| First Author | Lu Z | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 7 | Pages | 2626-30 |
| PubMed ID | 26011641 | Mgi Jnum | J:224476 |
| Mgi Id | MGI:5662334 | Doi | 10.1172/JCI81070 |
| Citation | Lu Z, et al. (2015) Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J Clin Invest 125(7):2626-30 |
| abstractText | The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the mu-opioid receptor. mu-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) mu-opioid receptors that mediate the actions of the traditional mu-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6beta-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM mu-opioid receptors but has no activity in mice lacking a set of 6TM truncated mu-opioid receptor splice variants. Unlike traditional opioids, IBNtxA does not depress respiration or result in physical dependence or reward behavior, suggesting it acts through an alternative mu-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a mu-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating mu-opioid activity in these animals. Intrathecal administration of lentivirus containing the 6TM variant mMOR-1G restored IBNtxA, but not morphine, analgesia in Oprm1-deficient animals. Together, these results confirm that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia. |
