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 ␤ -endorphin three times more avidly than the more commonStress threatens homeostasis and is counteracted by a series of physiological and behavioral responses that improve the chances for survival. A successful response to stress plays an important role in maintaining health and well-being. Abnormalities in the stress response heighten an individual's vulnerability to endocrine, metabolic, psychiatric, and immunological disorders (Kreek and Koob 1998; Bjorntorp and Rosmond 2000a,b;Chrousos 2000). The unique characteristics of an individual's stress response are the product of genetic and environmental determinants (Francis et al. 1999;Wust et al. 2000).Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al. 1998 (Wand et al. 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al. 1997;Wendel and Hoehe 1998). In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the common Asn40 variant and also induces a 3-fold increase in agonist-induced activation of G protein-coupled potassium channels (Bond et al. 1998). Because the Asn40Asp substitution alters receptor binding and signal transduction, it is plausible that this polymorphism alters processes under opioidergic regulation (LaForge et al. 2000a,b). The CRF neuron is also modulated by serotonergic fibers (Contesse et al. 2000;Isogawa et al. 2000). As opposed to ␤ -endorphin, which inhibits CRF secretion, serotonin activates the CRF neuron and stimulates CRF release. The serotonin transporter regulates the concentration of serotonin within the synaptic cleft and thereby modulates magnitude and duration of serotonin-induced postsynaptic mediated signals (Lesch and Mossner 1998). Recently a functional polymorphism has been described in the promoter region of the transporter, which modulates transcriptional activity of this gene as well as tissue expression of transporter activity (Hanna et al. 1998;Heils et al. 1997;Little et al. 1998). Like the A118G polymorphism in the mu-opioid receptor, it is plausible that this functional polymorphism within the serotonin transporter is associated with altered HPA axis dynamics.The present study was designed to test whether the Asn40Asp substitution polymorphism in the mu-opioid receptor or a functional mutation in the polymorphic region of serotonin transporter influences HPA axis activation induced by opioid receptor blockade. METHODS SubjectsHealthy men were recruited by newspaper from the Baltimore area. Respondents gave informed conse...

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

“…Previous reports have shown that subjects with a 118G allele have increased cortisol response following administration of the opioid antagonist naloxone (Hernandez-Avila et al, 2003;Wand et al, 2002;Chong et al, 2006) and, possibly, decreased response to a social stressor (Chong et al, 2006). These reports did not note an effect of the 118G allele on basal levels of either ACTH or cortisol.…”

“…Other studies have also identified reduced receptor expression in transfected cell lines of receptors encoded by the 118G allele, a finding also noted in our ongoing studies (Beyer et al, 2004;Kroslak et al, 2003). The mu opioid receptor system is also involved, through tonic inhibition, in modulation of the stress responsive HPA axis and normal volunteers with a 118G allele have an increased HPA response (measured through levels of plasma cortisol) following antagonism of this inhibition with the opioid antagonist medication naloxone (Chong et al, 2006;Hernandez-Avila et al, 2003;Wand et al, 2002).…”

A Functional Polymorphism of the μ-Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

“…Subjectively, some fraction of the rewarding effects of alcohol ingestion in high-risk subjects can be blocked by naltrexone (King et al, 1997). Moreover, Wand et al (1998Wand et al ( , 2002 found that both family history and the Asp40 variant explained some variance in the release of corticotrophin-releasing factor (CRF) after stimulation with naloxone. Taken together, these findings suggest a possible mechanism for naltrexone response in which the clinical effects of the drug on reducing alcohol consumption may be enhanced in those with the Asp40 genotype, while having only marginal efficacy in those homozygous for the Asn40 variant.…”

“…Bond et al (1998) showed that, in cell culture, m-opioid receptors encoded by the Asp40 variant bind b-endorphin and activate G-protein-coupled protein potassium ion channels with three times greater potency than receptors encoded by the Asn40 variant. Both Wand et al (2002) and Hernandez-Avila et al (2003) found that individuals with one or two copies of the Asp40 allele had altered HPA-axis activation induced by the opioid receptor antagonist naloxone, while Smolka et al (1999) showed that individuals with the Asp40 variant display greater dopaminergic sensitivity during acute alcohol withdrawal.…”

Genetic variability of the μ-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women ☆

“…An adenine to guanine substitution in gene OPRM1 1 that results in an asparagine residue replacing an aspartate 2 has been reported to occur at a minor allelic frequency of f(−) 0.10-0.30 [4,20,28]. There is major interest in this polymorphism due to its potential pharmacological [4] and physiological consequences [3,9,21,46]. In vitro, Bond et al determined that the presence of at least one 304G (called G118 in that study) allele increases binding affinity and potency of β-endorphin [4].…”