title: Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS.
abstract: The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6β-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of α2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or α2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and α2 actions from analgesia.
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; Neuroscience and Pharmacology Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065;
authors.forename: Gina F
authors.initials: GF
authors.lastname: Marrone
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; Neuroscience and Pharmacology Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065;
authors.forename: Steven G
authors.initials: SG
authors.lastname: Grinnell
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Psychology, Post Campus, Long Island University, Brookville, NY 11548;
authors.forename: Grace C
authors.initials: GC
authors.lastname: Rossi
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Valerie
authors.initials: V
authors.lastname: Le Rouzic
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; Neuroscience and Pharmacology Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065; Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 pasterng@mskcc.org.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D017398:Alternative Splicing; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D059408:Pain Management; D010147:Pain Measurement; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; C485764:OPRM1 protein, human; C404943:Oprm protein, mouse; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone; D009020:Morphine
keywords: GPCR; analgesia; morphine; mu opioid receptor; truncation