DOCSLIB.ORG

The Opioid-Pain Nexus: Safe Opioid Prescribing at This Cultural Moment October 4, 2019

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Opioid-Pain Nexus: Safe Opioid Prescribing at This Cultural Moment October 4, 2019 The Opioid-Pain Nexus: Safe Opioid Prescribing at this Cultural Moment October 4, 2019 Daniel L. Millspaugh, MD Nothing to Disclose Director, Opioid Stewardship Program Director, Comprehensive Pain Management US Opioid Prescribing ~30% of World’s Opioids, ~5% World’s Population FDA and IQVIA 2018 ✓ Poor Illicit Quality Control Prescriptions ✓ Also Cocaine & Meth in 2010 ✓ Polypharmacy ✓ Life Expectancy (3 yrs.) Polypharmacy Alcohol in 7-22% also Warner et al. National Vitals Statistics Report 2016; 65:10 Regional Variation in Overdose Deaths 2014-2016 c/w 2002-2004 Economic Distress + Opioid OD Deaths Monnat 6/20/19. Institute for New Economic Thinking Motivation & Reward Mesocorticolimbic Circuitry (ACC) PRIORITIZING • Natural Rewards • Addiction • Mood • Chronic Pain • Sleep Hedonic Valuation Hedonostat Opioids LIKING Dopamine WANTING (drive) Hyman et al. 2006, modified AN RV278-N E29-20 ARI 9 M ay 2006 14:29 Neurocircuitry of Addiction Nicotine, + alcohol Opiates Opioid Glutamate inputs peptides – (e.g. from cortex) Alcohol VTA Opiates GABA interneuron ? – PCP – Alcohol ? Stimulants NMDAR + DA D1R + CREB Nicotine NAChR DA or ΔFosB D2R g r – o + Cannabinoids . s Glutamate y l w e n inputs i o v e (e.g. from e r s l VTA NAc u amygdala) a l u a n n n o a Hyman et al. 2006 s . Figure 4 r s l e a p n Actions of opiates, nicotine, alcohol, and phencycline (PCP) in reward circuits. Ventral tegmental area r r o u F bottom left bottom right o (VTA) dopamine neurons ( ) project to the nucleus accumbens (N Ac) ( ). Different j . r 8 a interneurons, schematically diagrammed above, interact with VTA neurons and N Ac neurons. T he 0 / m 2 rewarding properties of opiatesare mediated by µ opiate receptors found in two locations in brain reward o 2 r / f 8 circuits. VTA dopamine neuronsare tonically inhibited by GABAergic interneurons that expressµ opiate d 0 e n d receptors. Opiates acutely inhibit these interneurons thusdisinhibiting the dopamine projection neurons, o a o n l which then release dopamine in the N Ac and other terminal fields. In addition, there are µ opiate o n i t w receptors expressed by N Ac and dorsal striatal neurons. Opiates can stimulate these receptors directly a t o S D and produce reward in a dopamine-independent manner. N icotine, acting on nicotinic acetylcholine e . g 8 receptors (N AChRs) in the VTA, cause dopamine release. Ethyl alcohol, acting on GABA receptors in e A 9 l l 5 - o the VTA, can also cause dopamine release. Phencyclidine (PCP), which blocks the NMDA glutamate 5 C 6 - 5 receptor channel and cannabinoids acting via CB1 cannabinoid receptors in the VTA (not shown), also : y 9 t i produce dopamine release. Cannabinoids, alcohol, and PCP can also act directly on the N Ac. PCP, 2 . s r 6 e phencyclidine (“angel dust”). 0 v 0 i 2 n . i U c s M o r & u e A information about rewards to motivate goal- there is strong evidence (e.g., in intact non- s N a . x v directed behaviors(Robinson et al. 2005); i.e., human primates) to suggest that, under nor- e e T R . y they cannot act on their preferences. Overall, mal circumstances (e.g., in the absence of u b n n however, theconclusionstobedrawn from le- lesions), dopamine plays a central role in A sionsor from dopamine-deficient TH knock- reward-related learning (Schultz et al. 1997, out mice are not entirely clear. T he knockout Schultz 2006). Finally, dopamine appears to mice, for example, likely have developmental be required for motivated behaviors aimed compensations to the lack of dopamine, re- at obtaining rewards. Based on such