Research Paper
Subject Category: Gastrointestinal pharmacology
British Journal of Pharmacology advance online publication 14 July 2008; doi: 10.1038/bjp.2008.294
Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between 
-opioid and cannabinoid CB1 receptors
R Capasso1,4, F Borrelli1,4, M G Cascio2,4, G Aviello1,4, K Huben3, J K Zjawiony3,5, P Marini2,4, B Romano1,4, V Di Marzo2,4, F Capasso1,4 and A A Izzo1,4
- 1Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy
- 2Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy
- 3Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, MS, USA
- 4Endocannabinoid Research Group, Italy
- 5National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA
Correspondence: Dr R Capasso, Department of Experimental Pharmacology, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy. E-mail: rafcapas@unina.it; Professor AA Izzo, E-mail: aaizzo@unina.it
Received 29 May 2008; Accepted 18 June 2008; Published online 14 July 2008.
Abstract
Background and purpose:
Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of 
-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 CB1 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 CB1 and CB2 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 CB1 receptors and KORs in the inflamed—but not in the normal—gut in vivo.
Keywords:
cannabinoid receptors, fatty acid amide hydrolase, endocannabinoid transport, inflammatory bowel disease, intestinal motility, -opioid receptors (KORs), myenteric plexus, Salvia divinorum, salvinorin A
Abbreviations:
ACEA, arachidonyl-2-chloroethylamide; [3H]-CP-55,940, [3H]-(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexanol|EFS, electrical field stimulation; EMT, endocannabinoid membrane transporter; FAAH, fatty acid amide hydrolase; GC, geometric centre; JWH 015, (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenymethanone; KOR, -opioid receptor; MAG, monoacylglycerol; SR144528, N-[-1S-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; WIN 55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-gmorpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone
