Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB(1) receptors.
OBJECTIVE
Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-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.


METHODS
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.


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
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.
Capasso
R
R
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy. rafcapas@unina.it
Borrelli
F
F
Cascio
M G
MG
Aviello
G
G
Huben
K
K
Zjawiony
J K
JK
Marini
P
P
Romano
B
B
Di Marzo
V
V
Capasso
F
F
Izzo
A A
AA
D000581:Amidohydrolases / Q000096:biosynthesis; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003436:Croton Oil / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000302:isolation & purification / Q000494:pharmacology*; D004558:Electric Stimulation; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007079:Ileitis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018515:Plant Leaves / Q000737:chemistry; D011485:Protein Binding; D020239:Receptor Cross-Talk / Q000187:drug effects*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D027544:Salvia / Q000737:chemistry*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D003436:Croton Oil; D045785:Diterpenes, Clerodane; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D017473:Receptors, Opioid, kappa; D000099252:Fatty Acid Amide Hydrolases; C090499:salvinorin A