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Non-Commercial Use Only ORIGINAL PAPER Reumatismo, 2021; 73 (1): 24-31 Does human serotonin-1A receptor polymorphism (rs6295) code for pain and associated symptoms in fibromyalgia syndrome? S. Tanwar1, B. Mattoo1, U. Kumar2, R. Dada3, R. Bhatia1 1Department of Physiology; 2Department of Rheumatology; and 3Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, India SUMMARY Genetic predisposition may play an important role in the development of fibromyalgia syndrome (FMS). Sero- tonin is known to be involved in pain modulation and serotonin-1A receptor plays a considerable role in deter- mining the central 5-HT tone. Consequently, variation in 5-HT1A receptor gene (HTR1A) may be responsible for inter-individual variability in pain sensitivity and other clinical symptoms of FMS. Therefore, the objectives of this research work were to study the gene polymorphism of 5-HTR1A gene and to explore the correlation between rs6295 genotype (−1019C/G HTR1A) and duration of pain, painonly intensity and pain related depression and anxiety, if any, in FMS. 5-HTR1A genotype for the C(-1019)G polymorphism was typed in 62 patients with FMS and 42 healthy sub- jects. Present pain intensity, components of pain and pain related depression and anxiety were assessed using the numerical pain rating scale, McGill pain questionnaireuse and Hamilton depression and anxiety rating scale respectively. 5-HTR1A gene was represented by three different genotypes, homozygous C/C, heterozygous C/G and ho- mozygous G/G. Analysis of the 5-HTR1A gene showed a frequency of 58%, 31% and 11% for the C/C, C/G and G/G genotypes, respectively in FMS group. This proportion was 69%, 23% and 8% in healthy subjects. No significant correlation was observed between5-HTR1A gene polymorphism and pain and related symptoms in FMS patients. To the best of our knowledge this is the first study which investigated the correlation between the 5-HTR1A gene polymorphism and pain intensity, the affective component of pain, pain related depression and anxiety in FMS. Key words: Fibromyalgia; serotonin-1A receptor polymorphism (rs6295); pain intensity, pain related depres- sion and anxiety. Reumatismo, 2021; 73 (1): 24-31 Non-commercial n INTRODUCTION metabolites in the cerebrospinal fluid (3). Several studies have also shown potential ibromyalgia syndrome (FMS) is a se- association between FMS and polymor- Fverely debilitating chronic pain syn- phisms in serotonin-related genes, further drome. It is defined by widespread muscu- corroborating the fact that the serotonergic loskeletal pain, for more than three months, system is markedly involved in the modu- and accompanied by auxiliary symptoms, lation of homeostatic, affective and pain- like joint stiffness, chronic fatigue, unre- related mechanisms (4). A previous study Corresponding author: Renu Bhatia freshing sleep, depression, anxiety and has suggested that serotonin is essential in Department of Physiology, AIIMS cognitive malfunction (1). Genetic pre- the regulation of anxiety, fear, and also in New Delhi 110029, India E-mail: [email protected] disposition plays an important role in the the tendency to commit suicide and other Present address of the first author: progression of FMS (2). Previous studies violent actions (5). These behaviours are S. Tanwar on genetic vulnerability in FMS reported a mediated by at least 14 different serotonin Department of Zoology, Govt. College for Girls, Sec-14, dysregulation of central serotonergic me- receptors (6). Additionally, the serotonin- Gurugram, Haryana 122001, India tabolism, and reduced serotonin (5-HT) 1A receptor (5-HTR1A) has been shown to 24 Reumatismo 1/2021 ORIGINAL Serotonin-1A receptor polymorphism and fibromyalgia PAPER help in detecting anxiety disorders as prov- n MATERIALS AND METHODS en by the results of a clinical study showing Patient enrollment that selective 5-HT1A receptor agonists are The study was conducted in the Pain Re- common tranquilizers (7). search and TMS Laboratory, Department of 5-HT1A receptors are vastly expressed in Physiology, All India Institute of Medical brain areas such as orbitofrontal cortex, Sciences (AIIMS), New Delhi and was ap- amygdala, hippocampus, insula, cingulate proved by the Institute Human Ethics com- cortex and midbrain raphe areas which are mittee (Ref No: IESC/T-251/15.06.2013). associated with affective and emotional The current data is a part of one of the ob- processes (8). Altered 5-HT1A levels are jectives of a doctoral thesis which included also observed in major depressive disor- the investigation on the effect of repetitive der (9), bipolar disorder (10) and anxiety transcranial magnetic stimulation on pain disorder (11). and its modulation (which was performed Clinically, the partial 5-HT1A agonists with subjective, objective pain assessment and serotonin reuptake inhibitor are used tools and biochemical markers) in FMS pa- to treat anxiety disorders (12) and depres- tients (24). All procedures performed dur- sion (13). ing the study involving patients were in ac- Many genetic studies demonstrated that cordance with the