Pretreatment with several kappa-opioid receptor agonists, including salvinorin A (Sal A), the active compound in Salvia divinorum, reduced cocaine-induced drug-seeking in rats. After learning to self-administer cocaine, rats underwent extinction and then received a cocaine priming injection. Cocaine-induced reinstatement of drug-seeking was attenuated by U69593, U50488H, spiradoline, and Sal A. Sal A did not affect sucrose-reinforced responding or cocaine-induced hyperactivity, suggesting its effects are specific to drug-seeking. These findings indicate that Sal A, like other kappa-opioid agonists, can suppress cocaine-seeking behavior.
A potent and selective kappa opioid receptor (KOPr) analogue of Salvinorin A, Mesyl Sal B, reduces cocaine-induced hyperactivity and behavioral sensitization to cocaine in male rats without causing aversion, sedation, anxiety, or learning and memory deficits. It does not alter sucrose self-administration. However, it increases immobility in the forced swim test, indicating pro-depressive effects. In male mice, Mesyl Sal B is less potent than Salvinorin A at reducing pain in antinociceptive assays. The compound has fewer side effects and longer in vivo action than Salvinorin A, but its pain-relieving effects are limited.
Activating the κ opioid receptor with the salvinorin A analogue 2-methoxy-methyl salvinorin B (MOM Sal B) at 0.3 mg/kg reduced cocaine-seeking behavior in rats, but also reduced sucrose reinforcement. No sedation was observed—locomotion in cocaine-induced hyperactivity and open field tests was unchanged—yet the forced swim test showed increased immobility and decreased swimming times, indicating pro-depressive effects. The compound thus modulates cocaine-seeking non-selectively without sedation, but depressive side effects may limit its therapeutic use.