title: Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors.
abstract: In the ventrolateral periaqueductal gray (PAG), activation of excitatory output neurons projecting monosynaptically to OFF cells in the rostral ventromedial medulla (RVM) causes antinociceptive responses and is under the control of cannabinoid receptor type-1 (CB1) and vanilloid transient receptor potential vanilloid type 1 (TRPV1) receptors. We studied in healthy rats the effect of elevation of PAG endocannabinoid [anandamide and 2-arachidonoylglycerol (2-AG)] levels produced by intra-PAG injections of the inhibitor of fatty acid amide hydrolase URB597 [cyclohexylcarbamic acid-3'-carbamoyl-biphenyl-3-yl ester] on 1) nociception in the "plantar test" and 2) spontaneous and tail-flick-related activities of RVM neurons. Depending on the dose or time elapsed since administration, URB597 (0.5-2.5 nmol/rat) either suppressed or increased thermal nociception via TRPV1 or CB1 receptors, respectively. TRPV1 or cannabinoid receptor agonists capsaicin (6 nmol) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN55,212-2 (4 nmol)] also suppressed or enhanced nociception, respectively. URB597 dose dependently enhanced PAG anandamide and 2-AG levels, with probable subsequent activation of TRPV1/CB1 receptors and only CB1 receptors, respectively. The TRPV1-mediated antinociception and CB1-mediated nociception caused by URB597 correlated with enhanced or reduced activity of RVM OFF cells, suggesting that these effects occur via stimulation or inhibition of excitatory PAG output neurons, respectively. Accordingly, several ventrolateral PAG neurons were found by immunohistochemistry to coexpress TRPV1 and CB1 receptors. Finally, at the highest doses tested, URB597 (4 nmol/rat) and, as previously reported, WIN55,212-2 (25-100 nmol) also caused CB(1)-mediated analgesia, correlating with stimulation (possibly disinhibition) of RVM OFF cells. Thus, endocannabinoids affect the descending pathways of pain control by acting at either CB1 or TRPV1 receptors in healthy rats.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bisogno
authors.forename: Vito
authors.initials: V
authors.lastname: de Novellis
authors.forename: Enza
authors.initials: E
authors.lastname: Palazzo
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.forename: Marta
authors.initials: M
authors.lastname: Valenti
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Vittorio
authors.initials: V
authors.lastname: Guglielmotti
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000698:Analgesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators / Q000032:analysis / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology*; D063388:Endocannabinoids; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010487:Periaqueductal Gray / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000502:physiology*; D050916:TRPV Cation Channels / Q000032:analysis / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C493922:Trpv1 protein, rat; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone