Naloxone benzylhydrazone is a µ-selective opioid antagonist without kappa agonist effects in rhesus monkeys

Naloxone benzoylhydrazone (NalBzoH) has been suggested to be a selective opioid agonist, exerting its effects through the kappa(3) subtype of opioid receptor. In the present experiments NalBzoH was studied for its discriminative stimulus, analgesic, and respiratory effects in rhesus monkeys. Up to the largest doses administered (1.0-3.2mg/kg), NalBzoH failed to substitute for the discriminative stimulus effects of the kappa agonist ethylketocyclazocine or those of the µ agonist alfentanil. However, in morphine-treated (3.2mg/kg/day) monkeys NalBzoH substituted completely for the discriminative stimulus effects of the opioid antagonist naltrexone. NalBzoH antagonized the discriminative stimulus effects of alfentanil in morphine-treated subjects and, at larger doses, antagonized the discriminative stimulus effects of ethylketocyclazocine. NalBzoH did not produce analgesic effects and had only modest effects on respiration. However, NalBzoH antagonized the analgesic effects as well as the respiratory-depressant effects of alfentanil; at doses 10-15 times larger than those that antagonized alfentanil, NalBzoH also antagonized analgesic effects of the kappa agonist U-50,488. For both µ and kappa agonists, NalBzoH was slightly more potent in antagonizing discriminative stimulus effects as compared to analgesic effects. Thus, NalBzoH is a µ-selective opioid antagonist in rhesus monkeys and is equipotent to naloxone in antagonizing alfentanil. While demonstrating µ-selective antagonism, the current study fails to provide support for the proposed kappa agonist actions of NalBzoH.