TY - JOUR
T1 - Pharmacologic characterization in the rat of a potent analgesic lacking respiratory depression, IBNtxA
AU - Grinnell, Steven G.
AU - Majumdar, Susruta
AU - Narayan, Ankita
AU - Le Rouzic, Valerie
AU - Ansonoff, Michael
AU - Pintar, John E.
AU - Pasternak, Gavril W.
N1 - Funding Information: This work was supported, in part, by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA002615, R01-DA07242, and R01-DA06241]; the Harrington Research Institute; Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research; the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (to G.W.P.); a fellowship from the PhRMA Foundation (to S.G.G.); and a core grant from the National Institutes of Health National Cancer Institute [Grant CA08748] (to the Memorial Sloan-Kettering Cancer Center). Funding Information: This work was supported, in part, by the National Institutes of Health National Institute on Drug Abuse [Grants R01-DA002615, R01-DA07242, and R01-DA06241]; the Harrington Research Institute; Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research; the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center (to G.W.P.); a fellowship from the PhRMA Foundation (to S.G.G.); and a core grant from the National Institutes of Health National Cancer Institute [Grant CA08748] (to the Memorial Sloan-Kettering Cancer Center). dx.doi.org/10.1124/jpet.114.213199. Publisher Copyright: Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907283322&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907283322&partnerID=8YFLogxK
U2 - https://doi.org/10.1124/jpet.114.213199
DO - https://doi.org/10.1124/jpet.114.213199
M3 - Article
C2 - 24970924
VL - 350
SP - 710
EP - 718
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -