TY - JOUR
T1 - Methocinnamox produces long-lasting antagonism of the behavioral effects of m-opioid receptor agonists but not prolonged precipitated withdrawal in rats
AU - Gerak, Lisa R.
AU - Minervini, Vanessa
AU - Latham, Elizabeth
AU - Ghodrati, Saba
AU - Lillis, Katherine V.
AU - Wooden, Jessica
AU - Disney, Alex
AU - Husbands, Stephen M.
AU - France, Charles P.
N1 - Funding Information:
Male Sprague-Dawley rats (Envigo Inc., Chicago, IL) were maintained under a 14-hour light/10-hour dark cycle; experiments were conducted during the light cycle. Rats were housed individually in colony rooms that were maintained at a constant temperature and humidity. While in their home cage, they had continuous access to water and, with the exception of one study, unlimited access to food (Envigo Teklad, Madison, WI). The eight rats in which gastrointestinal transit was measured did not have unlimited access to food; instead, they were maintained at 375 6 5 g body weight with daily food rations of 15 g, except on days preceding tests when the ration was decreased to 5 g. All animals used in these studies were maintained in accordance with the Institutional Animal Care and Use Committee at The University of Texas Health Science Center at San Antonio, and the Guide for the Care and Use of Laboratory Animals, as adopted and promulgated by the US National Institutes of Health (National Research Council, 2011).
Funding Information:
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01DA048417 (to C.P.F.) and R01DA07315 (to S.M.H.)] and by the Welch Foundation [Grant AQ-0039 (to C.P.F.)]. The authors thank J. Juarez and A. Nelson for excellent technical assistance.
Funding Information:
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants R01DA048417 (to C.P.F.) and R01DA07315 (to S.M.H.)] and by the Welch Foundation [Grant AQ-0039 (to C.P.F.)]. All funding sources had no involvement beyond financial support of this study. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or the National Institute on Drug Abuse. The authors have no conflict of interest. https://doi.org/10.1124/jpet.119.260331.
Publisher Copyright:
© 2019 American Society for Pharmacology and Experimental Therapy. All rights reserved.
PY - 2019
Y1 - 2019
N2 - A novel m-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1–10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund’s adjuvant). Before MCAM, morphine, fentanyl, and the k-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective m-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by m-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.
AB - A novel m-opioid receptor antagonist, methocinnamox (MCAM), attenuates some abuse-related and toxic effects of opioids. This study further characterized the pharmacology of MCAM in separate groups of rats using procedures to examine antinociception, gastrointestinal motility, and withdrawal in morphine-dependent rats. Antinociceptive effects of opioid receptor agonists were measured before and after MCAM (1–10 mg/kg) using warm water tail withdrawal and sensitivity to mechanical stimulation in inflamed paws (complete Freund’s adjuvant). Before MCAM, morphine, fentanyl, and the k-opioid receptor agonist spiradoline dose dependently increased tail-withdrawal latency from 50°C water; MCAM attenuated the antinociceptive effects of morphine and fentanyl, but not spiradoline. Morphine increased sensitivity to mechanical stimulation and decreased gastrointestinal motility, and MCAM blocked both effects. These antagonist effects of 10 mg/kg MCAM were persistent, lasting for 2 weeks or longer. Withdrawal emerged after discontinuation of morphine treatment or administration of 10 mg/kg MCAM or 17.8 mg/kg naloxone; other than the day of antagonist administration when withdrawal signs were greater in rats that received antagonist compared with rats that received vehicle, there was no difference among groups in directly observable withdrawal signs or decreased body weight. These results confirm that MCAM is a selective m-opioid receptor antagonist with an exceptionally long duration of action, likely due to pseudoirreversible binding. Despite its sustained antagonist effects, the duration of withdrawal precipitated by MCAM is not different from that precipitated by naloxone, suggesting that the long duration of antagonism provided by MCAM could be particularly effective for treating opioid abuse and overdose. SIGNIFICANCE STATEMENT The opioid receptor antagonist MCAM attenuates some abuse-related and toxic effects of opioids. This study demonstrates that MCAM selectively antagonizes multiple effects mediated by m-opioid receptor agonists for 2 weeks or longer, and like naloxone, MCAM precipitates withdrawal in morphine-dependent rats. Despite this persistent antagonism, withdrawal signs precipitated by MCAM are not significantly different from signs precipitated by naloxone or occurring after discontinuation of morphine, suggesting that using MCAM for opioid abuse or overdose would not produce sustained withdrawal.
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U2 - 10.1124/jpet.119.260331
DO - 10.1124/jpet.119.260331
M3 - Article
C2 - 31439807
AN - SCOPUS:85073652605
SN - 0022-3565
VL - 371
SP - 507
EP - 516
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -