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Haythornthwaite JA, Campbell CM, Edwards RR. When thinking about pain contributes to suffering: the example of pain catastrophizing. Pain 2024; 165:S68-S75. [PMID: 39560417 PMCID: PMC11581624 DOI: 10.1097/j.pain.0000000000003372] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/07/2024] [Indexed: 11/20/2024]
Abstract
ABSTRACT The extensive literature on the potent role negative thoughts about pain have on the experience of pain and pain-related suffering has documented associations with important neurobiological processes involved in amplifying nociceptive signals. We focus this review on pain catastrophizing (pCAT)- appraisals of pain as threatening, overwhelming, and unmanageable- and review the evidence that these thoughts are learned in childhood through experience and observation of others, particularly caretakers and parents. For children who have learned pCAT, repeated exposures to pain over time activate pCAT and likely contribute to further amplification of pain through changes in the neurobiological pain regulatory systems, which overlap with those regulating the stress response. We propose that repeated pain and stress exposures throughout childhood, adolescence, and into adulthood alter the neurobiology of pain via a repetitive positive feedback loop that increases risk for heightened pain sensitivity over time with repeated exposures. At some point, often precipitated by an acute episode of pain and possibly influenced by allostatic load, pCAT contributes to persistence of episodic or acute pain and exacerbates pain-related suffering. This developmental trajectory is not inevitable, as the impact of pCAT on pain and pain-related suffering can be influenced by various factors. We also present future directions for work in this area.
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Affiliation(s)
- Jennifer A Haythornthwaite
- Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Claudia M Campbell
- Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Robert R Edwards
- Department of Anesthesiology, Perioperative & Pain Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, United States
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2
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Yongming L, Yizhe X, Zhikai Q, Yupeng W, Xiang W, Mengyuan Y, Guoqing D, Hongsheng Z. Identification of ion channel-related genes as diagnostic markers and potential therapeutic targets for osteoarthritis through bioinformatics and machine learning-based approaches. Biomarkers 2024; 29:285-297. [PMID: 38767974 DOI: 10.1080/1354750x.2024.2358316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 05/05/2024] [Indexed: 05/22/2024]
Abstract
BACKGROUND Osteoarthritis (OA) is a debilitating joint disorder characterized by the progressive degeneration of articular cartilage. Although the role of ion channels in OA pathogenesis is increasingly recognized, diagnostic markers and targeted therapies remain limited. METHODS In this study, we analyzed the GSE48556 dataset to identify differentially expressed ion channel-related genes (DEGs) in OA and normal controls. We employed machine learning algorithms, least absolute shrinkage and selection operator(LASSO), and support vector machine recursive feature elimination(SVM-RFE) to select potential diagnostic markers. Then the gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore the potential diagnostic markers' involvement in biological pathways. Finally, weighted gene co-expression network analysis (WGCNA) was used to identify key genes associated with OA. RESULTS We identified a total of 47 DEGs, with the majority involved in transient receptor potential (TRP) pathways. Seven genes (CHRNA4, GABRE, HTR3B, KCNG2, KCNJ2, LRRC8C, and TRPM5) were identified as the best characteristic genes for distinguishing OA from healthy samples. We performed clustering analysis and identified two distinct subtypes of OA, C1, and C2, with differential gene expression and immune cell infiltration profiles. Then we identified three key genes (PPP1R3D, ZNF101, and LOC651309) associated with OA. We constructed a prediction model using these genes and validated it using the GSE46750 dataset, demonstrating reasonable accuracy and specificity. CONCLUSIONS Our findings provide novel insights into the role of ion channel-related genes in OA pathogenesis and offer potential diagnostic markers and therapeutic targets for the treatment of OA.
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Affiliation(s)
- Liu Yongming
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Xiong Yizhe
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Qian Zhikai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Wang Yupeng
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Wang Xiang
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Yin Mengyuan
- Department of Traditional Chinese Orthopedics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Du Guoqing
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Zhan Hongsheng
- Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
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3
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Arribas-Romano A, Fernández-Carnero J, Rodríguez-Lagos L, Molina-Álvarez M, Zabala-Zambrano J, Lezaun-Hernández L, Contreras-Padilla L, Mercado F. CPM-Related Mechanisms Could Play a Key Role in the Effects on Pain Sensitivity Induced by Manual Therapy: Three Crossover Trials Investigating the Effects of Manual Pressure. J Clin Med 2024; 13:3648. [PMID: 38999214 PMCID: PMC11242484 DOI: 10.3390/jcm13133648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/15/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Objective: The aim of this study is to assess whether pain-inducing manual pressure (PIMP) leads to effects on pressure pain threshold (PPT) mediated by conditioned pain modulation (CPM) and whether these effects are influenced by the intensity and repetition of the stimulus. Additionally, the influence of psychological factors and physical activity on the response to PIMP was explored. Methods: A total of 72 pain-free students were randomly assigned to three crossover trials. Trial 1 compared the effects of PIMP with the cold pressor task and pain-inducing electrostimulation. Trial 2 compared the effects of manual pressure that elicited moderate pain, mild pain, and no pain. Trial 3 compared a single PIMP stimulation with four stimuli applied at the same site or at different sites. Results: PIMP produced a lower increase in PPT than cold pressor task and no difference with electrostimulation. Manual pressure that caused moderate pain led to a greater increase in PPT compared to mild pain and pain-free application. Repetition of PIMP stimulus, whether at the same or different sites, did not significantly increase PPT compared to a single stimulation. No association with psychological factors or physical activity was found. Conclusions: PIMP produces an increase in PPT, suggesting the involvement of CPM-related mechanisms.
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Affiliation(s)
- Alberto Arribas-Romano
- Escuela Internacional de Doctorado, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, 28933 Madrid, Spain; (A.A.-R.); (L.R.-L.)
- Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain; (M.M.-Á.); (F.M.)
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Rey Juan Carlos University, 28922 Madrid, Spain
| | - Josué Fernández-Carnero
- Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain; (M.M.-Á.); (F.M.)
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Rey Juan Carlos University, 28922 Madrid, Spain
- Motion in Brains Research Group, Institute of Neuroscience and Movement Sciences (INCIMOV), Centro Superior de Estudios Universitarios La Salle, Universidad Autonoma de Madrid, 28049 Madrid, Spain; (J.Z.-Z.); (L.L.-H.)
- La Paz Hospital Institute for Health Research, IdiPAZ, 28029 Madrid, Spain
| | - Leonardo Rodríguez-Lagos
- Escuela Internacional de Doctorado, Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Universidad Rey Juan Carlos, 28933 Madrid, Spain; (A.A.-R.); (L.R.-L.)
- Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain; (M.M.-Á.); (F.M.)
| | - Miguel Molina-Álvarez
- Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain; (M.M.-Á.); (F.M.)
- Area of Pharmacology, Nutrition and Bromatology, Department of Basic Health Sciences, Rey Juan Carlos University, Unidad Asociada I+D+i Instituto de Química Médica (IQM) CSIC-URJC, 28922 Alcorcón, Spain
| | - Jesús Zabala-Zambrano
- Motion in Brains Research Group, Institute of Neuroscience and Movement Sciences (INCIMOV), Centro Superior de Estudios Universitarios La Salle, Universidad Autonoma de Madrid, 28049 Madrid, Spain; (J.Z.-Z.); (L.L.-H.)
- Advance Rehabilitation Center Sanitas, 28046 Madrid, Spain
| | - Lucas Lezaun-Hernández
- Motion in Brains Research Group, Institute of Neuroscience and Movement Sciences (INCIMOV), Centro Superior de Estudios Universitarios La Salle, Universidad Autonoma de Madrid, 28049 Madrid, Spain; (J.Z.-Z.); (L.L.-H.)
- Edurne Esquide Fisioterapia, 31200 Estella, Spain
| | - Lucía Contreras-Padilla
- iCentro Fix You, 28009 Madrid, Spain;
- School of Physiotherapy ONCE, Universidad Autónoma de Madrid, 28022 Madrid, Spain
| | - Francisco Mercado
- Cognitive Neuroscience, Pain and Rehabilitation Research Group (NECODOR), Faculty of Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain; (M.M.-Á.); (F.M.)
