Antagonism of the antinociceptive and discriminative stimulus effects of heroin and morphine by 3-methoxynaltrexone and naltrexone in rhesus monkeys

It has been suggested that heroin and morphine may act on different opioid receptor populations in rodents. In support of this hypothesis, the opioid antagonist 3-methoxynaltrexone was reported to be more potent as an antagonist of the antinociceptive effects of heroin than of morphine in mice and rats. To assess the generality of this finding across species and experimental endpoints, the present study compared the potencies of naltrexone and 3-methoxynaltrexone as antagonists of heroin and morphine in two behavioral assays in rhesus monkeys. In the thermal nociception study, tail-withdrawal latencies were measured from water heated to 50degreesC. In the heroin discrimination study, monkeys were trained to discriminate 0.1 mg/kg heroin from saline in a two-key, food-reinforced drug discrimination procedure, and percentage of heroin-appropriate responding and response rates were measured. Both heroin and morphine produced dose-dependent antinociception, increases in percentage of heroin-appropriate responding, and decreases in response rates. Heroin was approximately 20-fold more potent than morphine. Naltrexone (0.032-0.1 mg/kg) was equipotent in antagonizing all effects of heroin and morphine (pA(2) values = 7.90-8.22). 3-Methoxynaltrexone (0.1-3.2 mg/kg) was also equipotent in antagonizing the antinociceptive, discriminative stimulus, and rate-suppressant effects of heroin and morphine; however, 3-methoxynaltrexone was approximately 100-fold less potent than naltrexone (pA(2)/pK(B) values = 5.96-6.36). These results suggest that heroin and morphine act on pharmacologically similar populations of opioid receptors in rhesus monkeys, and also indicate that 3-methoxynaltrexone does not differentially antagonize the effects of heroin and morphine in rhesus monkeys.