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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: 7.83). 11/2006; 31(10):2313-7. DOI: 10.1038/sj.npp.1301128
Source: PubMed

ABSTRACT 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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    • "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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2011; 36(6):1165-70. DOI:10.1038/npp.2010.251 · 7.83 Impact Factor
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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.
    Behavioural pharmacology 07/2010; 21(4):251-77. DOI:10.1097/FBP.0b013e32833bb9f8 · 2.19 Impact Factor
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    • "Our laboratory has shown that healthy persons with one or two copies of this A118G variant have higher baseline levels of cortisol than persons with the prototype mu-opioid receptor (A118A), under stress-minimized circumstances. Further, we found females with A118G variant contribute to this basal hormonal difference to a greater extend than males (Bart et al., 2006). More recently, in work in progress, we have found in healthy volunteers that other aspects of the HPA axis, under tonic inhibition of the mu-opioid receptor system, are significantly modified in individuals with one or two copies of the A118G variant (Ducat et al., in preparation). "
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    ABSTRACT: From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor, and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants, and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin, and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review.
    Brain research 11/2009; 1314:235-52. DOI:10.1016/j.brainres.2009.11.015 · 2.83 Impact Factor
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