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


Authors: Grinnell, S. G.; Majumdar, S.; Narayan, A.; Le Rouzic, V.; Ansonoff, M.; Pintar, J. E.; Pasternak, G. W.
Article 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. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
Keywords: mouse; animal; metabolism; animals; mice; mice, knockout; protein binding; drug effect; physiology; narcotic analgesic agent; rat; drug derivative; rats; randomization; rats, sprague-dawley; analgesics, opioid; oxygen consumption; sprague dawley rat; knockout mouse; respiratory insufficiency; respiratory failure; naltrexone; random allocation; iodobenzoylnaltrexamide; male; article
Journal Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 350
Issue: 3
ISSN: 0022-3565
Publisher: American Society for Pharmacology and Experimental Therapeutics  
Date Published: 2014-09-01
Start Page: 710
End Page: 718
Language: English
DOI: 10.1124/jpet.114.213199
PUBMED: 24970924
PROVIDER: scopus
PMCID: PMC4152881
DOI/URL:
Notes: Export Date: 3 November 2014 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Gavril W Pasternak
    312 Pasternak