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

Abstract

Interactions between ␦ and opioid agonists in rhesus monkeys vary as a function of the behavioral endpoint. The present study compared interactions between the ␦ agonist SNC80 [(ϩ)-4-[(␣R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the agonist heroin in assays of schedule-controlled responding, thermal nociception, and drug self-administration. Both SNC80 (ED 50 ϭ 0.43 mg/kg) and heroin (ED 50 ϭ 0.088 mg/kg) produced a dose-dependent and complete suppression of response rates in the assay of schedule-controlled responding. Heroin also produced thermal antinociception (ED 5°C ϭ 0.18 mg/kg) and maintained drug self-administration under both a fixed ratio schedule [dose-effect curve peak at 0.0032 mg/kg/injection (inj)] and under a food versus heroin concurrent-choice schedule (ED 50 ϭ 0.013 mg/kg/inj), whereas SNC80 did not produce thermal antinociception or maintain self-administration. Fixed ratio mixtures of SNC80 and heroin (1.6:1, 4.7:1, and 14:1 SNC80/heroin) produced additive effects in the assay of schedule-controlled responding and superadditive effects in the assay of thermal nociception. Also, SNC80 did not enhance the reinforcing effects of heroin, indicating that mixtures of SNC80 and heroin produced additive or infra-additive reinforcing effects. These results provide additional evidence to suggest that ␦/ interactions depend on the experimental endpoint and further suggest that ␦ agonists may selectively enhance the antinociceptive effects of agonists while either not affecting or decreasing the sedative and reinforcing effects of agonists.Biochemical and behavioral evidence indicates the existence of three opioid receptor types, the ␦, , and receptors (Martin et al., 1976;Lord et al., 1977;Evans et al., 1992). Agonists selective for ␦, , and receptors produce distinct profiles of physiological and behavioral effects (Gutstein, 2001). In addition, selective ␦, , and agonists may also produce interacting effects. Studies of opioid receptor interactions in rodents and nonhuman primates have been conducted primarily with ␦ and agonists using assays of nociception, and results from these studies suggest that ␦ agonists enhance the antinociceptive effects of agonists and that this interaction depends on such variables as the species studied, the particular agonists used, the relative doses tested, and the behavioral endpoint (Heyman et al., 1989;Adams et al., 1993;Dykstra et al., 2002;Stevenson et al., 2003).Interactions between ␦ and agonists have also been reported for other behavioral endpoints, such as bladder motility, convulsions, Straub tail, respiratory depression, and sedation (Sheldon et al., 1989;O'Neill et al., 1997;Su et al.,

Behavioral Pharmacology of the μ/δ Opioid Glycopeptide MMP2200 in Rhesus Monkeys

“…Previous studies have reported that mixtures of selective and ␦ agonists produce superadditive antinociception in both nonhuman primates (Dykstra et al, 2002;Stevenson et al, 2003Stevenson et al, , 2005 and rodents (Vaught and Takemori, 1979;Heyman et al, 1989;Adams et al, 1993). One consequence of superadditivity is that enhanced antinociception produced by mixtures of and ␦ agonists requires activity at both and ␦ receptors and is sensitive to either or ␦ antagonists (e.g., Stevenson et al, 2003).…”

“…Behavioral studies were conducted using four procedures: 1) an assay of thermal nociception using warm water as the thermal stimulus; 2) an assay of capsaicin-induced thermal allodynia using warm water as the thermal stimulus; 3) an assay of schedule-controlled responding for food presentation; and 4) an assay of drug self-administration. These procedures have been used extensively by our laboratory to examine jpet.aspetjournals.org the effects of other opioids and of ␦/ interactions in rhesus monkeys (Negus et al, 1998;Brandt et al, 2001;Stevenson et al, 2003;Stevenson et al, 2005). In each assay, the effects of MMP2200 were compared with the effects of the prototype -opioid analgesic morphine.…”

Morphine in Combination with Metabotropic Glutamate Receptor Antagonists on Schedule-Controlled Responding and Thermal Nociception

“…Notably, as demonstrated in the current study, the behavioral effects of two drugs may depend on the experimental endpoint under study (Stevenson et al, 2005;Fischer and Dykstra, 2006). In addition, these interactive effects may depend on factors including the relative proportion of the drugs in the mixture and the type of nociceptive assay used (Tallarida, 2000;Nemmani et al, 2004;Craft and Lee, 2005).…”

“…Previous research suggests that interactions between two drugs may depend on the experimental endpoint under study (Stevenson et al, 2005;Fischer and Dykstra, 2006). For example, we have previously demonstrated that mixtures containing the NMDA antagonist LY235959 and morphine produced supra-additive effects on thermal nociception and additive or infra-additive effects on schedule-controlled responding (Fischer and Dykstra, 2006).…”

Choice between Heroin and Food in Nondependent and Heroin-Dependent Rhesus Monkeys: Effects of Naloxone, Buprenorphine, and Methadone

“…Behavioral sessions were conducted 7 days a week from 11:00 AM to 1:00 PM as described previously (Negus, 2005;Stevenson et al, 2005). Following initial shaping of key press responding for food reinforcement (1-g food pellets) and drug injections (0.1 mg/kg/injection heroin), choice training was initiated.…”