consid- quire intermittent l -dopa (which transiently erations, Berridge & Robinson (1998) have restores dopamine) in order to survive, and proposed that dopamine transmission in the require behavioral activation by caffeine to N Ac mediates the assignment of “incentive exhibit learning. It appears dopamine is not salience” to rewards and reward-related cues, needed for hedonic responses. T helesion and such that these cues can subsequently trig- knockout mice suggest that, under certain ger a state of “wanting” for the goal object circumstances, dopamine is not required for as distinct from “liking.” An animal can still reward-related learning. At the same time, like something in the absence of dopamine www.annualreviews.org • Neural Mechanismsof Addiction 573 Substance Use Disorder Risks Exposure, Gateway, Common Liability Models of Susceptibility ▪ Exposure (% SUD in NMU) ▪ Context – McCabe et al. Pain 2016 o EtOH 9%, MJ 11%, Heroin 67% o Medical use only in HS seniors NOT o Rx Opioid Abusers ➔ OUD 16% associated w/ SUD at 35 ▪ Genetics 40-70% o NMUPO + Medical AOR 1.49, ▪ Epigenetics – ACEs & stress NMUPO only 2.61 for SUD Sx o SUD most commonly AUD ▪ Adolescence – impulsivity, PFC fxn ▪ SUD & Mental Health Conditions o >40% with SUD had MHC o Multiple SUDs common Facing Addiction in America, HHS, 2016 ▪ 2011 IOM: Relieving Pain in America o Major public health problem o 100 million adults o $635 billion/year o $19.5 billion/year for children ▪ 2016 National Pain Strategy New IASP Pain Definition An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury Notes: 1. Always subjective and biopsychosocial 2. Pain and Nociception are different phenomena 3. Learn concept of pain and its applications through experiences Pain Processes & Pathways ▪ Learning ▪ Action ▪ Interpretation ▪ Perception ▪ Modulation ▪ Transmission ▪ Transduction Opioids for CNCP? ▪ Nociception & Pain Perception - ▪ Neuropathic pain – improved efficacy opioids affect both with longer duration Tx o Lancet Neurology, Finnerup et al. 2015 – ▪ Cochrane Review, Noble et al. tramadol 2nd & strong opioids 3rd line 2010: weak evidence of significant o Pain Physician, Howard 2012 – methadone pain relief, inconclusive fxn & QOL (NMDA), buprenorphine, Nav blockers ▪ Annals of IM, Chou et al. 2015: No ▪ Inflammatory Pain – later stages may long-term opioid studies (similar to be opioid responsive other analgesics); unable to ▪ German Guideline: contraindicated for evaluate pain, fxn, QOL outcomes primary HA and Functional PS (e.g., FM, IBS) CDC Opioid Guideline for Adults with Chronic Pain – 2016 Cornerstone for regulations and statutes, e.g., new TJC standards 50 MME/day, 90 MME/day Increasing pushback occurring 3 days, 7 days Pain Management Best Practices HHS Inter-Agency Task Force Report – May 2019 www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf Medications Section Deprioritized, not eliminated www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf Opium & Opiates ▪ Opium is dried latex from seed pod of opium poppy (Papaver somniferum) ▪ Phenanthrene alkaloids o Morphine (12%) o Codeine o Thebaine (semi-synthetics) Exogenous Opioids Opium-Derived Phenathrenes (opiates) Fully Synthetic Phenyl- Diphenyl- Synthetic Morphine Thebaine Codeine piperidines heptanes Phenathrenes Morphine§ Hydrocodone Codeine§* Meperidine Methadone Levorphanol Heroin Oxycodone Fentanyl Propoxyphene Butorphanol Hydromorphone Sufentanil (Darvon) Oxymorphone Alfentanil Buprenorphine Remifentanil Naloxone Carfentanil Nalbuphine Benzomorphans Other Naltrexone Diphenoxylate (Lomotil) Tramadol* Loperamide (Imodium) Tapentadol § Naturally-derived; other opium-derived are semi-synthetic * Prodrugs, CYP2D6 metabolism – new FDA contraindication/warning (<12,T&A, OSA) Endogenous Opioid System Precursors