title: Mediation of opioid analgesia by a truncated 6-transmembrane GPCR.
abstract: 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.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Grace C
authors.initials: GC
authors.lastname: Rossi
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
mesh_terms: D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D005091:Exons; D018390:Gene Targeting; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D010446:Peptide Fragments; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone; D009020:Morphine; D008691:Methadone