Inhibitory effect of salvinorin A, fromSalvia divinorum, on ileitis‐induced hypermotility: cross‐talk between κ‐opioid and cannabinoid CB1receptors

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Abstract
Background and purpose: Salvinorin A, the active component of the hallucinogenic herbSalvia divinorum, inhibits intestinal motility through activation of κ‐opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A‐induced delay in motility in the inflamed gut.Experimental approach: Motilityin vivowas measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.Key results: Salvinorin A as well as the KOR agonist U‐50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U‐50488 was counteracted by the KOR antagonist nor‐binaltorphimine and by the cannabinoid CB1receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB1and CB2and no inhibitory effect on 2‐arachidonoylglycerol and anandamide hydrolysis and cellular uptake.Conclusions and implications: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB1receptors and KORs in the inflamed—but not in the normal—gutin vivo.British Journal of Pharmacology(2008)155, 681–689; doi:10.1038/bjp.2008.294; published online 14 July 2008