Antagonism of the Antinociceptive and Discriminative Stimulus Effects of Heroin and Morphine by 3-Methoxynaltrexone and Naltrexone in Rhesus Monkeys

Abstract

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 50°C. 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 ϭ 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 ϭ 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.

Interactions between Δ9-tetrahydrocannabinol and μ opioid receptor agonists in rhesus monkeys: discrimination and antinociception

“…additive interaction). It is unlikely that different mechanisms mediate the discriminative stimulus and antinociceptive effects of morphine because the same drugs (μ receptor agonists) share effects with morphine and the affinity estimates for antagonists are the same under the two conditions (Bowen et al 2002). A positive interaction between the antinociceptive effects of cannabinoid and opioid receptor agonists in monkeys confirms previous findings in rodents (for reviews see Welch and Eades 1999;Cichewicz 2004) and suggests that the differential (e.g.…”

Interactions betweenμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

“…Differences in interactions are not likely to be attributable to pharmacokinetics, because the routes of administration and pretreatment times for morphine and cannabinoid receptor agonists were consistent across studies. Moreover, it is clear from the consistent rank order potency of agonists and from quantitatively consistent antagonism studies that these behavioral effects of morphine and heroin are mediated by m-opioid receptors (Bowen et al, 2002;Gerak et al, 1994). Opioid receptor agonists and cannabinoid receptor agonists individually can have robust and pharmacologically distinct discriminative stimulus effects.…”

Interactions between δ and μ Opioid Agonists in Assays of Schedule-Controlled Responding, Thermal Nociception, Drug Self-Administration, and Drug versus Food Choice in Rhesus Monkeys: Studies with SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and Heroin

“…It is important to note that, in the present study, heroin was used as a representative opioid agonist to facilitate subsequent assessment of the reinforcing effects associated with ␦ ϩ interactions. Pharmacological studies suggest that the behavioral effects of heroin in rhesus monkeys are mediated primarily by receptors (Bowen et al, 2002;Negus et al, 2003).…”

“…SNC80 was used as the representative ␦ agonist in these studies because it functions as a potent, selective, and systemically active ␦ agonist in rhesus monkeys (Negus et al, 1998). Heroin was used as the representative agonist because it functions as a selective and relatively high-efficacy agonist in rhesus monkeys (Bowen et al, 2002;Negus et al, 2003) and because rhesus monkeys had already been trained to self-administer heroin in our laboratory under both the drug-alone and drug versus food choice procedures.…”