INTERACTIONS BETWEEN SYNTHETIC VANILLOIDS AND THE ENDOGENOUS CANNABINOID SYSTEM

The chemical similarity between some synthetic agonists of vanilloid r eceptors, such as olvanil (N-vanillyl-cis-9-octadecenoamide), and the 'endocannabinoid' anandamide (arachidonoyl-ethanolamide, AEA), suggest s possible interactions between the cannabinoid and vanilloid signalli ng systems. Here we report that olvanil is a stable and potent inhibit or of AEA facilitated transport into rat basophilic leukemia (RBL-2H3) cells, Olvanil blocked both the uptake and the hydrolysis of [C-14]AE A by intact RBL-2H3 cells (IC50=9 mu M), while capsaicin and pseudocap saicin (N-vanillyl-nonanamide) were much less active. Olvanil was more potent than previously reported inhibitors of AEA facilitated transpo rt, i,e; phloretin (IC50=80 mu M), AM404 (12.9% inhibition at 10 mu M) or oleoylethamolamide (27.5% inhibition at 10 mu M) Olvanil was a poo r inhibitor of [C-14]AEA hydrolysis by RBL-2H3 and N18TG2 cell membran es, suggesting that the inhibitory effect on [C-14]AEA breakdown obser ved in intact cells vr,as due to inhibition of [C-14]AEA uptake. Olvan il was stable to enzymatic hydrolysis, and (i) displaced the binding o f high affinity cannabinoid receptor ligands to membrane preparations from N18TG2 cells and guinea pig forebrain (K-i = 1.64-7.08 mu M), but not from cells expressing the CB2 cannabinoid receptor subtype; (ii) inhibited forskolin-induced cAMP formation in intact N18TG2 cells (IC5 0 = 1.60 mu M), this effect being reversed by the selective CB1 antago nist SR141716A. Pseudocapsaicin, but not capsaicin, also selectively b ound to CB1 receptor-containing membranes. These data suggest that som e of the analgesic actions of olvanil may be due to its interactions w ith the endogenous cannabinoid system, and may lead to the design of a novel class of cannabimimetics with potential therapeutic application s as analgesics. (C) 1998 Federation of European Biochemical Societies .