Altered Levels of Basal Cortisol in Healthy Subjects with a 118G Allele in Exon 1 of the Mu Opioid Receptor Gene

The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY 10021, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 11/2006; 31(10):2313-7. DOI: 10.1038/sj.npp.1301128
Source: PubMed


The mu opioid receptor is centrally involved in the development of the addictive diseases. It also modulates the stress responsive hypothalamic-pituitary-adrenal axis. Receptors encoded by the variant 118G polymorphism in exon 1 of the mu opioid receptor gene have a threefold increase in beta-endorphin binding and beta-endorphin is three times more potent in receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels. Humans with this variant have increased stress response following opioid antagonism. Here, we study basal levels of adrenocorticotropic hormone and cortisol in subjects with this variant. In all, 59 healthy adults were genotyped and had morning levels of adrenocorticotropic hormone and cortisol measured following intravenous administration of saline placebo. Subjects with a 118G allele had significantly greater levels of cortisol than subjects with the prototype gene. Groups did not differ in levels of adrenocorticotropic hormone. A planned comparison revealed significantly greater cortisol in females with at least one copy of the 118G allele compared to females with the prototype gene. There was no significant effect of gender alone, nor was there a significant interaction between gender and genotype, on ACTH or cortisol. Subjects with at least one copy of the 118G allele have increased basal levels of cortisol, which may influence the susceptibility to and treatment of the stress responsive dyscrasia.

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    • "Moreover, in one human experimental study, region-specific differences in OPRM1 levels between individuals with AA and G alleles have been demonstrated [34]. Additionally, the OPRM1 genotype may influence stress responses, immune and pro-inflammatory responses [21,35-37], and reactivity to social rejection [27]. Also, acute and chronic stress has been suggested to affect available μ-opioid receptor pools in GABAergic interneurons differentially in female and male rats [38]. "
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    ABSTRACT: Background Earlier observations show that development of persistent pain may be associated with the genetic variability in the gene encoding for the μ-opioid receptor 1, the OPRM1 A118G (rs1799971). The aim of this study was to investigate the association between OPRM1 genotype and subjective health complaints in patients with radicular pain and disc herniation. Methods A prospective, 1-year observational study was conducted at a hospital back clinic, including 118 Caucasian patients with lumbar radicular pain and MRI confirmed disc herniation. Single nucleotide polymorphism genotyping regarding the OPRM1 A118G was performed. The data of individuals with AA versus AG or GG were analysed separately by linear mixed models. The Subjective Health Complaints Inventory (0-81) including 27 common complaints experienced the previous month on a scale from not at all (0) to severe (3) was used as outcome. Pain, prior duration of leg pain, age, smoking status, and lumbar disc surgery were considered as covariates. Results In total 23 of 118 patients were carriers of the OPRM1 G-allele. All patients except female carriers of the G-allele reported a decrease in pain from baseline to 1 year. Female carriers of the G-allele reported significantly higher subjective health complaints score during the study time span than male carriers of the G-allele when controlling for pain and pain duration. Conclusion The present data indicate that, when controlling for pain intensity and duration, subjective health complaints are associated with a sex - OPRM1 A118G polymorphism interaction in patients with radicular pain.
    Full-text · Article · May 2014 · BMC Musculoskeletal Disorders
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    • "However, despite the inconsistencies listed above, a variety of studies demonstrate that the G allele behaves in vivo as a gain-of-function allele for opioidmodulated intermediate phenotypes, such as HPA-axis activity (Bart et al, 2006; Wand et al, 2002) pain threshold (Fillingim et al, 2005), and alcohol response (Ray and Hutchison, 2007; Ray, 2005). In fact, robust effects of OPRM1 genotype have been found in functional studies focused on narrowly defined quantitative phenotypes that were most closely related to the proposed function of the genetic variant (see, eg, Wand et al, 2002; Bart et al, 2006; Fillingim et al, 2005; Ray and Hutchison, 2007). This study employed a similar approach. "
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    ABSTRACT: Variation in the μ-opioid receptor gene has been associated with early social behavior in mice and rhesus macaques. The current study tested whether the functional OPRM1 A118G predicted various indices of social relations in children. The sample included 226 subjects of self-reported European ancestry (44% female; mean age 13.6, SD=2.2) who were part of a larger representative study of children aged 9-17 years in rural North Carolina. Multiple aspects of recent (past 3 months) parent-child relationship were assessed using the Child and Adolescent Psychiatric Assessment. Parent problems were coded based upon a lifetime history of mental health problems, substance abuse, or criminality. Child genotype interacted with parent behavior such that there were no genotype differences for those with low levels of parent problems; however, when a history of parent problems was reported, the G allele carriers had more enjoyment of parent-child interactions (mean ratio (MR)=3.5, 95% CI=1.6, 8.0) and fewer arguments (MR=3.1, 95% CI=1.1, 8.9). These findings suggest a role for the OPRM1 gene in the genetic architecture of social relations in humans. In summary, a variant in the μ-opioid receptor gene (118G) was associated with improved parent-child relations, but only in the context of a significant disruption in parental functioning.
    Full-text · Article · Feb 2011 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "Each study has shown that whereas challenge with a specific mu-directed opioid antagonist will cause activation of the HPA axis in all subjects, as can be measured by ACTH or by serum cortisol levels, persons with one or two copies of the A118G variant respond with much greater activation of the HPA axis, as documented by a greater rise in serum cortisol (Wand et al., 2002, Hernandez-Avila et al., 2003, Chong et al., 2006). Further, we have recently shown that in healthy individuals with one or two copies of the variant, basal levels of serum cortisol are significantly higher than in those with the prototype variant; however, these increased levels were not elevated beyond the upper level of normal and would probably have no physiological or pathological significance, and could only be determined in a stress-minimized setting, such as our clinical research unit (Bart et al., 2006). Finally, in a very exciting study, all volunteers who had participated in the naltrexone trials for the treatment of alcoholism were invited to come back for further study; about one in six did so, and after obtaining informed consent, they were each genotyped. "
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    ABSTRACT: A symposium held at the 50th annual meeting of the Behavioral Pharmacology Society in May 2007 reviewed progress in the human behavioral pharmacology of drug abuse. Studies on drug self-administration in humans are reviewed that assessed reinforcing and subjective effects of drugs of abuse. The close parallels observed between studies in humans and laboratory animals using similar behavioral techniques have broadened our understanding of the complex nature of the pharmacological and behavioral factors controlling drug self-administration. The symposium also addressed the role that individual differences, such as sex, personality, and genotype play in determining the extent of self-administration of illicit drugs in human populations. Knowledge of how these factors influence human drug self-administration has helped validate similar differences observed in laboratory animals. In recognition that drug self-administration is but one of many choices available in the lives of humans, the symposium addressed the ways in which choice behavior can be studied in humans. These choice studies in human drug abusers have opened up new and exciting avenues of research in laboratory animals. Finally, the symposium reviewed behavioral pharmacology studies conducted in drug abuse treatment settings and the therapeutic benefits that have emerged from these studies.
    Full-text · Article · Jul 2010 · Behavioural pharmacology
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