title: Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects.
abstract: Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.
authors: Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Susruta
authors: S
authors: Majumdar
authors: Steven
authors: S
authors: Grinnell
authors: Valerie
authors: V
authors: Le Rouzic
authors: Maxim
authors: M
authors: Burgman
authors: Lisa
authors: L
authors: Polikar
authors: Michael
authors: M
authors: Ansonoff
authors: John
authors: J
authors: Pintar
authors: Ying-Xian
authors: YX
authors: Pan
authors: Gavril W
authors: GW
authors: Pasternak
mesh_terms: D017398:Alternative Splicing; D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D017450:Receptors, Opioid, mu; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone