic effects 2 Markers; mechanisms of Methamphetamine action 1 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 3 TRPV1 Bupivacaine Therapeutic effects 2 (IS = 9.81; n = 1) Lidocaine Therapeutic effects 12 Markers; mechanisms of Methamphetamine action 1 ITGAM Bupivacaine Therapeutic effects 2 (IS = 9.70; n = 1) Lidocaine Therapeutic effects 1 N-Methyl-3,4- Markers; mechanisms of methylenedioxyamphetamine action 2 CALCA Lidocaine Therapeutic effects 4 (IS = 9.68; n = Markers; mechanisms of 2) Ranitidine action 1

Supplement 5. A list of the top 12 associated diseases, and their top associated genes, with MPS, compiled from MalaCards (Rappaport et al., 2017) data status March 2021.

Associated Disease or Associated Condition Gene (CRS =)

Fibromyalgia POMC

(CRS = 31.6) NGF CALCA

BDNF

Glossopharyngeal neuralgia TAC1

(CRS = 30.8) POMC Bruxism TAC1

(CRS = 30.6) LAPTM4A Radiculopathy TAC1

(CRS = 30.3) LAPTM4A Hypochondriasis POMC

(CRS = 30.2) BDNF

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Frozen Shoulder LAPTM4A

(CRS = 30.2) ASIC3 Pulpitis TRPV1

(CRS = 30.1) KNG1 Facial Neuralgia TAC1

(CRS = 30.1) LIPN LAPTM4A

Complex Regional Pain TAC1 Syndrome (CRS = 30.1) POMC CALCA

Sleep Disorder TAC1

(CRS = 29.9) POMC BDNF

Bursitis TAC1

(CRS = 29.8) LAPTM4A KNG1

CALCA

Anxiety TAC1

(CRS = 29.5) POMC NGF BDNF

Supplement 6. A list of the associated physiological processes, and their top associated genes, with MPS, compiled from MalaCards (Rappaport et al., 2017) data status April

2021.

Associated Biological Process Associated Gene (CRS =)

G protein-coupled receptor signalling pathway TAC1 (CRS = 9.98) POMC PDGFRB

KNG1

CALCA

Inflammatory response TRPV1 (CRS = 9.83) TAC1 KNG1

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CALCA

Positive regulation of apoptotic process TRPV1

(CRS = 9.81) PDGFRB NGF

KNG1

Cell-cell signalling TAC1 (CRS = 9.77) POMC CALCA

Transmembrane receptor protein tyrosine kinase signalling PDGFRB pathway (CRS = 9.72) NGF BDNF

Neuropeptide signalling pathway TAC1

(CRS = 9.63) POMC CALCA

Regulation of neuron differentiation NGF (CRS = 9.59) BDNF

Peripheral nervous system development NGF

(CRS = 9.58) BDNF

Regulation of blood pressure TAC1 (CRS = 9.58) POMC CALCA

Vasodilation KNG1

(CRS = 9.57) CALCA

Neurotrophin TRK receptor signalling pathway NGF (CRS = 9.56) BDNF

Nerve development NGF (CRS = 9.54) BDNF

Response to heat TRPV1 (CRS = 9.54) CALCA ASIC3

Nerve growth factor signalling pathway NGF (CRS = 9.49) BDNF

Negative regulation of heart rate TRPV1 (CRS = 9.48) TAC1

Positive regulation of cytosolic calcium ion concentration TRPV1 (CRS = 9.46) TAC1 KNG1

CALCA

Positive regulation of collateral sprouting NGF (CRS = 9.43) BDNF

UST College of Science Department of Biological Sciences 75

Cellular response to nerve growth factor stimulus TRPV1 (CRS = 9.43) TAC1 CALCA

Detection of chemical stimulus involved in sensory perception TRPV1 of pain (CRS = 9.32) ASIC3

Response to pain TRPV1 (CRS = 9.13) TAC1 CALCA Detection of temperature stimulus involved in sensory perception TRPV1 of pain (CRS = 8.8) CALCA ASIC3