A single injection of a novel kappa opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats

Abstract

Kappa opioid receptor (KOPr) activation antagonizes many cocaine-related behaviors but adverse side effects such as sedation, dysphoria and depression limit their therapeutic use. Recently, salvinorin A (Sal A), a naturally occurring KOPr agonist, has been shown to attenuate cocaine-induced drug-seeking in a model of relapse in rats. The present study evaluated the effects of acute Sal A exposure on cocaine-induced hyperactivity and cocaine sensitization in rats. Acute treatment with the dose of Sal A that decreased drug-seeking in a previous study (0.3 mg/kg), significantly attenuated the expression of cocaine sensitization. This dose of Sal A failed to affect spontaneous locomotion or to produce a conditioned taste aversion to a novel-tasting saccharin solution. However, Sal A decreased climbing and swimming time and increased time spent immobile in the forced swim test. These findings indicate that Sal A, just like traditional KOPr agonists, attenuates cocaine-induced behavioral sensitization but does not produce the adverse effect of conditioned aversion, suggesting improved potential compliance. However, pro-depressive effects were also produced and these effects may limit the therapeutic potential.

Salvinorin A Analogs and Other Kappa-Opioid Receptor Compounds as Treatments for Cocaine Abuse

“…It also attenuates the effects of cocaine hyperactivity when administered acutely, but potentiates the same effects when chronically administered. On the other hand, low doses of Sal A (< 0.25 mg/kg) (ip) consistently display less aversive effects (Morani et al, 2009; Morani et al, 2012) and is within the range with known anti-cocaine effects. Given this, Sal A possesses desirable anti-addiction effects with fewer side effects compared to traditional KOPr agonists.…”

“…Recently Sal A (0.3mg/kg) was shown to attenuate cocaine-prime-induced reinstatement, similar to U69,593 (0.3 mg/kg), U50,488 (30 mg/kg) and spiradoline (1 mg/kg) (Morani et al, 2009). Sal A also attenuated the expression of cocaine-induced behavioural sensitization in rats (Morani et al, 2012) comparable to U69,593 (Heidbreder, Babovicvuksanovic, Shoaib, & Shippenberg, 1995). The decrease in cocaine self-administration with traditional KOPr agonist U69,593 was accompanied by a decrease in food intake in rhesus monkeys (Mello & Negus, 1998; Negus, et al, 1997) and decreases in self-administration were only apparent when rats were trained with a cue (Schenk, Partridge, & Shippenberg, 1999).…”

“…In contrast to these effects, Sal A did not attenuate responses for a natural reward in rats (10% sucrose solution) at the dose (0.3 mg/kg) (intraperitoneal, ip) that attenuated cocaine prime-induced reinstatement (Morani et al, 2009). Morani et al (2012) also showed that 0.3 mg/kg of Sal A had no effect on spontaneous locomotion, cocaine induced stereotypy, cocaine induced hyperactivity, or conditioned taste aversion, suggesting that the Sal A dose sufficient to produce attenuation of drug-seeking in rats does not cause sedation or aversion. However, decreased swimming and increased immobility times were observed in the forced swim test (FST) indicating that pro-depressive effects are still seen at this dose.…”

“…While Sal A has been found to have many actions similar to traditional kappa opioid agonists there are many differences in its actions. Sal A has been shown to induce analgesia (McCurdy et al, 2006), has both aversive (behavioural conditional place aversion models) (Zhang, Butelman, Schlussman, Ho, & Kreek, 2005) and rewarding effects (Braida, Limonta, Capurro, Fadda, Rubino, Mascia et al, 2008) as well as pro-depressive (Carlezon, Beguin, DiNieri, Baumann, Richards, Todtenkopf et al, 2006; Morani, Schenk, Prisinzano, & Kivell, 2012) and anti-depressive effects (Braida, Limonta, Pegorini, Zani, Guerini-Rocco, Gori et al, 2007; Hanes, 2001). While many of these contradicting effects can be explained by use of different doses and acute versus chronic administration, a clearer understanding of these effects and their underlying mechanisms are needed.…”

Why Do Plants Contain Biologically Active Compounds?

“…The rewarding effects of salvinorin A were also reported by other authors, implicating the involvement or "cross-talk" of the endocannabinoid system in the mechanism of this action (Capasso et al 2008;Walentiny et al 2010). It has been also shown that salvinorin A may decrease responses to cocaine and in this way attenuate cocaine-induced drug-seeking behavior (Chartoff et al 2008;Morani et al 2009Morani et al , 2012.…”