Ligands Receptors Notes μ/MOR Pro- β-endorphin HPA+, analgesia, acupuncture, κ/KOR opiomelanocortin (also ACTH, MSH) massage, placebo, stress opponent δ/DOR Pro-enkephalin Enkaphalins δ (also μ) GI motility, less respiratory depression Pro-dynorphin Dynorphins κ Dysphoria, μ opponent, mood Pro-nociceptin Nociceptin NOR Pain threshold modulation ? Endomorphins μ Analgesia selective, fewer SEs Spinal Cord: μ 70%, δ 20%, κ 10% Opioid Mechanism of Action G-Protein Coupled Receptors desensitization Ca2+ influx K+ efflux Inhibition cAMP Transcriptome Δ Al-Hasani et al. 2011 Receptor/Channel Affinity Drug MOR KOR DOR NOP NE 5HT NMDA QT Metabolism Morphine +++ + + UGT2B7 [➔M6G, M3G] Hydromorphone ++ + UGT2B7 Oxycodone ++ + + CYP3A4, CYP2D6 Hydrocodone + + + CYP2D6, CYP3A4 Fentanyl +++ CYP3A4 CYP3A4, CYP2B6, CYP2C8, Methadone ++ + + + + - Yes CYP2C19, CYP2D6, CYP2C9 Levorphanol +++ ++ ++ + + -- UGT2B7* Tramadol + + + ? CYP2D6*, CYP3A4 UGT1A9, UGT2B7, CYP2C9/19 Tapentadol + + (no active metabolites) Dependence Abstinence Syndrome ▪ Onset: 8-12 hrs (IR ▪ Bone Aching ▪ Vomiting drugs) ▪ Sleep Disturbance ▪ Diarrhea ▪ Peak: 2-4 days ▪ Sweating ▪ Palpitations ▪ Duration: 7-10 days ▪ Hot & Cold Flushes ▪ HTN (IR) ▪ Piloerection ▪ Tachycardia ▪ Anxiety/Agitation ▪ Lacrimation ▪ Mydriasis ▪ Muscle effects o Tension ▪ Rhinorrhea/Sneezing ▪ Yawning! o Cramps ▪ Abdominal Cramps o Aching ▪ Nausea Tolerance & OIH Highly Plastic, Allostatic Load ➔Overload ▪ Fentanyl > Morphine > Methadone ▪ OIH MOA (like nociplastic pain) > Endomorphin o Glutamate activity (NMDA, KOR, AMPA Δs, Uptake) - LTP ▪ Euphoria > Analgesia > RD/OIVI > o Spinal Dynorphin Constipation o Descending facilitation ▪ Goldilocks Phenomena o MOR & G-protein coupling Δs o Ultra-low Naloxone: Tolerance (filamin o Nociceptin activity Δs A); Suboxone relevance o Neuro-inflammation (microglia, BDNF, o Low & high Morphine pro-nociceptive Cl- current Δs) Velayudhan et al. 2013 Endogenous Opioids “Purposes” ▪ Pain/Nociception Regulation ▪ Brain Opioid Theory of Social ▪ Salience Network – Attachment (BOTSA) Motivational Valence oBeyond oxytocin/vasopressin
Load more

Recommended publications
  • Endomorphins and Activation of the Hypothalamo–Pituitary–Adrenal Axis
    185 Endomorphins and activation of the hypothalamo–pituitary–adrenal axis T L Coventry, D S Jessop, D P Finn, M D Crabb, H Kinoshita and M S Harbuz University Research Centre for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK (Requests for offprints should be addressed to M S Harbuz; Email: [email protected]) Abstract Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides unaffected by either morphine or endomorphins. Since recently located in the central nervous system and immune release of other opioids are elevated in response to acute tissues with high selectivity and affinity for the µ-opioid stress, we exposed rats to a range of stressors to determine receptor. Intracerebroventricular (i.c.v.) administration of whether plasma EM-1 and EM-2 can be stimulated by morphine stimulates the hypothalamo–pituitary–adrenal HPA axis activation. Plasma corticosterone, ACTH and (HPA) axis. The present study investigated the effect of -endorphin were elevated following acute restraint stress, centrally administered EM-1 and EM-2 on HPA axis but concentrations of plasma EM-1-immunoreactivity (ir) activation. Rats received a single i.c.v. injection of either and EM-2-ir did not change significantly. Corticosterone, EM-1 (0·1, 1·0, 10 µg), EM-2 (10 µg), morphine (10 µg), ACTH and -endorphin were further elevated in or vehicle (0·9% saline). Blood samples for plasma cortico- adjuvant-induced arthritis (AA) rats by a single injection of sterone determinations were taken immediately prior to lipopolysaccharide (LPS), but not by restraint stress.
