Mediation of opioid analgesia by a truncated 6-transmembrane GPCR

• Published in: The Journal of clinical investigation Vol. 125; no. 7; pp. 2626 - 2630
• Main Authors: Lu, Zhigang, Xu, Jin, Rossi, Grace C, Majumdar, Susruta, Pasternak, Gavril W, Pan, Ying-Xian
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2015
• Subjects: Alternative Splicing; Amino acids; Analgesics; Analgesics, Opioid - pharmacology; Animals; Behavior; Binding sites; Biomedical research; Brief Report; Cancer; Drugs; Exons; Gene Targeting; Labeling; Lentivirus; Methadone - pharmacology; Mice; Mice, Knockout; Morphine - pharmacology; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Pain - drug therapy; Pain - physiopathology; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - physiology; Protein Structure, Tertiary; Receptors, Opioid, mu - deficiency; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - physiology; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Spinal cord
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI81070

The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-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) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contrast, 3-iodobenzoyl-6β-naltrexamide (IBNtxA) is a potent analgesic against thermal, inflammatory, and neuropathic pain that acts independently of 7TM μ-opioid receptors but has no activity in mice lacking a set of 6TM truncated μ-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 μ-opioid receptor target. Here we demonstrated that a truncated 6TM splice variant, mMOR-1G, can rescue IBNtxA analgesia in a μ-opioid receptor-deficient mouse that lacks all Oprm1 splice variants, ablating μ-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.