Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice

Background and PurposeThe opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice. Experimental ApproachTo examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus. In order to elucidate the mechanism of action of tested compounds, specific antagonists of opioid and cannabinoid receptors were used. The effect of PR-37 on the CNS was assessed by measuring motor parameters and exploratory behaviours in mice. Key ResultsPR-37 and PR-38, jnjected s.c., significantly reduced the number of compound 48/80-induced scratching behaviours in mice in a dose- and time-dependent manner. PR-38 was also active when orally administered. The antiscratch activity of PR-37 was blocked by the selective opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective opioid receptor antagonist, -funaltrexamine. Conclusion and ImplicationsIn conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated.