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
Citation Impact
BMJ Impact Analytics
Related MSK Work