Effects of the delta-opioid agonist SNC80 on the abuse liability of methadone in rhesus monkeys: a behavioral economic analysis

Rationale Delta-opioid agonists enhance the antinociceptive efficacy of methadone and other mu-opioid agonists. However, relatively little is known about the degree to which delta agonists might enhance the abuse-related effects of mu agonists. Objective This study used a behavioral economic approach to examine effects of the delta agonist SNC80 [(+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide] on the reinforcing effects of methadone in a drug self-administration assay. Interactions between SNC80 and cocaine were also examined for comparison. Methods Rhesus monkeys (n=4), surgically implanted with indwelling intravenous catheters, were tested in two phases. In phase 1, drug self-administration dose-effect curves for methadone (0.0032-0.1 mg/kg/injection (inj)) and cocaine (0.0032-0.32 mg/kg/inj) alone were determined under a fixed-ratio 10 (FR 10) schedule of reinforcement. In phase 2, FR values were increased every 3 days (FR 1-FR 1800) during availability of methadone alone (0.032 mg/kg/inj) and in combination with varying proportions of SNC80 (0.1:1, 0.3:1, and 0.9:1 SNC80/methadone) or of cocaine alone (0.032 mg/kg/inj) and in combination with varying proportions of SNC80 (0.33:1, 1: 1, and 3: 1 SNC80/cocaine). Demand curves related drug intake to FR price, and measures of reinforcement were derived. Results Methadone and cocaine alone each functioned as a reinforcer. SNC80 did not alter measures of reinforcement for either methadone or cocaine. Conclusions SNC80 at proportions previously shown to enhance methadone-induced antinociception did not enhance the abuse-related effects of methadone. These results support the proposition that delta agonists may selectively enhance mu agonist analgesic effects without enhancing mu agonist abuse liability.