Naloxonazine antagonism of levorphanol-induced antinociception and respiratory depression in rhesus monkeys.
The mu-opioid receptor antagonist effects of naloxonazine on levorphanol-induced thermal antinociception and respiratory depression were examined in rhesus monkeys. Levorphanol (0.032-3.2 mg/kg) produced dose-dependent increases in tail-withdrawal latencies from 50 degrees C water in a warm-water tail-withdrawal assay and dose-dependent decreases in ventilation in both air and 5% CO2 mixed in air. Naloxonazine (0.1-3.0 mg/kg) antagonized both the antinociceptive and ventilatory effects of levorphanol to a similar degree, and the antagonist effects of naloxonazine were greater after 1 h than after 24 h. Under all conditions, the antagonist effects of naloxonazine were fully surmountable. Schild analysis of the antagonist effects of naloxonazine after 1 h pretreatment in the antinociception assay yielded a pA2 value of 7.6 and a slope of -0.50; by comparison, quadazocine yielded a pA2 value of 7.5 and a slope of -1.05. These results suggest that naloxonazine acts as a potent and fully reversible mu-opioid receptor antagonist with a moderately long duration of action in rhesus monkeys. In addition, these results suggest that the antinociceptive and ventilatory effects of mu-opioid receptor agonists in rhesus monkeys are mediated by pharmacologically similar populations of mu opioid receptors.
Gatch
M B
MB
Alcohol and Drug Abuse Research Center, McLean Hospital, Belmont, MA 02178, USA.
Liguori
A
A
Negus
S S
SS
Mello
N K
NK
Bergman
J
J
Liguori
T
T
D000698:Analgesia; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007981:Levorphanol / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects*; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D007981:Levorphanol; D009270:Naloxone; C034643:naloxonazine