Buprenorphine signalling is compromised at the N 40 D polymorphism of the human μ opioid receptor in vitro

Background and Purpose There is significant variation in individual response to opioid drugs, which may result in inappropriate opioid therapy. Polymorphisms of the μ opioid receptor ( MOP receptor) may contribute to individual variation in opioid response by affecting receptor function, and the effect may be ligand‐specific. We sought to determine functional differences in MOP receptor signalling at several signalling pathways using a range of structurally distinct opioid ligands in cells expressing wild‐type MOP receptors ( MOP r‐ WT ) and the commonly occurring MOP receptor variant, N 40 D . Experimental Approach MOP r‐ WT and MOP r‐ N 40 D were stably expressed in CHO cells and in A t T ‐20 cells. Assays of AC inhibition and ERK 1/2 phosphorylation were performed on CHO cells, and assays of K activation were performed on A t T ‐20 cells. Signalling profiles for each ligand were compared between variants. Key Results Buprenorphine efficacy was reduced by over 50% at MOP r‐ N 40 D for AC inhibition and ERK 1/2 phosphorylation. Buprenorphine potency was reduced threefold at MOP r‐ N 40 D for K channel activation. Pentazocine efficacy was reduced by 50% for G ‐protein‐gated inwardly rectifying K channel activation at MOP r‐ N 40 D . No other differences were observed for any other ligands tested. Conclusions and Implications The N 40 D variant is present in 10–50% of the population. Buprenorphine is a commonly prescribed opioid analgesic, and many individuals do not respond to buprenorphine therapy. This study demonstrates that buprenorphine signalling to several effectors via the N 40 D variant of MOP receptors is impaired, and this may have important consequences in a clinical setting for individuals carrying the N 40 D allele.