title: Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor.
abstract: The endocannabinoid system is an important regulator of the nervous, neuroendocrine, and immune systems, thus representing a novel therapeutic target for stress-related neuroinflammatory and psychiatric disorders. However, there is a paucity of data relating to the effects of endocannabinoids on neuroinflammatory mediators following an immune stress/challenge in vivo. This study investigated the effects of URB597, a selective inhibitor of fatty acid amide hydrolyase (FAAH), the enzyme that preferentially metabolizes anandamide, on lipopolysaccharide (LPS)-induced increases in the expression of immune mediators in the hypothalamus. Systemic administration of URB597 increased the levels of anandamide and the related N-acylethanolamines, N-palmitoylethanolamide, and N-oleoylethanolamide, but not 2-arachidonoyl glycerol, in the hypothalamus and spleen. URB597 attenuated the LPS-induced increase in interleukin (IL)-1β expression while concurrently augmenting the LPS-induced increase in suppressor of cytokine signalling (SOCS)-3 expression. In addition, URB597 tended to enhance and reduce the LPS-induced increase in IL-6 and IL-10 mRNA expression, respectively. LPS-induced increases in peripheral cytokine levels or plasma corticosterone were not altered by URB597. The present study provides evidence for a role for FAAH in the regulation of LPS-induced expression of inflammatory mediators in the hypothalamus. Improved understanding of endocannabinoid-mediated regulation of neuroimmune function has fundamental physiological and potential therapeutic significance in the context of stress-related disorders.
authors.affiliation: Physiology, National University of Ireland, Galway, Ireland.
authors.forename: D M
authors.initials: DM
authors.lastname: Kerr
authors.forename: N N
authors.initials: NN
authors.lastname: Burke
authors.forename: G K
authors.initials: GK
authors.lastname: Ford
authors.forename: T J
authors.initials: TJ
authors.lastname: Connor
authors.forename: B
authors.initials: B
authors.lastname: Harhen
authors.forename: L J
authors.initials: LJ
authors.lastname: Egan
authors.forename: D P
authors.initials: DP
authors.lastname: Finn
authors.forename: M
authors.initials: M
authors.lastname: Roche
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D063388:Endocannabinoids; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*
chemical_list: D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D016207:Cytokines; D063388:Endocannabinoids; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester