Interactions between synthetic vanilloids and the endogenous cannabinoid system

FEBS Letters

Di Marzo, Vincenzo³  Melck, Dominique³  Brockie, Heather²  De Petrocellis, Luciano¹  Stevenson, Lesley²  Bisogno, Tiziana³  Ross, Ruth²  Pertwee, Roger² 

[1] Istituto di Cibernetica, CNR, Via Toiano 6, 80072, Arco Felice, Napoli, Italy;Department of Biomedical Sciences, University of Aberdeen, Aberdeen, UK;Istituto per la Chimica di Molecole di Interesse Biologico, CNR, Via Toiano 6, 80072, Arco Felice, Napoli, Italy

关键词: Vanilloid receptor;    Cannabinoid receptor;    Endocannabinoid;    Anandamide;    Capsaicin;    Inflammation;    Antinociception;    Mast cell;   

DOI  :  10.1016/S0014-5793(98)01175-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The chemical similarity between some synthetic agonists of vanilloid receptors, such as olvanil (N-vanillyl-cis-9-octadecenoamide), and the ‘endocannabinoid’ anandamide (arachidonoyl-ethanolamide, AEA), suggests possible interactions between the cannabinoid and vanilloid signalling systems. Here we report that olvanil is a stable and potent inhibitor of AEA facilitated transport into rat basophilic leukemia (RBL-2H3) cells. Olvanil blocked both the uptake and the hydrolysis of [¹⁴C]AEA by intact RBL-2H3 cells (IC₅₀=9 μM), while capsaicin and pseudocapsaicin (N-vanillyl-nonanamide) were much less active. Olvanil was more potent than previously reported inhibitors of AEA facilitated transport, i.e. phloretin (IC₅₀=80 μM), AM404 (12.9% inhibition at 10 μM) or oleoylethanolamide (27.5% inhibition at 10 μM). Olvanil was a poor inhibitor of [¹⁴C]AEA hydrolysis by RBL-2H3 and N18TG2 cell membranes, suggesting that the inhibitory effect on [¹⁴C]AEA breakdown observed in intact cells was due to inhibition of [¹⁴C]AEA uptake. Olvanil was stable to enzymatic hydrolysis, and (i) displaced the binding of high affinity cannabinoid receptor ligands to membrane preparations from N18TG2 cells and guinea pig forebrain (K _i=1.64–7.08 μM), but not from cells expressing the CB2 cannabinoid receptor subtype; (ii) inhibited forskolin-induced cAMP formation in intact N18TG2 cells (IC₅₀=1.60 μM), this effect being reversed by the selective CB1 antagonist SR141716A. Pseudocapsaicin, but not capsaicin, also selectively bound to CB1 receptor-containing membranes. These data suggest that some of the analgesic actions of olvanil may be due to its interactions with the endogenous cannabinoid system, and may lead to the design of a novel class of cannabimimetics with potential therapeutic applications as analgesics.

【 授权许可】

Unknown