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

Steven G. Grinnell, Susruta Majumdar, Ankita Narayan, Valerie Le Rouzic, Michael Ansonoff, John E. Pintar, Gavril W. Pasternak

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)710-718
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume350
Issue number3
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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