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

A new compound called P-3l, an analogue of salvinorin A, reduces pain and anxiety-like behaviors in mice after oral administration at doses of 1, 3, 10, and 30 mg/kg. It lessened acetic acid-induced writhing, formalin-induced paw licking, hotplate responses, and aversion in elevated plus-maze, open field, and light-dark box tests. P-3l also boosted the effects of morphine and diazepam at low doses without causing changes in organ weight or blood parameters. The pain and anxiety relief were blocked by naloxone, naloxonazine, nor-binaltorphimine, and flumazenil, indicating involvement of opioid receptors and the benzodiazepine site. These findings suggest P-3l may have clinical potential for pain and anxiety treatment.

Study at a glance

Abstract

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 salvinorin 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 μ-OR), and nor-binaltorphimine (selective ĸ-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 additional pharmacological characterization.