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

Abstract

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-[(αR)-α-((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.

Fig. 1

Self-administration of intravenous methadone (0.0032–0.1 mg/ kg/inj) or cocaine (0.0032–0.32 mg/kg/inj) under a fixed-ratio 10 schedule of reinforcement in rhesus monkeys (n=4). Abscissa: unit dose of methadone or cocaine in milligrams/kilogram/injection (log scale). Ordinate: number of injections earned in the 120-min session. Downward triangle above S represents the mean±SEM number of injections delivered during saline substitution sessions that preceded test sessions. Upward triangle above C represents mean±SEM number of injections delivered during maintenance sessions of 0.032 mg/kg/inj cocaine availability that preceded test sessions. Filled symbols represent drug doses that maintained significantly greater self-administration than saline (p<0.05)

Fig. 2

Effects of fixed-ratio manipulations on responding maintained by methadone (top panels) or cocaine (bottom panels) available alone or in mixtures with the delta-opioid agonist SNC80. Left panels (a and d) show the effects of varying the fixed ratio (log scale) on the numbers of injections per session. Center panels (b and e) show the same data but with rates of self-administration at each FR expressed as the percent self-administration rate at FR 1. Linear regression through these data was used to generate EFR50 values as a measure of reinforcement. Right panels (c and f) show the same data expressed as normalized demand curves. Non-linear regression through these curves using the exponential model of demand was used to generate 1/α values as a measure of reinforcement. All points represent the mean of four rhesus monkeys, and error bars show SEM. Filled symbols represent fixed ratios at which cocaine in some combination with SNC80 maintained significantly greater rates of self-administration than cocaine alone (p<0.05)

Fig. 3

Correlation between EFR50 and 1/α metrics of reinforcement derived from curves shown in Fig. 2 b, c, e and f. Abscissa: log EFR50 values. Ordinate: log 1/α values. Each point represents the mean of four monkeys, and different symbols represent the different treatment conditions as shown in Fig. 2. Filled points represent methadone alone (filled circle) or in combinations with SNC80. Open points represent cocaine alone (open circle) or in combinations with SNC80. Linear regression was used to determine R² and p values