- Department of Psychology, Faculty of Health Sciences, Universidad Rey Juan Carlos, 28922 Madrid, Spain
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Simic K, Savic B, Knezevic NN. Pain Catastrophizing: How Far Have We Come. Neurol Int 2024; 16:483-501. [PMID: 38804476 PMCID: PMC11130925 DOI: 10.3390/neurolint16030036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/19/2024] [Accepted: 04/24/2024] [Indexed: 05/29/2024] Open
Abstract
The perception of pain is strongly influenced by various social, emotional, and cognitive factors. A psychological variable which has consistently been shown to exert its influence on pain is a cognitive process referred to as pain catastrophizing. Numerous studies have found it to be a strong predictor of pain intensity and disability across different clinical populations. It signifies a maladaptive response to pain marked by an exaggerated negative assessment, magnification of symptoms related to pain, and, in general, a tendency to experience marked pain-related worry, as well as experiencing feelings of helplessness when it comes to dealing with pain. Pain catastrophizing has been correlated to many adverse pain-related outcomes, including poor treatment response, unsatisfactory quality of life, and high disability related to both acute and chronic pain. Furthermore, there has been consistent evidence in support of a correlation between pain catastrophizing and mental health disorders, such as anxiety and depression. In this review, we aim to provide a comprehensive overview of the current state of knowledge regarding pain catastrophizing, with special emphasis on its clinical significance, and emerging treatment modalities which target it.
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Affiliation(s)
- Katarina Simic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (K.S.); (B.S.)
| | - Boris Savic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (K.S.); (B.S.)
| | - Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center, Chicago, IL 60657, USA; (K.S.); (B.S.)
- Department of Anesthesiology, University of Illinois, Chicago, IL 60612, USA
- Department of Surgery, University of Illinois, Chicago, IL 60612, USA
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5
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Castelo-Branco L, Pacheco-Barrios K, Cardenas-Rojas A, de Melo PS, Gianlorenco AC, Gonzalez-Mego P, Marduy A, Shaik ES, Teixeira P, Caumo W, Fregni F. Cross-sectional and longitudinal analysis of conditioned pain modulation and pain in fibromyalgia: CPM as an effect modifier of pain changes over time. PHYSIOTHERAPY RESEARCH INTERNATIONAL 2024; 29:e2072. [PMID: 39055778 PMCID: PMC11268874 DOI: 10.1002/pri.2072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 01/11/2024] [Indexed: 07/27/2024]
Abstract
Background and purpose Fibromyalgia (FM) is associated with altered descending pain modulatory pathways, which can be assessed through Conditioned Pain Modulation (CPM). In this study, we aimed to explore the relationship between CPM and self-reported baseline characteristics in patients with fibromyalgia. We also performed a longitudinal analysis exploring CPM as a potential predictor of clinical improvement over time in individuals with FM. Methods We performed cross-sectional univariable and multivariable analyses of the relationship between CPM and other variables in 41 FM patients. We then performed longitudinal analyses, building linear mixed effects models with pain in the Visual Analogue Scale (VAS) as the dependent variable, and testing for the interaction between time and CPM. We also tested the interaction between CPM and time in models using other outcomes, such as the revised Fibromyalgia Impact Questionnaire (FIQR) and Quality of Life Scale (QOLs). Results We found no association between CPM and other demographic and clinical variables in the univariable analysis. We found a statistically significant association in the multivariable linear regression model between CPM and the QOLs at baseline, after controlling for age, sex, and duration of symptoms. In the longitudinal analyses, we found that CPM is an effect modifier for clinical improvement over time for the pain VAS, QOLs and FIQR: individuals with low-efficient CPM at baseline have a different (improved) pattern of response over time when compared to those with high-efficient CPM. Conclusions Our findings suggest that CPM is not a reliable biomarker of clinical manifestations in chronic pain patients during cross-sectional assessments. However, our results are consistent with previous findings that CPM can be used to predict the evolution of clinical pain over time. We expect that our findings will help in the selection of patients with the best profile to respond to specific interventions and assist clinicians in tailoring pain treatments.
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Affiliation(s)
- Luis Castelo-Branco
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kevin Pacheco-Barrios
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Universidad San Ignacio de Loyola, Vicerrectorado de Investigación, Unidad de Investigación para la Generación y Síntesis de Evidencias en Salud. Lima, Peru
| | - Alejandra Cardenas-Rojas
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paulo S. de Melo
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anna C. Gianlorenco
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Laboratory of neuroscience, Department of Physical Therapy, Federal University of Sao Carlos, SP, Brazil
| | - Paola Gonzalez-Mego
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anna Marduy
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Emad S. Shaik
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Paulo Teixeira
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wolnei Caumo
- Laboratory of Pain & Neuromodulation, Hospital de Clinicas de Porto Alegre da Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Felipe Fregni
- Neuromodulation Center and Center for Clinical Research Learning, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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6
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Wang L, Wang M, Zhao C, Jian J, Qiao D. Association of HTR3B gene polymorphisms with depression and its executive dysfunction: a case-control study. BMC Psychiatry 2023; 23:128. [PMID: 36849934 PMCID: PMC9972617 DOI: 10.1186/s12888-023-04625-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/22/2023] [Indexed: 03/01/2023] Open
Abstract
BACKGROUND Previous studies have shown that depression was associated with HTR3B gene. The aim of this study was to investigate the relationship between polymorphisms of the HTR3B gene and depression and its executive dysfunction in Chinese Han population. METHODS A total of 229 patients with depressive disorder and 202 healthy controls were enrolled. Six Single nucleotide polymorphism sites (SNPs) including rs10789970, rs4938056, rs12421126, rs1176744, rs2276305 and rs12795805 were genotyped by Snapshot. Clinical features were collected using a general demographic questionnaire. The 24-item Hamilton Depression Scale (HAMD) was used to assess the symptoms' severity of the patients. The patients' executive function was assessed using a series of cognitive tests including Maze Test, Symbolic Coding Test, Spatial Span Inverse Order Test, Linking Test, and Emotional Management Test. RESULTS The genotypic and allelic distributions of rs1176744 in HTR3B gene were significantly different (χ2 = 11.129, P = 0.004, χ2 = 9.288, P = 0.002, respectively) between patients and controls. The A allele was positively correlated with depression. The proportion of A carriers was significantly higher and that of C carriers was lower in patients than those in controls. Patients had significantly lower scores of Spatial Span Inverse Order Test in carriers of A allele at locus rs1176744 and higher scores in carriers of C alleles at locus rs1176744 and rs12795805. CONCLUSIONS The polymorphisms of HTR3B gene may be associated with depression in Chinese Han population. The A allele of rs1176744 may increase the risk of developing depression and executive dysfunction while C alleles of rs1176744 and rs12795805 may be the protective factors for executive dysfunction in patients with depression.
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Affiliation(s)
- Lina Wang
- Department of Psychology, Shandong Normal University, Jinan, 250358, Shandong, China.,Department of Psychiatry, Shandong Mental Health Center, Shandong University, Jinan, 250014, Shandong, China
| | - Miao Wang
- School of Mental Health, Jining Medical University, Jining, 272000, Shandong, China
| | - Chaoben Zhao
- School of Mental Health, Jining Medical University, Jining, 272000, Shandong, China
| | - Jia Jian
- Department of Psychiatry, Shandong Mental Health Center, Shandong University, Jinan, 250014, Shandong, China
| | - Dongdong Qiao
- Department of Psychiatry, Shandong Mental Health Center, Shandong University, Jinan, 250014, Shandong, China.
