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-methoxy-benzyl]-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.

Latent factor structure of a behavioral economic marijuana demand curve

“…The entered variables were breakpoint, observed P max , observed O max , observed intensity, and elasticity (α). Originally proposed by Hursh and Silberberg (2008), the inverse value for elasticity was used (1/α; i.e., essential value) in order to make interpretation of the factor structure more intuitive, consistent with previous work (Banks et al 2011; Bidwell et al 2012; O’Connor et al 2016). The following transformations were used in order to meet normality assumptions: breakpoint (square-root), observed P max (log 10 ), observed O max (log 10 ), observed intensity (log 10 ), and elasticity (cube-root).…”

Corn oil, but not cocaine, is a more effective reinforcer in obese than in lean Zucker rats

“…A custom-designed GraphPad Prism 5.0 template (freely available from the Institutes for Behavior Resources, www.ibrinc.org) plotted reinforcers earned in a session as a function of FR value and the data were fit with the Exponential Model of Demand introduced by Hursh and Silberberg (2008). In cases where the injections per session were a value of 0 (i.e., responses were not sufficient to earn a reinforcer), a value of 0.1 was entered because the log of 0 cannot be calculated (see Banks et al 2011; Freeman et al, 2014). …”

Molecular Pharmacology ofδ-Opioid Receptors

“…DOPr participation in reward responses is also considerably less than that of MOPrs, being mostly associated with learning of physiologic rewards (Laurent et al, 2012;Charbogne et al, 2014). Consequently, DOPr activation does not facilitate intracranial self-stimulation (Do Carmo et al, 2009), their agonists are not discriminated as morphine substitutes (Gallantine and Meert, 2005), and DOPrs do not display reinforcing properties (Banks et al, 2011). Despite these advantages, DOPr agonists display considerable potential for tolerance (Pradhan et al, 2010;Audet et al, 2012) and may increase forebrain excitability by reducing the threshold for seizures (Jutkiewicz et al, 2005(Jutkiewicz et al, , 2006Chu Sin Chung and Kieffer, 2013).…”