THE STIMULATION OF CAPSAICIN-SENSITIVE NEURONS IN A VANILLOID RECEPTOR-MEDIATED FASHION BY PUNGENT TERPENOIDS POSSESSING AN UNSATURATED 1,4-DIALDEHYDE MOIETY

1 The irritant fungal terpenoid isovelleral caused protective eye-wipi ng movements in the rat upon intraocular instillation and showed cross -tachyphylaxis with capsaicin, the pungent principle in hot pepper. 2 Isovelleral induced a dose-dependent calcium uptake by rat dorsal root ganglion neurones cultured in vitro with an EC(50) of 95 nM, which wa s fully inhibited by the competitive vanilloid receptor antagonist cap sazepine. 3 Isovelleral inhibited specific binding of [H-3]-resinifera toxin (RTX), an ultrapotent capsaicin analogue, to rat trigeminal gang lion or spinal cord preparations with an IC50 of 5.2 mu M; in experime nts in which the concentration of [H-3]-RTX was varied, isovelleral ch anged both the apparent affinity (from 16 pM to 37 pM) and the co-oper ativity index (from 2.1 to 1.5), but not the B-max. 4 The affinity of isovelleral for inducing calcium uptake or inhibiting RTX binding was in very good agreement with the threshold dose (2.2. nmol) at which it provoked pungency on the human tongue. 5 For a series of 14 terpenoid s with an unsaturated 1,4-dialdehyde, a good correlation was found bet ween pungency on the human tongue and affinity for vanilloid receptors on the rat spinal cord. 6 The results suggest that isovelleral-like c ompounds produce their irritant effect by interacting with vanilloid r eceptors on capsaicin-sensitive sensory neurones. Since these pungent diterpenes are structurally distinct from the known classes of vanillo ids, these data provide new insights into structure-activity relations and may afford new opportunities for the development of drugs targeti ng capsaicin-sensitive pathways.