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7
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Fritz N, Berens S, Dong Y, Martínez C, Schmitteckert S, Houghton LA, Goebel-Stengel M, Wahl V, Kabisch M, Götze D, D’Amato M, Zheng T, Röth R, Mönnikes H, Tesarz J, Engel F, Gauss A, Raithel M, Andresen V, Keller J, Frieling T, Pehl C, Stein-Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Bustamante M, Estivil X, Rabionet R, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Schmidt B, Franke A, Lieb W, Herzog W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo-Bermejo J, Niesler B. The serotonin receptor 3E variant is a risk factor for female IBS-D. J Mol Med (Berl) 2022; 100:1617-1627. [PMID: 36121467 PMCID: PMC9592668 DOI: 10.1007/s00109-022-02244-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/18/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
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Affiliation(s)
- Nikola Fritz
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabrina Berens
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Yuanjun Dong
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Cristina Martínez
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.420395.90000 0004 0425 020XInstitut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain ,Lleida Institute for Biomedical Research Dr, Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Stefanie Schmitteckert
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Lesley A. Houghton
- grid.443984.60000 0000 8813 7132University of Leeds, St. James’s University Hospital, Leeds, UK ,grid.417467.70000 0004 0443 9942Mayo Clinic, Jacksonville, FL USA
| | - Miriam Goebel-Stengel
- grid.411544.10000 0001 0196 8249Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany ,Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
| | - Verena Wahl
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Maria Kabisch
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Dorothea Götze
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Mauro D’Amato
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden ,grid.420175.50000 0004 0639 2420Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Derio Spain ,grid.424810.b0000 0004 0467 2314IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Tenghao Zheng
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ralph Röth
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Hubert Mönnikes
- grid.461755.40000 0004 0581 3852Martin-Luther-Hospital, Berlin, Germany
| | - Jonas Tesarz
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Felicitas Engel
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Annika Gauss
- grid.7700.00000 0001 2190 4373Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany
| | - Martin Raithel
- grid.5330.50000 0001 2107 3311University of Erlangen, Erlangen, Germany
| | - Viola Andresen
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | - Jutta Keller
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | | | | | | | - Gerard Clarke
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Paul J. Kennedy
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Eamonn M. M. Quigley
- grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.63368.380000 0004 0445 0041Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX USA
| | - Robin Spiller
- grid.4563.40000 0004 1936 8868Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Caroll Beltrán
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Ana María Madrid
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Verónica Torres
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Emeran A. Mayer
- grid.19006.3e0000 0000 9632 6718Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA USA
| | - Gregory Sayuk
- grid.4367.60000 0001 2355 7002Washington University School of Medicine, St. Louis, MO USA
| | - Maria Gazouli
- grid.5216.00000 0001 2155 0800Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Karamanolis
- grid.5216.00000 0001 2155 0800Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Mariona Bustamante
- grid.11478.3b0000 0004 1766 3695CRG, Centre for Genomic Regulation, Barcelona, Spain ,grid.434607.20000 0004 1763 3517ISGlobal, Barcelona, Spain
| | - Xavier Estivil
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Raquel Rabionet
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Per Hoffmann
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | - Markus M. Nöthen
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | | | - Börge Schmidt
- grid.410718.b0000 0001 0262 7331Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
| | - André Franke
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Wolfgang Lieb
- grid.417834.dInstitute of Epidemiology, Kiel, Germany
| | - Wolfgang Herzog
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Guy Boeckxstaens
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Mira M. Wouters
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Magnus Simrén
- grid.8761.80000 0000 9919 9582Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Gudrun A. Rappold
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Maria Vicario
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain ,grid.419905.00000 0001 0066 4948Nestlé Institute of Health Sciences, Nestlé Research, Société Des Produits Nestlé S.A, Vers-chez-les-Blanc, Lausanne, Switzerland
| | - Javier Santos
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain
| | - Rainer Schaefert
- grid.410567.1Department of Psychosomatic Medicine, Division of Theragnostics, University Hospital Basel, Basel, Switzerland ,grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Justo Lorenzo-Bermejo
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Beate Niesler
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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Seneviratne C, Gorelick DA, Lynch KG, Brown C, Romer D, Pond T, Kampman K, Kranzler HR. A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder. Alcohol Clin Exp Res 2022; 46:1900-1912. [PMID: 36055978 PMCID: PMC9901168 DOI: 10.1111/acer.14932] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 08/04/2022] [Accepted: 08/22/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT3A (HTR3A), and 5-HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. METHODS In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. RESULTS Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. CONCLUSIONS We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.
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Affiliation(s)
- Chamindi Seneviratne
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
| | - David A. Gorelick
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
| | - Kevin G. Lynch
- Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104
- Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, Philadelphia, PA 19104
| | - Clayton Brown
- Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
| | - Danielle Romer
- Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, Philadelphia, PA 19104
| | - Timothy Pond
- Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, Philadelphia, PA 19104
- Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
| | - Kyle Kampman
- Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, Philadelphia, PA 19104
- Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
| | - Henry R. Kranzler
- Mental Illness Research, Education and Clinical Center, Crezcenz VAMC, Philadelphia, PA 19104
- Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland, MD 21201
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9
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Psychiatric Comorbidities Associated with Persistent Postoperative Opioid Use. Curr Pain Headache Rep 2022; 26:701-708. [PMID: 35960447 DOI: 10.1007/s11916-022-01073-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW This review outlines the psychiatric comorbidities associated with persistent opioid use in the postoperative period. We finish our analysis with evidence-based, patient-centered interventions that can be rendered in the perioperative setting to decrease postoperative opioid requirements. RECENT FINDINGS Opioids are overprescribed in the USA, especially in the postoperative setting. Excess opioids can result in diversion and contribute to the ongoing opioid epidemic. Mental health and substance use disorders can contribute to persistent postoperative opioid use. Adequately managing these disorders preoperatively promises to reduce persistent postoperative opioid use. Due to the lack of homogenous, evidence-based recommendations on the appropriate quantity and duration of postoperative opioid therapy, there is wide variability in provider prescribing habits. Further research is needed to establish surgery-specific postoperative opioid therapy protocols. Opioids continue to be a mainstay in the treatment of postoperative pain. Unmonitored postoperative opioid use can lead to opioid use disorder. Mental health disorders increase susceptibility to persistent postoperative opioid use. By managing these psychiatric illnesses preoperatively, clinicians have the ability to decrease opioid consumption postoperatively. Lastly, given the healthcare burden of opioid misuse and abuse, it is important to establish concrete protocols to guide provider-prescribing habits.
