Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis‐induced hypermotility: cross‐talk between κ‐opioid and cannabinoid CB₁ receptors

Abstract

Background and purpose: Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of k-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: Motility in vivo was 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 CB 1 receptor 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 CB 1 and CB 2 and 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 CB 1 receptors and KORs in the inflamed-but not in the normal-gut in vivo.

Why Do Plants Contain Biologically Active Compounds?

“…These observations are in accord with earlier studies in animal models, where rewarding effects were observed after administration of low doses of salvinorin A to zebrafish and rats (Braida et al 2007(Braida et al , 2008. The rewarding effects of salvinorin A were also reported by other authors, implicating the involvement or "cross-talk" of the endocannabinoid system in the mechanism of this action (Capasso et al 2008;Walentiny et al 2010). It has been also shown that salvinorin A may decrease responses to cocaine and in this way attenuate cocaine-induced drug-seeking behavior (Chartoff et al 2008;Morani et al 2009Morani et al , 2012.…”

Unconditioned Behavioral Effects of the Powerful κ-Opioid Hallucinogen Salvinorin A in Nonhuman Primates: Fast Onset and Entry into Cerebrospinal Fluid

“…Salvinorin A does not have affinity at CB1 receptors (Roth et al, 2002;Capasso et al, 2008); therefore, this observed effect could be potentially because of a downstream interaction between -opioid and CB1 systems (Mason et al, 1999). However, in contrast to the full blockade observed with nalmefene herein, the CB1 antagonist rimonabant (1 mg/kg i.v.)…”

Novel Orally Available Salvinorin A Analog PR-38 Inhibits Gastrointestinal Motility and Reduces Abdominal Pain in Mouse Models Mimicking Irritable Bowel Syndrome

“…Originally, SA was identified as a potent KOR agonist, but recently it has also been shown to possess, unusual for plantderived opioids, the ability to activate CB receptors in in vitro and in vivo assays (Roth et al, 2002;Capasso et al, 2008;Fichna et al, 2009aFichna et al, , 2012Aviello et al, 2011). Here, we observed that the inhibitory effect of PR-38 on twitch contractions in mouse colon in vitro and on the GI motility in vivo was blocked by MOR and KOR antagonists.…”

“…Our earlier experimental data suggest that the antimotility action of SA is stronger in pathophysiological conditions than in healthy mice (Capasso et al, 2006(Capasso et al, , 2008, and thus in this study, we used models of diarrhea and hypermotility to evaluate the antidiarrheal properties of PR-38. The administration of PR-38 significantly prolonged the time that elapsed from administration of croton oil to emergence of liquid pellets and significantly altered defecation pattern in stressed mice.…”

“…Additionally, in the ileum and the colon, the inhibitory effect of SA was blocked by selective antagonists of cannabinoid type 1 (CB1) [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, AM 251] and cannabinoid type 2 (CB2) [6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM 630)] receptors. In the in vivo studies, it has been shown that SA slowed upper intestinal transit, as indicated by a lower geometric center (GC) of the upper GI tract (Fichna et al, 2009a) and colonic motility (Fichna et al, 2009a), and inhibited GI motility in croton oil-induced intestinal inflammation in mice (Capasso et al, 2008). Moreover, Guida et al (2012) have shown that SA reduces mechanical allodynia induced by peripheral formalin injection in mice.…”