title: N-palmitoyl-vanillamide (palvanil) is a non-pungent analogue of capsaicin with stronger desensitizing capability against the TRPV1 receptor and anti-hyperalgesic activity.
abstract: N-acyl-vanillamide (NAVAM) analogues of the natural pungent principle of capsicum, capsaicin, were developed several years ago as potential non-pungent analgesic compounds. N-oleoyl-vanillamide (olvanil) and N-arachidonoy-vanillamide (arvanil), in particular, were described in several publications and patents to behave as potent anti-hyperalgesic compounds in experimental models of chronic and inflammatory pain, and to activate both "capsaicin receptors", i.e. the transient receptor potential of vanilloid type-1 (TRPV1) channel, and, either directly or indirectly, cannabinoid receptors of type-1. Here we report the biochemical and pharmacological characterization of a so far neglected NAVAM, N-palmitoyl-vanillamide (palvanil), and propose its possible use instead of capsaicin, as a possible topical analgesic. Palvanil exhibited a kinetics of activation of human recombinant TRPV1-mediated intracellular calcium elevation significantly slower than that of capsaicin (t(1/2)=21s and 8s, respectively at 1μM). Slow kinetics of TRPV1 agonists were previously found to be associated with stronger potencies as TRPV1 desensitizing agents, which in turn are usually associated with lower pungency and stronger anti-hyperalgesic activity. Accordingly, palvanil desensitized the human recombinant TRPV1 to the effect of capsaicin (10nM) with significantly higher potency than capsaicin (IC(50)=0.8nM and 3.8nM, respectively), this effect reaching its maximum more rapidly (50 and 250min, respectively). Palvanil was also more potent than capsaicin at desensitizing the stimulatory effect of TRPV1 by low pH together with anandamide, which mimics conditions occurring during inflammation. In the eye-wiping assay carried out in mice, palvanil was not pungent and instead caused a strong and long-lasting inhibition of capsaicin-induced eye-wiping. Finally, intraplantar palvanil inhibited the second phase of the nociceptive response to formalin in mice. In conclusion, palvanil appears to be a non-pungent analogue of capsaicin with stronger desensitizing effects on TRPV1 and hence potentially higher anti-hyperalgesic activity.
authors.affiliation: Endocannabinoid Research Group, Institute of Cybernetics - CNR, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Aniello Schiano
authors.initials: AS
authors.lastname: Moriello
authors.forename: Maria
authors.initials: M
authors.lastname: De Chiaro
authors.forename: Fabiana
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000287:Administration, Topical; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D063388:Endocannabinoids; D005123:Eye / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010146:Pain / Q000188:drug therapy*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D063388:Endocannabinoids; C558407:N-palmitoyl-vanillamide; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002211:Capsaicin; D002118:Calcium; C078814:anandamide