Expansion of the human μ-opioid receptor gene architecture: novel functional variants

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Abstract

The μ-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5′-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.

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Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.

H Matthes, R. Maldonado, F Simonin … (1996)

Despite tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes, mu, delta and kappa, whose genes have been cloned. Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the mu-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system in these animals. Investigation of the behavioural effects of morphine reveals that a lack of mu receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. We observed no behavioural responses related to delta- or kappa-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the mu-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action.

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Genetic basis for individual variations in pain perception and the development of a chronic pain condition.

Luda Diatchenko, Gary D Slade, Andrea Nackley … (2005)

Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.

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Strategies to manage the adverse effects of oral morphine: an evidence-based report.

Ann M. Fallon, C Ripamonti, Tatiana Pereira … (2001)

Successful pain management with opioids requires that adequate analgesia be achieved without excessive adverse effects. By these criteria, a substantial minority of patients treated with oral morphine (10% to 30%) do not have a successful outcome because of (1) excessive adverse effects, (2) inadequate analgesia, or (3) a combination of both excessive adverse effects along with inadequate analgesia. The management of excessive adverse effects remains a major clinical challenge. Multiple approaches have been described to address this problem. The clinical challenge of selecting the best option is enhanced by the lack of definitive, evidence-based comparative data. Indeed, this aspect of opioid therapeutics has become a focus of substantial controversy. This study presents evidence-based recommendations for clinical-practice formulated by an Expert Working Group of the European Association of Palliative Care (EAPC) Research NETWORK: These recommendations highlight the need for careful evaluation to distinguish between morphine adverse effects from comorbidity, dehydration, or drug interactions, and initial consideration of dose reduction (possibly by the addition of a co analgesic). If side effects persist, the clinician should consider options of symptomatic management of the adverse effect, opioid rotation, or switching route of systemic administration. The approaches are described and guidelines are provided to aid in selecting between therapeutic options.

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Author and article information

Journal

Journal ID (nlm-ta): Hum Mol Genet

Journal ID (publisher-id): hmg

Journal ID (hwp): hmg

Title: Human Molecular Genetics

Publisher: Oxford University Press

ISSN (Print): 0964-6906

ISSN (Electronic): 1460-2083

Publication date (Print): 15 March 2009

Publication date (Electronic): 22 December 2008

Publication date PMC-release: 22 December 2008

Volume: 18

Issue: 6

Pages: 1037-1051

Affiliations

[1 ]National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health , Bethesda, MD 20894, USA

[2 ]National Institute of Environmental Health Sciences, National Institutes of Health , Research Triangle Park, NC 27709, USA

[3 ]Center for Neurosensory Disorders, School of Dentistry, University of North Carolina at Chapel Hill , CB 7455, Chapel Hill, NC 27599, USA

[4 ]Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health , Bethesda, MD 20892, USA

[5 ]Laboratory of Neurogenetics, Department of Health and Human Services, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , 5625 Fishers Lane, Room 3S-32, Rockville, MD 20852, USA

[6 ]Department of Anesthesiology, University of Pittsburgh , Pittsburgh, PA 15261, USA

[7 ]Department of Molecular Genetics and Microbiology, University of Florida College of Medicine , 1329 SW 16th Street, Gainesville, FL 32608, USA

[8 ]University of Florida College of Dentistry, Community Dentistry and Behavioral Science , 1329 SW 16th Street, Gainesville, FL 32608, USA

[9 ]Division of Therapeutic Proteins, Center for Drug Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892, USA

Author notes

[†]

We would like to dedicate the work presented in this manuscript to the memory of our dear friend and colleague Dr Mitchell B. Max whose untimely passing has created a loss to our scientific community and a void in our hearts.

[* ]To whom correspondence should be addressed. Tel: +1 3015945693; Fax: +1 3014802290; Email: shabalin@ 123456ncbi.nlm.nih.gov (S.A.S.) and lbdiatch@ 123456email.unc.edu (L.D.)

Article

Publisher ID: ddn439

DOI: 10.1093/hmg/ddn439

PMC ID: 2649019

PubMed ID: 19103668

SO-VID: cfa7fccf-0915-4b4b-b493-bd0cca54ed76

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Expansion of the human μ-opioid receptor gene architecture: novel functional variants

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Most cited references 69

Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.

Genetic basis for individual variations in pain perception and the development of a chronic pain condition.

Strategies to manage the adverse effects of oral morphine: an evidence-based report.

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