title: Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA.
abstract: IBNtxA (3'-iodobenzoyl-6β-naltrexamide) is a potent analgesic in mice lacking many traditional opioid side effects. In mice, it displays no respiratory depression, does not produce physical dependence with chronic administration, and shows no cross-tolerance to morphine. It has limited effects on gastrointestinal transit and shows no reward behavior. Biochemical studies indicate its actions are mediated through a set of μ-opioid receptor clone MOR-1 splice variants associated with exon 11 that lack exon 1 and contain only six transmembrane domains. Like the mouse and human, rats express exon 11-associated splice variants that also contain only six transmembrane domains, raising the question of whether IBNtxA would have a similar pharmacologic profile in rats. When given systemically, IBNtxA is a potent analgesic in rats, with an ED50 value of 0.89 mg/kg s.c., approximately 4-fold more potent than morphine. It shows no analgesic cross-tolerance in morphine-pelleted rats. IBNtxA displays no respiratory depression as measured by blood oxygen saturation. In contrast, oximetry shows that an equianalgesic dose of morphine lowers blood oxygen saturation values by 30%. IBNtxA binding is present in a number of brain regions, with the thalamus standing out with very high levels and the cerebellum with low levels. As in mice, IBNtxA is a potent analgesic in rats with a favorable pharmacologic profile and reduced side effects.
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: Steven G
authors: SG
authors: Grinnell
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: Susruta
authors: S
authors: Majumdar
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: Ankita
authors: A
authors: Narayan
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: Valerie
authors: V
authors: Le Rouzic
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: Michael
authors: M
authors: Ansonoff
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.).
authors: John E
authors: JE
authors: Pintar
authors: Department of Neurology (S.M., G.W.P.) and Molecular Pharmacology and Chemistry Program (V.L.R., G.W.P.), Memorial Sloan-Kettering Cancer Center, New York, New York; Neuroscience (S.G.G., A.N., G.W.P.) and Pharmacology (G.W.P.) Graduate Programs, Weill Cornell Graduate School of Medical Sciences, New York, New York; and Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey (M.A., J.E.P.) pasterng@mskcc.org.
authors: Gavril W
authors: GW
authors: Pasternak
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone