The A6V polymorphism of the human μ-opioid receptor negatively impacts signalling of morphine and endogenous opioids in vitro.

BACKGROUND AND PURPOSE: Polymorphisms of the μ-opioid receptor (MOPr) may contribute to the variation in responses to opioid drugs in clinical and unregulated situations. The A6V variant of MOPr (MOPr-A6V) is present in up to 20% of individuals in some populations, and may be associated with heightened susceptibility to drug abuse. There are no functional studies examining the acute signalling of MOPr-A6V in vitro, so we investigated potential functional differences between MOPr and MOPr-A6V at several signalling pathways using structurally distinct opioid ligands.EXPERIMENTAL APPROACH: CHO and AtT-20 cells stably expressing MOPr and MOPr-A6V used. Adenylyl cyclase (AC) inhibition and ERK1/2 phosphorylation assays were conducted in CHO cells, assays of K channel activation in AtT-20 cells.KEY RESULTS: Buprenorphine did not inhibit AC or stimulate ERK1/2 phosphorylation in CHO cells expressing MOPr-A6V, but buprenorphine activation of K channels in AtT-20 cells was preserved. DAMGO, morphine and β-endorphin inhibition of AC was significantly reduced via MOPr-A6V, as was signalling of all opioids to ERK1/2. However, there was little effect of the A6V variant on K channel activation.CONCLUSIONS AND IMPLICATIONS: This study shows that signalling to AC and ERK via MOPr-A6V is reduced for many opioids, including the clinically significant drugs morphine, buprenorphine and fentanyl, as well endogenous opioids. The MOPr-A6V variant can be common and this compromised signalling may affect individual responses to opioid therapy, while the possible disruption of the endogenous opioid system may contribute to susceptibility to substance abuse.This article is protected by copyright. All rights reserved.