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10
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Berens S, Dong Y, Fritz N, Walstab J, D'Amato M, Zheng T, Wahl V, Boekstegers F, Bermejo JL, Martinez C, Schmitteckert S, Clevers E, Engel F, Gauss A, Herzog W, Spiller R, Goebel-Stengel M, Mönnikes H, Andresen V, Thomas F, Keller J, Pehl C, Stein-Thöringer C, Clarke G, Dinan TG, Quigley EM, Sayuk G, Simrén M, Tesarz J, Rappold G, van Oudenhove L, Schaefert R, Niesler B. Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study. World J Gastroenterol 2022; 28:2334-2349. [PMID: 35800179 PMCID: PMC9185212 DOI: 10.3748/wjg.v28.i21.2334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/21/2021] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
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Affiliation(s)
- Sabrina Berens
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Yuanjun Dong
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Nikola Fritz
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Jutta Walstab
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio 48160, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao 48001, Spain
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Tenghao Zheng
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Verena Wahl
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Felix Boekstegers
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Cristina Martinez
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Av. Alcalde Rovira Roure, Lleida 25198, Spain
| | - Stefanie Schmitteckert
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Egbert Clevers
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven 3000, Belgium
| | - Felicitas Engel
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Annika Gauss
- Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg 69120, Germany
| | - Wolfgang Herzog
- Department of General Internal Medicine and Psychosomatics, Heidelberg University, Heidelberg 69120, Germany
| | - Robin Spiller
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2QL, United Kingdom
| | | | - Hubert Mönnikes
- Department of Medicine, Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, Belin 14193, Germany
| | - Viola Andresen
- Israelitisches Krankenhaus in Hamburg, Hamburg 22297, Germany
| | - Frieling Thomas
- Internal Medicine II, Helios Klinikum Krefeld, Krefeld 47805, Germany
| | - Jutta Keller
- Israelitisches Krankenhaus Hamburg, Hamburg 22297, Ghana
| | | | | | - Gerard Clarke
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Timothy G Dinan
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Eamonn M Quigley
- Medicine in Digestive Disorders, Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist, Houston, TX 77030, United States
| | - Gregory Sayuk
- Division of Gastroenterology, Washington University School of Medicine, Department of Psychiatry, School of Medicine, John Cochran Veteran Affairs Medical Center, St. Louis, MO 63110, United States
| | - Magnus Simrén
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg SE-41685, Sweden
| | - Jonas Tesarz
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Gudrun Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
| | - Lukas van Oudenhove
- Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03748, United States
- Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven 3000, Belgium
| | - Rainer Schaefert
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
- Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel CH-4031, Switzerland
| | - Beate Niesler
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
- Department of Human Molecular Genetics, Heidelberg University, Heidelberg 69120, Germany
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11
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Louca Jounger S, Christidis N, Hedenberg-Magnusson B, List T, Svensson P, Schalling M, Ernberg M. Polymorphisms in the HTR2A and HTR3A Genes Contribute to Pain in TMD Myalgia. FRONTIERS IN ORAL HEALTH 2022; 2:647924. [PMID: 35047998 PMCID: PMC8757775 DOI: 10.3389/froh.2021.647924] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Background: The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) related to monoaminergic neurotransmission, in particular the serotonergic pathway, contribute to pain perception in patients with temporomandibular disorder (TMD) myalgia and if there is a correlation to jaw function as well as psychosocial factors such as stress, anxiety and depression. Materials and Methods: One hundred and seventeen individuals with TMD myalgia were included. A venous blood or saliva sample was taken for genetic analyses and genotyped regarding HTR2A (rs9316233) HTR3A (rs1062613), HTR3B (rs1176744), SERT (5-HTTLPR) and COMT (rs4680). A clinical examination according to Diagnostic Criteria for TMD (DC/TMD) was performed and axis II data (psychosocial factors) were compared between participants with different genotypes for each gene using Kruskall–Wallis test. The characteristic pain intensity (CPI) was tested for correlations to scores for the Perceived Stress Scale, Generalized Anxiety Disorder, and Patient Health Questionnaires using Spearman's rank correlation test with Bonferroni correction for multiple testing. To further explore data factor analysis was performed to identify latent factors associated to the outcome variables. Results: Participants carrying at least one copy of the rare allele of the HTR2A (rs9316233) and HTR3A (rs1062613) had higher CPI compared with the participants with the homozygous common genotype (P = 0.042 and P = 0.024, respectively). Correlation analyses showed several significant positive correlations between CPI on one hand, and self-reported psychosocial distress and jaw function on the other hand for several genotypes that mostly were weak to moderate. The factor analysis identified two latent variables. One was positively correlated to the HTR3B gene, jaw function and self-reported parafunctions, and the other was positively correlated to psychological distress and negatively correlated to SERT. Conclusion: Taken together, the polymorphism rs1062613 in the HTR3A gene contributes to pain intensity in TMD myalgia. This together with positive interactions between pain variables and psychological factors in genotypes strengthens that pain and psychological distress are related. Further research is needed to explore this as well as the influence of gene-to-gene interactions on pain and psychological distress.
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Affiliation(s)
- Sofia Louca Jounger
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.,Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden
| | - Nikolaos Christidis
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.,Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden
| | - Britt Hedenberg-Magnusson
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.,Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden.,Department of Orofacial Pain and Jaw Function, Folktandvården Eastmaninstitutet, Stockholm, Sweden
| | - Thomas List
- Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden.,Department of Orofacial Pain and Jaw Function, Faculty of Odontology, Malmö University, Malmö, Sweden
| | - Peter Svensson
- Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden.,Department of Orofacial Pain and Jaw Function, Faculty of Odontology, Malmö University, Malmö, Sweden.,Section of Orofacial Pain and Jaw Function, Department of Dentistry and Oral Health, University of Aarhus, Aarhus, Denmark
| | - Martin Schalling
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Malin Ernberg
- Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.,Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden
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12
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Irving H, Turek I, Kettle C, Yaakob N. Tapping into 5-HT 3 Receptors to Modify Metabolic and Immune Responses. Int J Mol Sci 2021; 22:ijms222111910. [PMID: 34769340 PMCID: PMC8584345 DOI: 10.3390/ijms222111910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023] Open
Abstract
5-hydroxytryptamine type 3 (5-HT3) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or serotonin receptors. 5-HT3 receptors are well established targets for emesis and gastrointestinal mobility and are used as adjunct targets in treating schizophrenia. However, the distribution of these receptors is wider than the nervous system and there is potential that these additional sites can be targeted to modulate inflammatory and/or metabolic conditions. Recent progress in structural biology and pharmacology of 5-HT3 receptors have provided profound insights into mechanisms of their action. These advances, combined with insights into clinical relevance of mutations in genes encoding 5-HT3 subunits and increasing understanding of their implications in patient's predisposition to diseases and response to the treatment, open new avenues for personalized precision medicine. In this review, we recap on the current status of 5-HT3 receptor-based therapies using a biochemical and physiological perspective. We assess the potential for targeting 5-HT3 receptors in conditions involving metabolic or inflammatory disorders based on recent findings, underscoring the challenges and limitations of this approach.
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Affiliation(s)
- Helen Irving
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
- Correspondence:
| | - Ilona Turek
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
| | - Christine Kettle
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
| | - Nor Yaakob
- Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia;
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13
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Ignaszak-Kaus N, Duleba AJ, Mrozikiewicz A, Kurzawińska G, Różycka A, Hauke J, Gaca M, Pawelczyk L, Jagodziński PP, Jędrzejczak P. Relationship of Postoperative Pain and PONV after Minimally Invasive Surgery with the Serotonin Concentrations and Receptors' Gene Polymorphisms. J Pers Med 2021; 11:jpm11090833. [PMID: 34575611 PMCID: PMC8467521 DOI: 10.3390/jpm11090833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 01/11/2023] Open
Abstract
(1) Background: there is a steady increase in the number of procedures performed via minimally invasive surgery, which have many benefits, but post-operative nausea and vomiting (PONV) and significant pain are still a common problem (2) Methods: 300 infertile women (18–40 years old) undergoing minimal invasive surgery. Interventions: laparoscopy and hysteroscopy performing, evaluation of postoperative symptoms, serotonin concentrations assessment, identify genetic polymorphisms. (3) Results: serotonin concentrations were significantly lower among women who required opioids (p = 0.006). The presence of the GG genotype in the rs6318 polymorphism of the 5HTR2C gene had a protective effect on PONV (OR = 0.503; C.I. = [0.300–0.841]; p = 0.008), when the GG variant of the rs11214763 polymorphism of the 5HTR3B gene, when the risk of PONV was 1.65-fold higher (OR = 1.652; C.I. = [1.003–2.723]; p = 0.048). Pain intensity was significantly higher among women with GG genotype of the rs6296 polymorphism of the 5HTR1B gene (OR = 1.660; C.I. = [1.052–2.622]; p = 0.029).; (4) Conclusions: the evaluation of serotonin concentration predicts requirement for opioid pain relief medication. The polymorphisms of the serotonin receptors affect the intensity of postoperative complaints.
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Affiliation(s)
- Natalia Ignaszak-Kaus
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland; (A.M.); (L.P.); (P.J.)
- Correspondence: ; Tel.: +48-663360375
| | - Antoni J. Duleba
- Department of Reproductive Medicine, University of California, La Jolla, San Diego, CA 92093, USA;
| | - Aleksandra Mrozikiewicz
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland; (A.M.); (L.P.); (P.J.)
| | - Grażyna Kurzawińska
- Division of Perinatology and Women’s Diseases, Poznan University of Medical Sciences, 60-535 Poznan, Poland;
- Laboratory of Molecular Biology, Division of Perinatology and Women’s Diseases, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Agata Różycka
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 60-781 Poznan, Poland; (A.R.); (P.P.J.)
| | - Jan Hauke
- Faculty of Human Geography and Planning, Adam Mickiewicz University, 61-712 Poznan, Poland;
| | - Michał Gaca
- Clinics of Anaesthesiology in Obstetrics and Gynecology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland;
| | - Leszek Pawelczyk
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland; (A.M.); (L.P.); (P.J.)
