title: The mu-opioid receptor gene polymorphism (A118G) alters HPA axis activation induced by opioid receptor blockade.
abstract: An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor's extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds beta-endorphin three times more avidly than the more common Asn40 variant. Paraventricular corticotropin releasing hormone neurons, which activate the HPA axis, express mu-opioid receptors and are modulated by beta-endorphin neurons. This preliminary study was designed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade. Thirty-nine healthy men were genotyped (A vs. G) and then underwent opioid receptor blockade with Naloxone. Subjects expressing the A118G receptor variant had greater cortisol responses to opioid receptor blockade. Also, a significant difference in the rate of increase of ACTH (slope) between A/A and A/G was observed between 30-90 minutes as well as a significant difference in the rate of decrease after 90 minutes. Moreover, subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor. Because serotonin also modulates the CRF neuron, subjects were genotyped for a functional polymorphism within the serotonin transporter gene. We did not see differences in hormone responses resulting from expression of this functional polymorphism. It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor.
authors.affiliation: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. gwand@welch.jhu.edu
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wand
authors.forename: Mary
authors.initials: M
authors.lastname: McCaul
authors.forename: Xioaju
authors.initials: X
authors.lastname: Yang
authors.forename: Joanna
authors.initials: J
authors.lastname: Reynolds
authors.forename: Deidre
authors.initials: D
authors.lastname: Gotjen
authors.forename: Shing
authors.initials: S
authors.lastname: Lee
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ali
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D006728:Hormones / Q000097:blood; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D009154:Mutation / Q000502:physiology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D010551:Personality; D011110:Polymorphism, Genetic / Q000235:genetics; D011489:Protein Denaturation; D011957:Receptors, Opioid / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins
chemical_list: D002352:Carrier Proteins; D006728:Hormones; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D009270:Naloxone; D004247:DNA