Pharmacological inhibition of endocannabinoid degradation modulates the expression of inflammatory mediators in the hypothalamus following an immunological stressor

• Published in: Neuroscience 2012-03, Vol.204, p.53-63
• Main Authors: Kerr, D.M, Burke, N.N, Ford, G.K, Connor, T.J, Harhen, B, Egan, L.J, Finn, D.P, Roche, M
• Format: Article
• Language: English
• Subjects: 2-AG; anandamide; Animals; Benzamides - pharmacology; Cannabinoid Receptor Modulators - metabolism; Carbamates - pharmacology; cytokine; Cytokines - metabolism; endocannabinoid; Endocannabinoids; HPA axis; Hypothalamus - drug effects; Hypothalamus - metabolism; Inflammation Mediators - metabolism; Lipopolysaccharides - pharmacology; Male; Neurology; Rats; Rats, Sprague-Dawley; Stress, Physiological - drug effects; Stress, Physiological - physiology
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.09.032

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. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.