Heteroaromatic salvinorin A analogue (P-3 l) elicits antinociceptive and anxiolytic-like effects

Previous studies have attributed the prominent analgesic, hallucinogenic, sedative, and anxiolytic properties of Salvia divinorum to Salvinorin A. However, the overall pharmacological profile of this isolate limits its clinical applications. To address these limitations, our study evaluates the C(22)-fused-heteroaromatic analogue of sal-vinorin A [2-O-salvinorin B benzofuran-2-carboxylate] (P-3l) in mice nociception and anxiety models while assessing possible mechanism of action. In comparison with the control group, orally administered P-3l (1, 3, 10, and 30 mg/kg) attenuates acetic acid-induced abdominal writhing, formalin-induced hind paw licking, the thermal reaction to the hotplate, and/or aversive response in the elevated plus-maze, open field, and light-dark box; and potentiates the effect of morphine and diazepam at sub-effective doses (1.25 and 0.25 mg/kg, respectively) without eliciting significant alterations in relative organ weight, or haematological or biochemical parameters. The in vivo blockade of P-3 l effects by naloxone (non-selective opioid receptor antagonist), naloxonazine (antagonist of specific subtypes mu1 of mu-OR), and nor-binaltorphimine (selective kappa-OR antagonist) supports initial results from binding assays and the interpretations made possible from computational modeling of the interactions of P-3 l with the opioid receptor subtypes. In addition to the opioidergic mechanism, the blockade of the P-3 l effect by flumazenil suggests benzodiazepine binding site involvement in its biological activities. These results support P-3 l potentially possessing clinical utility and substantiate the need for addi-tional pharmacological characterization.

Automated summary

The study evaluated the effects and possible mechanisms of the C(22)-fused-heteroaromatic analogue of Salvinorin A, known as P-3l, in mice nociception and anxiety models. P-3l showed potential as an analgesic and anxiolytic agent without significant adverse effects on organ weight or biochemical parameters. The effects of P-3l were mediated through opioid receptors, particularly mu and kappa receptors, as well as benzodiazepine binding sites.