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 60-781 Poznan, Poland; (A.R.); (P.P.J.)
| | - Piotr Jędrzejczak
- Department of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland; (A.M.); (L.P.); (P.J.)
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Kimura A, Yamasaki H, Ishii H, Yoshida H, Shimizu M, Mori T. Effects of Polymorphisms in the Serotonin Transporter Promoter-Linked Polymorphic Region on Postthoracotomy Pain Severity. J Pain Res 2021; 14:1389-1397. [PMID: 34079356 PMCID: PMC8164694 DOI: 10.2147/jpr.s298685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/01/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose Serotonin (5-HT) is highly associated with pain modulation. The human 5-HT transporter (5-HTT) gene (SLC6A4) features several polymorphisms in its promoter region (5-HTTLPR) that affect the 5-HTT expression. The S allele of 5-HTTLPR induces low 5-HT tone, and it may influence the modulation of chronic pain. Meanwhile, pain occurs in 40–50% of patients after thoracic surgery, and its mechanism remains under investigation. This study assessed the role of 5-HTTLPR polymorphisms in postthoracotomy pain severity. Patients and Methods A total of 178 patients undergoing pneumonectomy were enrolled. The genotypes of 5-HTTLPR were divided into two groups: S/S group and S/L or L/L group. Linear mixed-effects models were used to assess the association between 5-HTTLPR genotypes and the numerical rating scale (NRS) score change over time. Results Among the participants, data were obtained for 162 patients. The genotype distribution was as follows: S/S, 67.3%; S/L or L/L, 32.7%. No significant difference in patient characteristics was found between the genotype groups. There was no significant interaction between the 5-HTTLPR genotypes and the NRS score change over time (p = 0.842). Conclusion Polymorphisms in 5-HTTLPR were not associated with postthoracotomy pain severity.
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Affiliation(s)
- Aya Kimura
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Hiroyuki Yamasaki
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Haruka Ishii
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
| | - Motoko Shimizu
- Department of Anesthesiology, Sumitomo Hospital, Osaka City, Osaka, Japan
| | - Takashi Mori
- Department of Anesthesiology, Osaka City University Graduate School of Medicine, Osaka City, Osaka, Japan
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Soldatelli MD, Siepmann T, Illigens BMW, Souza dos Santos V, Lucena da S Torres I, Fregni F, Caumo W. Mapping of predictors of the disengagement of the descending inhibitory pain modulation system in fibromyalgia: an exploratory study. Br J Pain 2021; 15:221-233. [PMID: 34055343 PMCID: PMC8138619 DOI: 10.1177/2049463720920760] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS). OBJECTIVES We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0-1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task. METHODS This cross-sectional study included 117 women with fibromyalgia ((n = 60) non-responders and (n = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol. RESULTS A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%). CONCLUSION Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.
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Affiliation(s)
- Matheus Dorigatti Soldatelli
- Graduate Program in Medical Science,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
- Center for Clinical Research and
Management Education, Division of Health Care Sciences, Dresden International
University, Dresden, Germany
- Laboratory of Pain and Neuromodulation,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
| | - Timo Siepmann
- Center for Clinical Research and
Management Education, Division of Health Care Sciences, Dresden International
University, Dresden, Germany
- Department of Neurology, University
Hospital Carl Gustav Carus Technische Universitat, Dresden, Germany
| | - Ben Min-Woo Illigens
- Center for Clinical Research and
Management Education, Division of Health Care Sciences, Dresden International
University, Dresden, Germany
- Department of Neurology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Vinicius Souza dos Santos
- Laboratory of Pain and Neuromodulation,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
| | - Iraci Lucena da S Torres
- Graduate Program in Medical Science,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
- Pain and Palliative Care Service at
Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
| | - Felipe Fregni
- Department of Neurology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Wolnei Caumo
- Graduate Program in Medical Science,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
- Laboratory of Pain and Neuromodulation,
School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre,
Brazil
- Pain and Palliative Care Service at
Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil
- Surgery Department, School of Medicine,
Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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16
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Karataş E, Kahraman ÇY, Akbıyık N. Association between polymorphisms in catechol-O-methyl transferase, opioid receptor Mu 1 and serotonin receptor genes with postoperative pain following root canal treatment. Int Endod J 2021; 54:1016-1025. [PMID: 33559241 DOI: 10.1111/iej.13493] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/05/2021] [Accepted: 02/05/2021] [Indexed: 11/29/2022]
Abstract
AIM To evaluate the effect of single nucleotide polymorphisms in the COMT, OPRM1, 5HT1A, 5HT2A and 5HTR3B genes on the intensity of postoperative pain following root canal treatment. METHODOLOGY Ninety-five patients with mandibular and maxillary molar teeth diagnosed with symptomatic apical periodontitis and a level of preoperative pain greater than 50 on a 100 mm visual analogue scale (VAS) were included. Salivary DNA was collected from the participants and stored in Eppendorf tubes at -80 °C. Preoperative percussion pain values were recorded before the root canal treatment procedures. After completion of root canal treatment, the participants were given instructions to record their postoperative pain intensity levels at 24, 48 and 72 h, 5 days and 1 week after treatment, using the VAS. A second visit for the patients after seven days was planned to record their intensity levels of percussion pain on VAS. The percussion test was performed by tapping on the occlusal surface of the tooth with a blunt instrument. A QIAamp DNA Mini Kit was used to isolate DNA from saliva, and SNP Genotyping Analysis software version 1 was used to analyse the genotypes by calculating FAM and HEX signals. The Kruskal-Wallis and Mann-Whitney U-tests were used to evaluate pain intensity values amongst the genotypes, alleles, haplotypes and allele combinations. Nominal data (gender, intake and tooth number) were analysed using a Chi-square test. Bonferroni correction was performed. Thus, the significance level was set at 1.6% (P = 0.016), 2.5% (P = 0.025) and 1.25% (P = 0.0125) for genotype, allele and haplotype comparisons, respectively. RESULTS There was no significant difference amongst the genotypes and alleles in terms of pre- and postoperative pain intensity. There was no significant difference amongst the haplotypes formed for the COMT gene in terms of pain intensity. Additionally, there was no significant association between the allelic combination formed for 5HT1A + 5HT2A genes and the intensity of postoperative pain. CONCLUSION The findings indicate that none of the evaluated SNPs for COMT, OPRM1, 5HT1A, 5HT2A and 5HTR3B genes were associated with the intensity of postoperative pain.
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Affiliation(s)
- E Karataş
- Department of Endodontics, Faculty of Dentistry, Atatürk University, Erzurum, Turkey
| | - Ç Y Kahraman
- Department of Medical Genetics, Medical Faculty, Atatürk University, Erzurum, Turkey
| | - N Akbıyık
- Department of Endodontics, Faculty of Dentistry, Atatürk University, Erzurum, Turkey
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da Silveira Alves CF, Caumo W, Silvestri JM, Zortea M, Dos Santos VS, Cardoso DF, Regner A, de Souza AH, Simon D. Pain catastrophizing is associated with the Val66Met polymorphism of the brain-derived neurotrophic factor in fibromyalgia. Adv Rheumatol 2020; 60:39. [PMID: 32736598 DOI: 10.1186/s42358-020-00141-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 07/20/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Fibromyalgia (FM) is a musculoskeletal chronic pain syndrome that impacts negatively patient's daily lives. Its pathogenesis is characterized by a complex relationship between biological and psychosocial factors not fully understood yet. Pain catastrophizing is associated with FM and is an important predictor of outcomes. This study aimed to answer two questions: (i) whether the allele and genotype frequencies of BDNF Val66Met (rs6265) polymorphism differs between FM patients and healthy controls (HC); and (ii) if the BDNF Val66Met polymorphism is a factor that predicts pain catastrophizing in FM. METHODS In a cross-sectional design, 108 FM patients and 108 HC were included. FM patients responded to the Brazilian Portuguese version of the Pain Catastrophizing Scale (BP-PCS) to assess pain catastrophizing, as well as other validated tools for anxiety (The State-Trait Anxiety Inventory - STAI), depression (Beck Depression Inventory II - BDI-II) and functional aspects (Fibromyalgia Impact Questionnaire - FIQ; Central Sensitization Inventory validated and adapted for Brazilian population - CSI-BP; Pittsburgh Sleep Quality Index - PSQI; and Resilience Scale). All subjects were genotyped for the BDNF Val66Met polymorphism. RESULTS Val allele was significantly more frequent in FM patients compared to the control group (p < 0.05). Also, FM patients with Val/Val genotype showed more pain catastrophizing thoughts, and this genotype was significantly associated with magnification and rumination dimensions of BP-PCS (p < 0.05). Furthermore, there were significant differences in levels of anxiety and symptoms of depression, years of education, and the functional situation between the FM and control groups. CONCLUSIONS The findings show an association of BDNF Val66Met polymorphism with pain catastrophizing in FM, which opens new avenues to comprehend the interplay between molecular genetic characteristics and neuroplasticity mechanisms underpinning FM.