ethical standardsonly of the GG genotype or G allele carriers of the Human Ethics committee of the AIIMS, 5-HT1A gene promoter polymorphisms New Delhi. are associated with depression (5, 9) and Female patients with FMS (age 18-50 years) may influence the response to antidepres- having regular menstrualuse cycle were re- sant therapy (14, 15). Studies on major de- cruited from the Rheumatology Clinic, at pression, anxiety, panic disorder, suicide the Department of Rheumatology. The en- and schizophrenia have also indicated the rollment was based on the American Col- involvement of the G allele as a ‘risk al- lege of Rheumatology (ACR) 1990 crite- lele’ (5, 14, 16). ria for the classification of FMS (19). Age There is considerable concomitance be- and gender matched healthy subjects were tween chronic pain and affective disorders recruited among patient relatives and Insti- (17) suggesting interlinked neurobiologi- tute staff. Only the subjects who were able cal pathways, such as potentially seroton- to give written informed consent were en- ergic deregulation (18). rolled in the study. The FMS patients were These findings suggest that the relation- excluded from the study, if they were: ship between FMS and polymorphisms in 1) pregnant or lactating; serotonin-related genes needs further clar- 2) having irregular menstrual cycle; ification and might be favoured by psychi- 3) having chronic systemic disease, in- atric comorbidity. ThoughNon-commercial many studies flammatory joint diseases, secondary have been conducted to find the involve- FMS, seizures, history of trauma; ment of the genes related to serotonergic 4) with a concomitant diagnosis of chronic pathways related to pain modulation, lim- fatigue syndrome and/or major psychi- ited work has been focused on 5-HT1A re- atric disorder, currently undergoing ceptor gene polymorphism in FMS. In our psychotherapy. literature search, no study has observed the effect of 5-HTR1A (rs6295) interac- Subjective assessment of pain and related tion on pain, its various affective compo- symptoms: nents, pain-related depression and anxi- The pain intensity was evaluated by Nu- ety. Therefore, in this study, HTR1A gene merical Pain Rating Scale (NPRS) or NRS polymorphism was compared between which is a 11-point numerical scale rang- patients with FMS and healthy volunteers ing from ‘0’ meaning ‘no pain’ to ‘10’ and correlated with pain intensity, the af- meaning ‘pain as bad as you can imagine’ fective component of pain, pain-related or ‘worst pain imaginable’ (20). The mul- depression and anxiety. tidimensional components of pain were Reumatismo 1/2021 25 ORIGINAL PAPER S. Tanwar, B. Mattoo, U. Kumar, et al. assessed by McGill pain questionnaire for 5 min. vi. PCR products were checked (MPQ), which is designed to measure the for amplification on 1.5% agarose gel. sensory, affective and evaluative aspects of Restriction fragment length polymorphism pain in adults suffering from chronic pain. (RFLP) analysis: The scale consists of 78 descriptive items Amplified PCR products were digested with categorized into 20 subclasses evaluating 2.5 U BtsCI (Fermentas, USA) and incubat- sensory (question 1 to 10), affective (ques- ed at 37°C for 35 min and separated on 2.5% tion 11 to 15), evaluative (question 16) and agarose gel. The 5-HTR1A-CC genotype miscellaneous components of pain (ques- was represented by fragments of 544bp, the tion 17 to 20) (21). Pain-related anxiety 5-HTR1A-CG genotype by fragments of was evaluated by Hamilton Anxiety Rating 544bp, 488bp and 56bp and 5-HTR1A-GG Scale (HARS). It contains 14 items, each genotype by fragments of 488bp and 56bp. defined by a series of symptoms, and meas- ures both psychic anxiety (psychological Statistical analysis distress and mental agitation) and somatic All the analyses were performed using anxiety (physical complaints related to IBM SPSS Statistics version 22.0 (IBM anxiety). Each item is scored on a scale of Statistics for Windows, Chicago, IL, USA) 0 (not present) to 4 (severe), with a total and graphsonly were created using Graphpad score range of 0-56, where <17 indicates Prism version 5.01 for Windows, (Graph- mild anxiety, 18-24 mild to moderate anxi- Pad Software, San Diego, California, USA). ety and 25-30 moderate to severe anxiety All data was checked for normality us- (22). Pain-related depression was studied useing D’Agostino and Pearson’s omnibus by utilizing Hamilton Depression Rating normality test. The Baseline scores of the Scale (HDRS). Eight items are scored on a parameters between healthy subjects and 5-point scale, ranging from 0, ‘not present’ FMS groups were compared using un- to 4, ‘severe’. Nine items are scored 0-2. paired t test/ Mann-Whitney U test. Chi- First 17 items are added to obtain the total Square test was applied to assess statisti- score (23). cal difference in frequency of genotypes of 5-HTR1A gene between healthy subjects Genotyping and FMS patients. One Way ANOVA was Blood samples were collected in EDTA applied to assess the statistical significance tubes and stored at -80°C until further use.
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