    [Show full text]
  • Neurotransmitter and Neuropeptide Regulation of Mast Cell Function
    Xu et al. Journal of Neuroinflammation (2020) 17:356 https://doi.org/10.1186/s12974-020-02029-3 REVIEW Open Access Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review Huaping Xu1, Xiaoyun Shi2, Xin Li3, Jiexin Zou4, Chunyan Zhou5, Wenfeng Liu5, Huming Shao5, Hongbing Chen5 and Linbo Shi4* Abstract The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell–related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell–related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell–related pathogenesis.
    [Show full text]
  • Endomorphin-1: Induction of Motor Behavior and Lack of Receptor Desensitization
    The Journal of Neuroscience, June 15, 2001, 21(12):4436–4442 Endomorphin-1: Induction of Motor Behavior and Lack of Receptor Desensitization Arpesh Mehta,1 George Bot,2 Terry Reisine,2 and Marie-Franc¸ oise Chesselet1 1Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles, California 90095, and 2Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 The endomorphins are recently discovered endogenous ago- ish the subsequent ability of the agonist to inhibit adenylate nists for the ␮-opioid receptor (Zadina et al., 1997). Endomor- cyclase activity in cells expressing the cloned ␮-opioid recep- phins produce analgesia; however, their role in other brain tor. Confirming the involvement of ␮-opioid receptors, the be- functions has not been elucidated. We have investigated the havioral effect of endomorphin-1 in the globus pallidus was behavioral effects of endomorphin-1 in the globus pallidus, a blocked by the opioid antagonist naloxone and the ␮-selective brain region that is rich in ␮-opioid receptors and involved in peptide antagonist Cys 2-Tyr 3-Orn 5-Pen 7 amide (CTOP). Fur- 2 4 motor control. Bilateral administration of endomorphin-1 in the thermore, the selective ␮ receptor agonist [D-Ala -N-Me-Phe - globus pallidus of rats induced orofacial dyskinesia. This effect Glycol 5]-enkephalin (DAMGO) also stimulated orofacial dyski- was dose-dependent and at the highest dose tested (18 pmol nesia when infused into the globus pallidus, albeit transiently. per side) was sustained during the 60 min of observation, Our findings suggest that endogenous ␮ agonists may play a indicating that endomorphin-1 does not induce rapid desensi- role in hyperkinetic movement disorders by inducing sustained tization of this motor response.
    [Show full text]
  • Peptides for Health Benefits 2019
    International Journal of Molecular Sciences Editorial Peptides for Health Benefits 2019 Cristina Martínez-Villaluenga 1 and Blanca Hernández-Ledesma 2,* 1 Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain; [email protected] 2 Institute of Food Science Research (CIAL, CSIC-UAM, CEI UAM+CSIC), Nicolás Cabrera, 9, 28049 Madrid, Spain * Correspondence: [email protected] Received: 31 March 2020; Accepted: 2 April 2020; Published: 6 April 2020 In recent years, peptides have received increased interest in pharmaceutical, food, cosmetics and various other fields. The high potency, specificity and good safety profile are the main strengths of bioactive peptides as new and promising therapies that may fill the gap between small molecules and protein drugs. Peptides possess favorable tissue penetration and the capability to engage into specific and high-affinity interactions with endogenous receptors. These positive attributes of peptides have driven research in evaluating peptides as versatile tools for drug discovery and delivery. In addition, among bioactive peptides, those released from food protein sources have acquired importance as active components in functional foods and nutraceuticals because they are known to possess regulatory functions that can lead to health benefits. This Special Issue of International Journal of Molecular Sciences represents the second in a series dedicated to peptides. This issue includes thirty-six outstanding papers describing examples of the most recent advances in peptide research and its applicability. The Special Issue begins with a group of papers exploring aspects of synthetic peptides that are of significance to develop novel drugs for controlling and/or managing chronic diseases.
