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J Pharmacol Exp Ther. 2014 Sep;350(3):710-8. doi: 10.1124/jpet.114.213199. Epub 2014 Jun 26.

Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA.

Author information

1
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.).
2
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.

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.

PMID:
24970924
PMCID:
PMC4152881
DOI:
10.1124/jpet.114.213199
[Indexed for MEDLINE]
Free PMC Article

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