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Affiliation(s)
- Camila Fernanda da Silveira Alves
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil.,Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil.,Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Wolnei Caumo
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.,Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre (HCPA); Department of Surgery, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Joana Morez Silvestri
- Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil
| | - Maxciel Zortea
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Vinicius Souza Dos Santos
- Laboratory of Pain and Neuromodulation at Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil.,Graduate Program in Medical Sciences at Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
| | - Dayane Favarin Cardoso
- Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil
| | - Andrea Regner
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil
| | - Alessandra Hübner de Souza
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil
| | - Daniel Simon
- Graduate Program in Cellular and Molecular Biology Applied to Health, Universidade Luterana do Brasil (ULBRA), Av. Farroupilha, 8001 - Prédio 22 - 5° andar, Canoas, RS, 92425-900, Brazil. .,Human Molecular Genetics Laboratory, Universidade Luterana do Brasil (ULBRA), Canoas, Brazil.
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Ledermann K, Hasler G, Jenewein J, Sprott H, Schnyder U, Martin-Soelch C. 5'UTR polymorphism in the serotonergic receptor HTR3A gene is differently associated with striatal Dopamine D2/D3 receptor availability in the right putamen in Fibromyalgia patients and healthy controls-Preliminary evidence. Synapse 2020; 74:e22147. [PMID: 31868947 DOI: 10.1002/syn.22147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/12/2019] [Accepted: 12/17/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Extensive literature has investigated the role of serotonin (5-HT) in the control of the central dopamine (DA) systems, and their dysfunction in the pathological conditions. 5-HT stimulates the local DA release in striatal regions via activation of various receptors including serotonin receptor-3 (5-HT3). Several studies have related polymorphisms (SNPs) in the serotonin receptor-3 (HTR3) genes to be associated with the pain modulation and endogenous pain suppression. A few studies suggested a functional role of 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) in the development of the chronic pain and Fibromyalgia syndrome (FMS) in particular. Here, we investigated the effect of a 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) on striatal dopamine D2/D3 receptor (DRD2) availability and reward-associated DA release in response to unpredictable monetary rewards in 23 women with FMS and 17 age-matched healthy female controls. Furthermore, we aimed to examine if SNP rs1062613 is associated with thermal pain and pain tolerance thresholds. METHODS We used PET and [11 C]raclopride to assess the DRD2 availability. In the same participants we used the [11 C]raclopride PET bolus-plus-infusion method to measure the [11 C]raclopride receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition. DRD2 availability and ΔBP were assessed in MRI-based striatal regions of interest. Thermal pain and pain tolerance thresholds were assessed outside the scanner. RESULTS The frequency of SNP rs1062613 genotype differed significantly between groups, indicating that CC homozygotes were more frequent in FMS patients (82.6%) than in healthy controls (41.3%). Our results showed a significant main effect of SNP rs1062613 on [11 C]raclopride binding potential in the right caudate nucleus indicating a higher DRD2 receptor availability for CC-genotype of this SNP. Furthermore, we found a significant group × SNP interaction on [11 C]raclopride binding potential in the right putamen, indicating a higher DRD2 availability in T-carriers compared to CC genotype of SNP rs1062613 in FMS patients, whereas this effect was not present in healthy controls. However, we did not find an influence of SNP rs1062613 on reward-related DA release. In addition, there was no association between SNP rs1062613 and pain threshold or pain tolerance threshold in our data. CONCLUSION These preliminary results indicate that SNP rs1062613 in the serotonergic receptor HTR3A gene possibly modulates the DRD2 receptor availability.
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Affiliation(s)
- Katharina Ledermann
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland.,Department of Consultation-Liaison Psychiatry and Psychosomatics, University Hospital, University of Zurich, Zurich, Switzerland
| | - Gregor Hasler
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland
| | - Josef Jenewein
- Department of Consultation-Liaison Psychiatry and Psychosomatics, University Hospital, University of Zurich, Zurich, Switzerland.,Clinic Zugersee, Center for Psychiatry and Psychotherapy, Oberwil-Zug, Switzerland
| | - Haiko Sprott
- University of Zurich and Arztpraxis Hottingen, Zurich, Switzerland
| | | | - Chantal Martin-Soelch
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland
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19
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Bonato LL, Quinelato V, de Felipe Cordeiro PC, Vieira AR, Granjeiro JM, Tesch R, Casado PL. Polymorphisms in COMT, ADRB2 and HTR1A genes are associated with temporomandibular disorders in individuals with other arthralgias. Cranio 2019; 39:351-361. [PMID: 31264537 DOI: 10.1080/08869634.2019.1632406] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Objective: To evaluate the association between polymorphisms in genes and comorbid presence of arthralgias and TMD.Methods: This is a case-control study. The groups formed were individuals with chronic arthralgia and 1) myofascial pain (n = 42); 2) articular (n = 16); 3) multiple diagnoses (n = 69); 4) with TMD and without some other arthralgia (n = 16); 5) without TMD but with pain in other joints (n = 82); and 6) a control group (n = 72). SNPs in COMT, ADRB2, and HTR1A genes were investigated.Results: The CT genotype for the COMT (rs9332377) gene was associated with the absence of myofascial pain (p = .05). In the ADRB2 (rs1042713) gene, the AA genotype was associated with the absence of myofascial pain (p = .03).Discussion: This study supports the hypothesis that alterations in the COMT, ADRB2, and HTR1A genes influence the presence of chronic pain and TMD.
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Affiliation(s)
| | | | | | - Alexandre Rezende Vieira
- Departments of Oral Biology and Pediatric Dentistry, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - José Mauro Granjeiro
- Federal University, Niterói, RJ, Brazil.,National Institute of Metrology, Quality and Technology, Rio de Janeiro, RJ, Brazil.,Cell Therapy Center, Clinical Research Unit and Biology Institute, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil
| | - Ricardo Tesch
- Temporomandibular Disorders and Orofacial Pain Clinic, School of Medicine of Petrópolis, Petrópolis, Rio de Janeiro, Brazil
| | - Priscila Ladeira Casado
- Department of Periodontics, Fluminense Federal University (UFF), Niterói, Rio de Janeiro, Brazil
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Cardinal TM, Antunes LC, Brietzke AP, Parizotti CS, Carvalho F, De Souza A, da Silva Torres IL, Fregni F, Caumo W. Differential Neuroplastic Changes in Fibromyalgia and Depression Indexed by Up-Regulation of Motor Cortex Inhibition and Disinhibition of the Descending Pain System: An Exploratory Study. Front Hum Neurosci 2019; 13:138. [PMID: 31105542 PMCID: PMC6494946 DOI: 10.3389/fnhum.2019.00138] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 04/08/2019] [Indexed: 01/02/2023] Open
Abstract
Background: Major depressive disorder (MDD) and fibromyalgia (FM) present overlapped symptoms. Although the connection between these two disorders has not been elucidated yet, the disruption of neuroplastic processes that mediate the equilibrium in the inhibitory systems stands out as a possible mechanism. Thus, the purpose of this cross-sectional exploratory study was: (i) to compare the motor cortex inhibition indexed by transcranial magnetic stimulation (TMS) measures [short intracortical inhibition (SICI) and intracortical facilitation (ICF)], as well as the function of descending pain modulatory systems (DPMS) among FM, MDD, and healthy subjects (HS); (ii) to compare SICI, ICF, and the role of DPMS evaluated by the change on Numerical Pain Scale (NPS) during the conditioned pain modulation test (CPM-test) between FM and MDD considering the BDNF-adjusted index; (iii) to assess the relationship between the role of DPMS and the BDNF-adjusted index, despite clinical diagnosis. Patients and Methods: A cohort of 63 women, aged 18 to 75 years [FM (n = 18), MDD (n = 19), and HC (n = 29)]. Results: The MANCOVA analysis revealed that the mean of SICI was 53.40% larger in FM compared to MDD [1.03 (0.50) vs. 0.55 (0.43)] and 66.99% larger compared to HC [1.03 (0.50) vs. 0.34 (0.19)], respectively. The inhibitory potency of the DPMS assessed by the change on the NPS during CPM-test was 112.29 % lower in the FM compared to MDD [0.22 (1.37) vs. -0.87 (1.49)]. The mean of BDNF from FM compared to MDD was 35.70% higher [49.82 (16.31) vs. 14.12 (8.86)]. In FM, the Spearman's coefficient between the change in the NPS during CPM-test with the SICI was Rho = -0.49, [confidence interval (CI) 95%; -0.78 to -0.03]. The BDNF-adjusted index was positively correlated with the disinhibition of the DPMS. Conclusion: These findings support the hypothesis that in FM a deteriorated function of cortical inhibition, indexed by a higher SICI parameter, a lower function of the DPMS, together with a higher level of BDNF indicate that FM has different pathological substrates from depression. They suggest that an up-regulation phenomenon of intracortical inhibitory networks associated with a disruption of the DPMS function occurs in FM.
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Affiliation(s)
- Tiago Madeira Cardinal
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Luciana Conceição Antunes
- Department of Nutrition, Health Science Center, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - Aline Patricia Brietzke
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Cristiane Schulz Parizotti
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Fabiana Carvalho
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Andressa De Souza
- Post-graduate Program in Health and Human Development, Universidade La Salle, Canoas, Brazil
| | - Iraci Lucena da Silva Torres
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Department of Pharmacology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | | | - Wolnei Caumo
- Post-graduate Program in Medical Sciences, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Department of Surgery, Pain, and Anesthesia, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Anesthesiologist, Pain and Palliative Care Service, Hospital de Clínicas de Porto Alegre, Laboratory of Pain and Neuromodulation, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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21
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Pain catastrophizing, neuroticism, fear of pain, and anxiety: Defining the genetic and environmental factors in a sample of female twins. PLoS One 2018; 13:e0194562. [PMID: 29566063 PMCID: PMC5864012 DOI: 10.1371/journal.pone.0194562] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 03/06/2018] [Indexed: 11/21/2022] Open
Abstract
The objective of the present study was to establish the heritability of pain catastrophizing and its subdomains of helplessness, magnification, and rumination and to further explore the genetic and environmental sources that may contribute to pain catastrophizing as well as to its commonly reported psycho-affective correlates, including neuroticism, anxiety sensitivity, and fear of pain. N = 2,401 female twin individuals from the TwinsUK registry were subject to univariate and multivariate twin analyses. Well validated questionnaires including the Pain Catastrophizing Scale, the Pain Anxiety Symptom Scale, the Ten Item Personality Index, and the Anxiety Sensitivity Index were used to assess the study variables. Moderate estimates of heritability for pain catastrophizing (36%) and the three subdomains of helplessness (35%), rumination (27%), and magnification (36%) were detected. The high correlations observed between the three subdomains were explained mainly by overlapping genetic factors, with a single factor loading on all three phenotypes. High genetic correlations between pain catastrophizing and its psycho-affective correlates of fear of pain and anxiety sensitivity were found, while the genetic overlap between neuroticism and pain catastrophizing was low. Each measure of negative affect demonstrated relatively distinct environmental contributing factors, with very little overlap. This is the first study to show shared genetic factors in the observed association between pain catastrophizing and other measures of negative affect. Our findings provide deeper insight into the aetiology of pain catastrophizing and confirm that it is at least partially distinct from other measures of negative affect and personality that may influence the development and treatment of chronic pain conditions. Further research in males is warranted to check the comparability of the findings.
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Pain Catastrophizing and Anxiety are Associated With Heat Pain Perception in a Community Sample of Adults With Chronic Pain. Clin J Pain 2017; 32:875-81. [PMID: 26626297 DOI: 10.1097/ajp.0000000000000333] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND The principle aim of this study was to investigate the associations between heat pain (HP) perception, pain catastrophizing, and pain-related anxiety in a heterogenous cohort of community-dwelling adults with chronic pain admitted to a 3-week outpatient pain rehabilitation program. METHODS All adults consecutively admitted to an outpatient pain rehabilitation program from July 2009 through January 2011 were eligible for study recruitment (n=574). Upon admission, patients completed the Pain Catastrophizing Scale (PCS), the short version of the Pain Anxiety Symptoms Scale (PASS-20), and HP perception was assessed using a standardized quantitative sensory testing (QST) method of levels. RESULTS Greater PCS scores were significantly correlated with lower standardized values of HP threshold (HP 0.5) (P=0.006) and tolerance (HP 5) (P=0.003). In a multiple variable model adjusted for demographic and clinical factors known to influence HP perception, every 10-point increase in the PCS was associated with a -0.124 point change in HP 0.5 (P=0.014) and a -0.142 change in HP 5 (P=0.014) indicating that participants with higher PCS scores had lower HP thresholds and tolerances, respectively. Similarly, greater PASS-20 scores significantly correlated with lower standardized values of HP 0.5 and HP 5. In a multiple variable model, every 10-point increase in the PASS-20 was associated with a -0.084 point change in HP 0.5 (P=0.005) and a -0.116 point change in HP 5 (P=0.001) indicating that participants with higher PASS-20 scores had lower HP thresholds and tolerances, respectively. CONCLUSIONS The findings of this study extend the use of a standardized method for assessing HP in a heterogenous sample of adults with chronic pain. Although pain catastrophizing shares significant variance with pain-related anxiety, our findings suggest that either measure would be appropriate for use in future studies that incorporate the QST method of levels.
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Influence of Polymorphisms in the HTR3A and HTR3B Genes on Experimental Pain and the Effect of the 5-HT3 Antagonist Granisetron. PLoS One 2016; 11:e0168703. [PMID: 28002447 PMCID: PMC5176308 DOI: 10.1371/journal.pone.0168703] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 12/04/2016] [Indexed: 02/08/2023] Open
Abstract
The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn.
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Celli J, Rappold G, Niesler B. The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database. Hum Mutat 2016; 38:137-147. [PMID: 27763704 DOI: 10.1002/humu.23136] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 10/11/2016] [Accepted: 10/15/2016] [Indexed: 12/17/2022]
Abstract
Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case-control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches.
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Affiliation(s)
- Jacopo Celli
- Center of Human and Clinical Genetics, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Gudrun Rappold
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
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De Gregori M, Diatchenko L, Ingelmo PM, Napolioni V, Klepstad P, Belfer I, Molinaro V, Garbin G, Ranzani GN, Alberio G, Normanno M, Lovisari F, Somaini M, Govoni S, Mura E, Bugada D, Niebel T, Zorzetto M, De Gregori S, Molinaro M, Fanelli G, Allegri M. Human Genetic Variability Contributes to Postoperative Morphine Consumption. THE JOURNAL OF PAIN 2016; 17:628-36. [PMID: 26902643 DOI: 10.1016/j.jpain.2016.02.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 01/22/2016] [Accepted: 02/04/2016] [Indexed: 11/27/2022]
Abstract
UNLABELLED High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. PERSPECTIVE This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752.
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Affiliation(s)
- Manuela De Gregori
- Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; YAP (Young Against Pain) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Luda Diatchenko
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Alan Edwards Pain Centre For Research on Pain, McGill University, Montrèal, Quebec, Canada
| | - Pablo M Ingelmo
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Anesthesia, Montreal Children's Hospital, Montrèal, Quebec, Canada
| | - Valerio Napolioni
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California
| | - Pal Klepstad
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Anesthesiology and Intensive Care Medicine, St. Olav's University Hospital, Trondheim, Norway, Norway
| | - Inna Belfer
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Valeria Molinaro
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - Giulia Garbin
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | | | - Giovanni Alberio
- First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Marco Normanno
- First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Federica Lovisari
- First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Marta Somaini
- First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy
| | - Stefano Govoni
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy
| | - Elisa Mura
- Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy
| | - Dario Bugada
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Clinical, Surgical, Pediatric and Diagnostic Science, University of Pavia, Pavia, Italy
| | - Thekla Niebel
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Clinical, Surgical, Pediatric and Diagnostic Science, University of Pavia, Pavia, Italy
| | - Michele Zorzetto
- Laboratory of Biochemistry and Genetics, Division of Pneumology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Simona De Gregori
- Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mariadelfina Molinaro
- Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Guido Fanelli
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Anesthesia, Critical Care and Pain Medicine, Department of Surgical Sciences, University of Parma, Parma, Italy; UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Massimo Allegri
- SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Anesthesia, Critical Care and Pain Medicine, Department of Surgical Sciences, University of Parma, Parma, Italy; UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
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Gazouli M, Wouters MM, Kapur-Pojskić L, Bengtson MB, Friedman E, Nikčević G, Demetriou CA, Mulak A, Santos J, Niesler B. Lessons learned--resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol 2016; 13:77-87. [PMID: 26726033 DOI: 10.1038/nrgastro.2015.206] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.
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Affiliation(s)
- Maria Gazouli
- Department of Basic Sciences, Laboratory of Biology, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Lejla Kapur-Pojskić
- Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Kemalbegova 10, 71.000 Sarajevo, Bosnia and Herzegovina
| | - May-Bente Bengtson
- Vestfold Hospital Trust, Tønsberg, Department of Internal Medicine, Division of Gastroenterology, P.O. Box 2168, 3103 Tønsberg, Norway
| | - Eitan Friedman
- The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Centre, 52621 Tel-Hashomer, Israel
| | - Gordana Nikčević
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 23 11010 Belgrade, Serbia
| | - Christiana A Demetriou
- Department of Electron Microscopy / Molecular Pathology, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus
| | - Agata Mulak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Javier Santos
- Neuro-immuno-gastroenterology Lab, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca. Department of Gastroenterology, Hospital Universitari Vall d'Hebron &Facultat de Medicina, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
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Samartzis D, Borthakur A, Belfer I, Bow C, Lotz JC, Wang HQ, Cheung KMC, Carragee E, Karppinen J. Novel diagnostic and prognostic methods for disc degeneration and low back pain. Spine J 2015; 15:1919-32. [PMID: 26303178 PMCID: PMC5473425 DOI: 10.1016/j.spinee.2014.09.010] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 09/09/2014] [Indexed: 02/06/2023]
Affiliation(s)
- Dino Samartzis
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Professorial Block, 5th Floor, 102 Pokfulam Road, Pokfulam, Hong Kong, SAR, China; The Laboratory and Clinical Research Institute for Pain, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong, SAR, China.
| | - Ari Borthakur
- Center for Magnetic Resonance and Optical Imaging, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia, PA, 19104, USA
| | - Inna Belfer
- Department of Anesthesiology, University of Pittsburgh, 4200 Fifth Ave, Pittsburgh, PA 15260, USA
| | - Cora Bow
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Professorial Block, 5th Floor, 102 Pokfulam Road, Pokfulam, Hong Kong, SAR, China
| | - Jeffrey C Lotz
- Department of Orthopaedic Surgery, University of California at San Francisco, 500 Parnassus Ave, San Francisco, CA 94143, USA
| | - Hai-Qiang Wang
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, No. 169, Changle West Road, Xi'an, Shaanxi, 710032, P.R. China
| | - Kenneth M C Cheung
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Professorial Block, 5th Floor, 102 Pokfulam Road, Pokfulam, Hong Kong, SAR, China
| | - Eugene Carragee
- Department of Orthopaedic Surgery, Stanford University, 450 Serra Mall, Stanford, CA 94305, USA
| | - Jaro Karppinen
- Medical Research Center Oulu, University of Oulu, Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
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Neuroplasticity underlying the comorbidity of pain and depression. Neural Plast 2015; 2015:504691. [PMID: 25810926 PMCID: PMC4355564 DOI: 10.1155/2015/504691] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/10/2015] [Indexed: 02/07/2023] Open
Abstract
Acute pain induces depressed mood, and chronic pain is known to cause depression. Depression, meanwhile, can also adversely affect pain behaviors ranging from symptomology to treatment response. Pain and depression independently induce long-term plasticity in the central nervous system (CNS). Comorbid conditions, however, have distinct patterns of neural activation. We performed a review of the changes in neural circuitry and molecular signaling pathways that may underlie this complex relationship between pain and depression. We also discussed some of the current and future therapies that are based on this understanding of the CNS plasticity that occurs with pain and depression.
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Is the experience of thermal pain genetics dependent? BIOMED RESEARCH INTERNATIONAL 2015; 2015:349584. [PMID: 25699274 PMCID: PMC4324494 DOI: 10.1155/2015/349584] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/10/2014] [Accepted: 11/10/2014] [Indexed: 01/06/2023]
Abstract
It is suggested that genetic variations explain a significant portion of the variability in pain perception; therefore, increased understanding of pain-related genetic influences may identify new targets for therapies and treatments. The relative contribution of the different genes to the variance in clinical and experimental pain responses remains unknown. It is suggested that the genetic contributions to pain perception vary across pain modalities. For example, it has been suggested that more than 60% of the variance in cold pressor responses can be explained by genetic factors; in comparison, only 26% of the variance in heat pain responses is explained by these variations. Thus, the selection of pain model might markedly influence the magnitude of the association between the pain phenotype and genetic variability. Thermal pain sensation is complex with multiple molecular and cellular mechanisms operating alone and in combination within the peripheral and central nervous system. It is thus highly probable that the thermal pain experience is affected by genetic variants in one or more of the pathways involved in the thermal pain signaling. This review aims to present and discuss some of the genetic variations that have previously been associated with different experimental thermal pain models.
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Schaldemose EL, Horjales-Araujo E, Demontis D, Børglum AD, Svensson P, Finnerup NB. No association of polymorphisms in the serotonin transporter gene with thermal pain sensation in healthy individuals. Mol Pain 2014; 10:76. [PMID: 25472558 PMCID: PMC4364075 DOI: 10.1186/1744-8069-10-76] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 11/19/2014] [Indexed: 12/21/2022] Open
Abstract
Background Recent studies have suggested an association between genotypes affecting the expression of the serotonin transporter and thermal pain perception and the thermal grill. The aim of this study was to investigate differences in thermal and mechanical pain perception and the thermal grill in two groups of healthy volunteers according to their genotype, associated with either high (n = 40) or low (n = 40) expression of the serotonin transporter and according to gender. Cold and warm detection and pain thresholds, pressure pain threshold and cold, warm and pain sensations to single or alternating stimuli with cold (20°C) and warm (40°C) temperatures (known as the thermal grill) were determined. In addition, intensity of ongoing pain and area and intensity of pinprick hyperalgesia in the secondary hyperalgesic area following topical application of capsaicin and vehicle control (ethanol) were determined. Results No significant differences in detection and pain thresholds for cold and warm temperatures, presence of paradoxical heat sensation, pressure pain threshold and pain responses to suprathreshold thermal stimuli were observed. There was also no difference in capsaicin-evoked ongoing pain and secondary hyperalgesia between the two genotype groups (p >0.4), also when subdivided by gender (p >0.17). In addition, there were no significant differences in the perception of the thermal grill between the two genotypes (p >0.5), also when subdivided by gender. Conclusions Genotypes associated with high or low expression of the serotonin transporter were not associated with thermal pain thresholds, pressure pain threshold, pain after capsaicin application or responses to the thermal grill. The present results do not support that the investigated genotypes play a major role in thermal pain perception among healthy individuals.
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Affiliation(s)
- Ellen Lund Schaldemose
- Danish Pain Research Center, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark.
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