title: Pharmacological inhibition of FAAH modulates TLR-induced neuroinflammation, but not sickness behaviour: An effect partially mediated by central TRPV1.
abstract: Aberrant activation of toll-like receptors (TLRs), key components of the innate immune system, has been proposed to underlie and exacerbate a range of central nervous system disorders. Increasing evidence supports a role for the endocannabinoid system in modulating inflammatory responses including those mediated by TLRs, and thus this system may provide an important treatment target for neuroinflammatory disorders. However, the effect of modulating endocannabinoid tone on TLR-induced neuroinflammation in vivo and associated behavioural changes is largely unknown. The present study examined the effect of inhibiting fatty acid amide hydrolyase (FAAH), the primary enzyme responsible for the metabolism of anandamide (AEA), in vivo on TLR4-induced neuroimmune and behavioural responses, and evaluated sites and mechanisms of action. Systemic administration of the FAAH inhibitor PF3845 increased levels of AEA, and related FAAH substrates N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), in the frontal cortex and hippocampus of rats, an effect associated with an attenuation in the expression of pro- and anti-inflammatory cytokines and mediators measured 2hrs following systemic administration of the TLR4 agonist, lipopolysaccharide (LPS). These effects were mimicked by central i.c.v. administration of PF3845, but not systemic administration of the peripherally-restricted FAAH inhibitor URB937. Central antagonism of TRPV1 significantly attenuated the PF3845-induced decrease in IL-6 expression, effects not observed following antagonism of CB1,CB2, PPARα, PPARγ or GPR55. LPS-induced a robust sickness-like behavioural response and increased the expression of markers of glial activity and pro-inflammatory cytokines over 24hrs. Systemic administration of PF3845 modulated the TLR4-induced expression of neuroimmune mediators and anhedonia without altering acute sickness behaviour. Overall, these findings support an important role for FAAH substrates directly within the brain in the regulation of TLR4-associated neuroinflammation and highlight a role for TRPV1 in partially mediating these effects.
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Henry
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kerr
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Flannery
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Marykate
authors.initials: M
authors.lastname: Killilea
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Edel M
authors.initials: EM
authors.lastname: Hughes
authors.affiliation: Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Louise
authors.initials: L
authors.lastname: Corcoran
authors.affiliation: Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: David P
authors.initials: DP
authors.lastname: Finn
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland; NCBES Centre for Pain Research and Neuroscience Centre, National University of Ireland, Galway, Ireland. Electronic address: Michelle.roche@nuigalway.ie.
authors.forename: Michelle
authors.initials: M
authors.lastname: Roche
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism; D055809:Illness Behavior / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D008070:Lipopolysaccharides; D010880:Piperidines; D011725:Pyridines; D050916:TRPV Cation Channels; D051197:Toll-Like Receptor 4; D000099252:Fatty Acid Amide Hydrolases; C557973:PF 3845; C495347:Tlr4 protein, rat; C493922:Trpv1 protein, rat
keywords: Anandamide; Anhedonia; Cytokines; Neuroinflammation; Sickness; Toll-like receptors