Buprenorphine signalling is compromised at the N40 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 ( MOPr- WT) and the commonly occurring MOP receptor variant, N40 D. Experimental Approach MOPr- WT and MOPr- N40 D were stably expressed in CHO cells and in At T-20 cells. Assays of AC inhibition and ERK1/2 phosphorylation were performed on CHO cells, and assays of K activation were performed on At T-20 cells. Signalling profiles for each ligand were compared between variants. Key Results Buprenorphine efficacy was reduced by over 50% at MOPr- N40 D for AC inhibition and ERK1/2 phosphorylation. Buprenorphine potency was reduced threefold at MOPr- N40 D for K channel activation. Pentazocine efficacy was reduced by 50% for G-protein-gated inwardly rectifying K channel activation at MOPr- N40 D. No other differences were observed for any other ligands tested. Conclusions and Implications The N40 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 N40 D variant of MOP receptors is impaired, and this may have important consequences in a clinical setting for individuals carrying the N40 D allele. [ABSTRACT FROM AUTHOR]