    [Show full text]
  • Release of Endomorphin Hormone and Its Effects on Our Body and Moods: a Review
    International Conference on Chemical, Biological and Environment Sciences (ICCEBS'2011) Bangkok Dec., 2011 Release of Endomorphin Hormone and Its Effects on Our Body and Moods: A Review Dr. P. B. Rokade we do continuous exercise for more than 30 minutes than Abstract—Endorphin is a hormone and types of endorphins are there is release of these hormones [2]. found in our body. Endorphin is like morphine in structure and When there is high stress in our mind, this stress stimulates effects and has same binding site in the brain cells or receptors. the release of endorphin hormones which calms the brain in Different endorphins are released during different exercises or eating stress situation and brings the feeling of happiness [2]. food or during sex, meditation etc. Anxiety is a disease which is widely spread and can be treated with this endogenous endorphin During an accident or injury our body is in high pain and without using any medication or tablets, only the thing is that we these signals of pain tend to release the endorphins from the must know how and when endorphin is released. It is in our hands to pituitary gland. Pain may be of any kind it initiates the release release endorphin where and when we need. of endorphins. During acupuncture when needles are inserted at prefixed points it causes pain and releases pain signals I. INTRODUCTION which stimulates pituitary gland to release endorphins [3, 4]. UR body produces hundreds of chemicals to make sure Endorphin seems to be released during meditation, high O the body works properly.
    [Show full text]
  • Substance P Induces Gastric Mucosal Protection at Supraspinal Level Via Increasing the Level of Endomorphin-2 in Rats
    Elsevier Editorial System(tm) for Brain Research Bulletin Manuscript Draft Manuscript Number: BRB-D-12-00460R1 Title: Substance P induces gastric mucosal protection at supraspinal level via increasing the level of endomorphin-2 in rats Article Type: Original Research Article Section/Category: Neuropharmacological Mechanisms and Neurotherapeutics Keywords: calcitonin gene-related peptide, endomorphin, gastric ulcer, substance P, tachykinins Corresponding Author: Prof. Klára Gyires, M.D., Ph.D Corresponding Author's Institution: Semmelweis University First Author: Serena B Brancati Order of Authors: Serena B Brancati; Zoltán S Zádori, Ph.D.; József Németh, Ph.D.; Klára Gyires, M.D., Ph.D Abstract: The aim of the present study was to analyze the potential role of substance P (SP) in gastric mucosal defense and to clarify the receptors and mechanisms, that may be involved in it. Gastric ulceration was induced by oral administration of acidified ethanol in male Wistar rats. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. We found that central (intracerebroventricular) injection of SP (9.3 - 74 pmol) dose- dependently inhibited the formation of ethanol-induced ulcers, while intravenously injected SP (0.37-7.4 nmol/kg) had no effect. The mucosal protective effect of SP was inhibited by pretreatment with neurokinin 1-, neurokinin 2-, neurokinin 3- and μ-opioid receptor antagonists, while δ- and κ-opioid receptor antagonists had no effect. Endomorphin-2 antiserum also antagonized the SP-induced mucosal protection. In the gastroprotective dose range SP failed to influence the gastric motor activity.
    [Show full text]
  • Dynorphinergic Mechanism Mediating Endomorphin-2-Induced Anti-Analgesia in the Mouse Spinal Cord Hsiang-En Wu, Han-Sen Sun, Mose
    JPET Fast Forward. Published on October 13, 2003 as DOI: 10.1124/jpet.103.056242 JPET FastThis articleForward. has not Published been copyedited on and October formatted. 13,The final2003 version as DOI:10.1124/jpet.103.056242 may differ from this version. Dynorphinergic mechanism mediating endomorphin-2-induced anti-analgesia in the mouse spinal cord Hsiang-En Wu, Han-Sen Sun, Moses Darpolar, Randy J. Leitermann, John P. Kampine and Leon F. Tseng* Department of Anesthesiology, Medical College of Wisconsin, Downloaded from Milwaukee, WI 53226, USA jpet.aspetjournals.org at ASPET Journals on September 26, 2021 Copyright 2003 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on October 13, 2003 as DOI: 10.1124/jpet.103.056242 This article has not been copyedited and formatted. The final version may differ from this version. a) Running title: Endomorphin-2-induced anti-analgesia b) Corresponding author: Leon F. Tseng, Ph.D. Department of Anesthesiology Medical College of Wisconsin Medical Education Building, Room M4308 8701 Watertown Plank Road Downloaded from Milwaukee, WI 53226 Tel: (414) 456-5686, jpet.aspetjournals.org Fax: (414) 456-6507 E-mail: [email protected] c) The number of text pages: 31 at ASPET Journals on September 26, 2021 The number of figures: 7 The number of table: 1 The number of references: 38 The number of words in Abstract: 259 The number of words in Introduction: 462 The number of words in Discussion: 1314 d) Abbreviations: Dyn, Dynorphin A(1-17); EM-1, endomorphin-1; EM-2, endomorphin-2; CCK, cholecystokinin; DAMGO, [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin; NTI, naltrindole; nor-BNI, nor-binaltorphimine; NRS, normal rabbit serum; TF, Tail-flick response; %MPE, percent maximum possible effect 2 JPET Fast Forward.
