Mediation of Opioid Analgesia by a Truncated Six Transmembrane G‐Protein‐Coupled Receptor

Abstract

Potent opioid analgesics lacking side‐effects may be possible by targeting truncated mu receptor splice variants. Mu opioids act through G‐protein coupled receptors generated from the mu opioid receptor (Oprm1) gene which undergoes extensive alternative splicing. The most abundant set of variants encode classical full‐length 7 transmembrane domain (TM) mu opioid receptors that mediate the actions of the traditional mu drugs morphine and methadone. In contrast, IBNtxA (3‐iodobenzoyl‐6β‐naltrexamide) is a potent analgesic against thermal, inflammatory and neuropathic pain whose actions are independent of the 7TM mu opioid receptors and lost in a knockout mouse lacking a set of 6TM truncated mu receptor splice variants. Unlike traditional opioids, IBNtxA has no respiratory depression, physical dependence or reward behavior, suggesting it acts through a novel mu opioid receptor target. Here we demonstrate that a truncated 6TM splice variant, mMOR‐1G, can rescue IBNtxA analgesia in a mu opioid receptor knockout mouse lacking all Oprm1 splice variants due to disruptions of both exons 1 and 11. No mu opioids were active in these mice. A lentivirus containing the 6TM variant mMOR‐1G administered intrathecally restored IBNtxA, but not morphine, analgesia, confirming that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia.This work was supported by the NIH with grants from NIDA (DA013997 and DA02944) to Y‐X.P. and (DA06241 and DA07242) to G.W.P. and a core grant from the NCI to MSKCC (CA08748).