Endogenous unsaturated C18 N-acylethanolamines are vanilloid receptor (TRPV1) agonists.
The endogenous C18 N-acylethanolamines (NAEs) N-linolenoylethanolamine (18:3 NAE), N-linoleoylethanolamine (18:2 NAE), N-oleoylethanolamine (18:1 NAE), and N-stearoylethanolamine (18:0 NAE) are structurally related to the endocannabinoid anandamide (20:4 NAE), but these lipids are poor ligands at cannabinoid CB(1) receptors. Anandamide is also an activator of the transient receptor potential (TRP) vanilloid 1 (TRPV(1)) on primary sensory neurons. Here we show that C18 NAEs are present in rat sensory ganglia and vascular tissue. With the exception of 18:3 NAE in rat sensory ganglia, the levels of C18 NAEs are equal to or substantially exceed those of anandamide. At submicromolar concentrations, 18:3 NAE, 18:2 NAE, and 18:1 NAE, but not 18:0 NAE and oleic acid, activate native rTRPV(1) on perivascular sensory nerves. 18:1 NAE does not activate these nerves in TRPV(1) gene knock-out mice. Only the unsaturated C18 NAEs elicit whole cell currents and fluorometric calcium responses in HEK293 cells expressing hTRPV(1). Molecular modeling revealed a low energy cluster of U-shaped unsaturated NAE conformers, sharing several pharmacophoric elements with capsaicin. Furthermore, one of the two major low energy conformational families of anandamide also overlaps with the cannabinoid CB(1) receptor ligand HU210, which is in line with anandamide being a dual activator of TRPV(1) and the cannabinoid CB(1) receptor. This study shows that several endogenous non-cannabinoid NAEs, many of which are more abundant than anandamide in rat tissues, activate TRPV(1) and thus may play a role as endogenous TRPV(1) modulators.
Movahed
Pouya
P
Department of Laboratory Medicine Lund University, SE-22185 Lund, Sweden.
Jönsson
Bo A G
BA
Birnir
Bryndis
B
Wingstrand
Johan A
JA
Jørgensen
Tino Dyhring
TD
Ermund
Anna
A
Sterner
Olov
O
Zygmunt
Peter M
PM
Högestätt
Edward D
ED
D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry; D019540:Area Under Curve; D001158:Arteries / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000737:chemistry; D002211:Capsaicin / Q000737:chemistry; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004983:Ethanolamines / Q000737:chemistry*; D005260:Female; D005470:Fluorometry / Q000379:methods; D005724:Ganglia / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D009474:Neurons / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012984:Software; D050916:TRPV Cation Channels / Q000819:agonists*; D013997:Time Factors
D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D004983:Ethanolamines; D008024:Ligands; D008055:Lipids; C022203:N-acylethanolamines; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin; D002118:Calcium; C078814:anandamide