    [Show full text]
  • Redalyc.Endomorphin Peptides
    Salud Mental ISSN: 0185-3325 [email protected] Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz México Leff Gelman, Philippe; González Herrera, Norma Estela; Matus Ortega, Maura Epifanía; Beceril Villanueva, Enrique; Téllez Santillán, Carlos; Salazar Juárez, Alberto; Antón Palma, Benito Endomorphin peptides: pharmacological and functional implications of these opioid peptides in the brain of mammals. Part two Salud Mental, vol. 33, núm. 3, mayo-junio, 2010, pp. 257-272 Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz Distrito Federal, México Available in: http://www.redalyc.org/articulo.oa?id=58216021007 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative Salud Mental 2010;33:257-272Endomorphin peptides: pharmacological and functional implications in the brain of mammals Endomorphin peptides: pharmacological and functional implications of these opioid peptides in the brain of mammals. Part two Philippe Leff Gelman,1 Norma Estela González Herrera,2 Maura Epifanía Matus Ortega,1 Enrique Beceril Villanueva,3 Carlos Téllez Santillán,3 Alberto Salazar Juárez,1 Benito Antón Palma1 Actualización por temas SUMMARY of stress and depression, whereby EM1-2 peptides have been shown to up-regulate in a dose-dependent manner the neuronal expression Endomorphin-1 (EM1) and Endomorphin-2 (EM2) represent the two of the BDNF mRNA in rat limbic areas involved in stress and endogenous C-terminal amide tetrapeptides shown to display a high depressive-like behaviors. Thus, these studies led to the proposition binding affinity and selectivity for the µ-opioid receptor as reported that endomorphin peptides may play crucial roles in psychiatric previously (see previous paper, Part I).
    [Show full text]
  • The Atypical Chemokine Receptor ACKR3/CXCR7 Is a Broad-Spectrum Scavenger for Opioid Peptides
    University of Southern Denmark The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Meyrath, Max; Szpakowska, Martyna; Zeiner, Julian; Massotte, Laurent; Merz, Myriam P.; Benkel, Tobias; Simon, Katharina; Ohnmacht, Jochen; Turner, Jonathan D.; Krüger, Rejko; Seutin, Vincent; Ollert, Markus; Kostenis, Evi; Chevigné, Andy Published in: Nature Communications DOI: 10.1038/s41467-020-16664-0 Publication date: 2020 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Meyrath, M., Szpakowska, M., Zeiner, J., Massotte, L., Merz, M. P., Benkel, T., Simon, K., Ohnmacht, J., Turner, J. D., Krüger, R., Seutin, V., Ollert, M., Kostenis, E., & Chevigné, A. (2020). The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides. Nature Communications, 11, [3033]. https://doi.org/10.1038/s41467-020-16664-0 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 05. Oct. 2021 ARTICLE https://doi.org/10.1038/s41467-020-16664-0 OPEN The atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides Max Meyrath1,9, Martyna Szpakowska 1,9, Julian Zeiner2, Laurent Massotte3, Myriam P.
    [Show full text]
  • Beta-Endorphin Peptide and Some Selected Psychiatric Disorders Zalewska-Kaszubska J* Department of Pharmacodynamics, Medical University of Lodz, Poland
    Open Access Journal of Psychiatry Studies REVIEW ARTICLE ISSN: 2641-8525 Beta-Endorphin Peptide and some Selected Psychiatric Disorders Zalewska-Kaszubska J* Department of Pharmacodynamics, Medical University of Lodz, Poland *Corresponding author: Zalewska-Kaszubska J, Department of Pharmacodynamics, Medical University of Lodz, Muszynskiego 1, PL 90-151 Lodz, Poland, E-mail: [email protected] Citation: Zalewska-Kaszubska J (2018) Beta-Endorphin Peptide and some Selected Psychiatric Disorders. J Psychiatry Stu 1: 105 Article history: Received: 04 September 2018, Accepted: 30 November 2018, Published: 03 December 2018 Abstract Beta-endorphin, an endogenous opioid peptide seems to play an important role in some psychiatric disorders. Some researchers observed a correlation between this peptide level in plasma or cerebrospinal fluid and several diseases such as: major mood disorders, schizophrenia, autism, self-injurious behavior and addiction. However, there are also many inconclusive reports which do not evidently prove that a deficit or an excess of this peptide is related to specific diseases. These discrepancies may depend on methodological methods and patients’ selection, who may present different subtypes of the same disease. It was also suggested to use beta-endorphin as an indicator of effectiveness of treatment in some psychiatric disorders. Conclusion: Beta-endorphin measurement may help assessing the effectiveness of therapy in some psychiatric diseases as well predicting the development of some diseases related to beta-endorphin as postpartum depression or PTSD. Keywords: Beta-Endorphin; Depression; Schizophrenia; Autism; Self-Injury Behavior; Post-Traumatic Stress Disorder Introduction Beta-endorphin is the most important peptide of the endogenous opioid system, which consists of 3 families of peptides: endorphins, enkephalins and dynorphins, as well as two additional peptides, endomorphin-1 and -2 [1,2].
