title: Fear-induced suppression of nociceptive behaviour and activation of Akt signalling in the rat periaqueductal grey: role of fatty acid amide hydrolase.
abstract: The endocannabinoid system regulates nociception and aversion and mediates fear-conditioned analgesia (FCA). We investigated the effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which inhibits the catabolism of the endocannabinoid anandamide and related N-acylethanolamines, on expression of FCA and fear and pain related behaviour per se in rats. We also examined associated alterations in the expression of the signal transduction molecule phospho-Akt in the periaqueductal grey (PAG) by immunoblotting. FCA was modelled by assessing formalin-evoked nociceptive behaviour in an arena previously paired with footshock. URB597 (0.3 mg/kg, i.p.) enhanced FCA and increased fear-related behaviour in formalin-treated rats. Conditioned fear per se in non-formalin-treated rats was associated with increased expression of phospho-Akt in the PAG. URB597 reduced the expression of fear-related behaviour in the early part of the trial, an effect that was accompanied by attenuation of the fear-induced increase in phospho-Akt expression in the PAG. Intra-plantar injection of formalin also reduced the fear-induced increase in phospho-Akt expression. These data provide evidence for a role of FAAH in FCA, fear responding in the presence or absence of nociceptive tone, and fear-evoked increases in PAG phospho-Akt expression. In addition, the results suggest that fear-evoked activation of Akt signalling in the PAG is abolished in the presence of nociceptive tone.
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, NCBES Neuroscience Cluster and Centre for Pain Research, National University of Ireland, Galway, Ireland.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Butler
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Ford
authors.forename: Michelle
authors.initials: M
authors.lastname: Hogan
authors.forename: Michelle
authors.initials: M
authors.lastname: Roche
authors.forename: Karen M
authors.initials: KM
authors.lastname: Doyle
authors.forename: John P
authors.initials: JP
authors.lastname: Kelly
authors.forename: David A
authors.initials: DA
authors.lastname: Kendall
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.forename: David P
authors.initials: DP
authors.lastname: Finn
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000698:Analgesia / Q000379:methods; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D063388:Endocannabinoids; D004983:Ethanolamines / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005557:Formaldehyde / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D010487:Periaqueductal Gray / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D004983:Ethanolamines; D005557:Formaldehyde; D053284:Polyunsaturated Alkamides; D051057:Proto-Oncogene Proteins c-akt; D000099252:Fatty Acid Amide Hydrolases; C022203:N-acylethanolamines; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C078814:anandamide