    [Show full text]
  • Another Opiate for the Masses?
    news and views Neuropharmacology increase selectivity for the J.L receptor. Further­ more, the long-lasting analgesic activity of Another opiate for the masses? endomorphin-1 and -2 could reflect pro­ tection from exoproteolytic degradation David Julius conferred by the carboxy-terminal amidation. By analogy with other peptide hormones he active ingredients of natural toxins and neurotransmitters8, including the endor­ Tand herbal remedies have helped to Endomorph ins phins, one would expect the endomorphins unlock the secrets of biological Dynorphins (3-endorphin Enkephalins to be excised from a larger polyprotein pre­ processes ranging from cell division to cursor. Cloning the gene for this hypothetical synaptic transmission. A notable example is pro-endomorphin would serve at least three opium- an extract of the poppy plant that purposes. First, it would confirm that the has been used for centuries to induce eu­ endomorphins are indeed endogenous phoria and relieve pain. The active compo­ neuropeptides, derived by specific proteolyt­ nent of opium is morphine, and its synthetic ic cleavage events. Second, sequence analysis congener is heroin 1'2• The analgesia, reward­ of the gene would clarify any genetic relation­ seeking behaviour and physical dependence ship between endomorphins and the pep­ elicited by rnorphine2'3 are mainly mediated Figure I Known agonists for the K, J.1 and o opioid tides that led to their isolation, including Tyr­ through the J.L opioid receptor and, on page receptors. Zadina et al.' have identified two MIF-1 and Tyr-W-MIF-1, and other biologi­ 499 of this issue, Zadina and colleagues4 naturally occurring endorphins (termed cally active peptides might be discovered in report the isolation of two new J.L-selective endomorphin-1 and -2) which bind with high the process.
    [Show full text]
  • Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives
    International Journal of Organic Chemistry, 2012, 2, 1-6 http://dx.doi.org/10.4236/ijoc.2012.21001 Published Online March 2012 (http://www.SciRP.org/journal/ijoc) Synthesis and Plasma Stability of Disulfide-Bridged Cyclic Endomorphin-1 Derivatives Friederike M. Mansfeld, Istvan Toth School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Australia Email: [email protected] Received December 12, 2011; revised January 14, 2012; accepted January 26, 2012 ABSTRACT Endomorphin-1 is an endogenous opioid peptide that mediates pain relief through interaction with the µ-opioid receptor in the central nervous system. To enhance the metabolic stability of this tetrapeptide, cyclisation through the formation of a disulfide bridge between the side chains of cysteine residues added to the sequence was explored. A further in- crease in stability was achieved through N-terminal modification with lipoamino acid and lactose succinamic acid, and the inclusion of D-amino acids. The latter also provided an alternative spatial arrangement of the aromatic side chains. The lipidated cyclic derivatives were insoluble in aqueous buffer, however, the cyclic peptides and glycopeptides showed greatly improved stability towards enzymatic degradation in human plasma. Keywords: Endomorphin-1; Opioid Peptide; Cyclisation; Disulfide 1. Introduction [13,14], not many cyclic analogues of the endomorphins have been synthesised so far. Cardillo, Gentilucci et al. The use of opium, the dried sap isolated from the opium [15-17] synthesised a series of diastereo- and enantio- poppy (Papaver somniferum), for pain relief dates back meric cyclic endomorphin-1 derivatives in which Tyr1 thousands of years. Although it contains more than 50 4 different alkaloids, morphine, which was first isolated by and Phe are connected through glycine by amide bonds.
    [Show full text]