Fatty acid amide hydrolase FAAH
Fatty s1p receptor amide hydrolase (FAAH) is a membrane-bound enzyme which releases arachidonic acid and ethanolamine by breaking amide bond of AEA. It also controls the cellular uptake of AEA, by creating and maintaining an inward concentration gradient leading to AEA-facilitated diffusion via a specific membrane transporter . In the present study, the mRNA and protein expression of AEA degrading enzyme, FAAH, did not differ among bulls with different fertility ratings. On contrary, a differential expression of FAAH between infertile and fertile men has been reported earlier . These researchers observed that in infertile sperm FAAH was reduced significantly to 50% of the values in fertile sperm. The differences in the results might be due to the variations in the species and experimental conditions.
Introduction The endocannabinoid system has been shown to exhibit potent immunomodulatory effects and represents a potential therapeutic target for peripheral and central inflammatory disorders [, , , , ]. N-arachidonoylethanolamine (anandamide; AEA), the most studied endocannabinoid to date, mediates its effects via cannabinoid (CB1 and CB2) and non-cannabinoid (TRPV1, PPARs and GPR55) receptors and is primarily broken down by fatty acid amide hydrolase (FAAH) . in vitro and in vivo evidence have demonstrated that FAAH inhibition, and associated increases in AEA and the related N-acylethanolamines N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), result in the modulation of inflammatory responses induced following the activation of the pattern recognition receptors, toll-like receptor (TLR)s [for review see . (TLR)3 activation results in the induction of type 1 interferon (IFN-α and IFN-β) and NFĸB-inducible (e.g. IL-1β, IL-6 and TNF-α) inflammatory cascades which are responsible for coordinating the innate immune response to viral infection. Recent data has highlighted that FAAH inhibition attenuates the TLR3-mediated increase in the expression of IFN-inducible genes and pro-inflammatory cytokines in brain regions such as the hippocampus and hypothalamus, without altering peripheral immune responses [8,9]. The behavioural and physiological consequences of TLR3 activation include the induction of sickness behaviours such as fever/hypothermia, hypoactivity and anorexia [8,, , , ] and enhanced pain sensitivity  which represents a highly adaptive coping mechanism by the CNS to fight viral infection. However, aberrant activation of TLR3 can elicit adverse effects on the CNS including increased neuronal excitability and seizure susceptibility [15,16], impaired contextual and working memory , anxiety- and depressive-like behaviour  and exacerbation of underlying neurodegenerative processes [18,19]. However, it is unknown if FAAH-induced modulation of TLR3-mediated inflammatory responses result in associated physiological and behavioural changes. Several studies have demonstrated that FAAH inhibition alters anxiety- [, , , , , ] and depressive-like behaviour [21,26] and elicits analgesic effects . However, few studies have evaluated if similar effects occur in the presence of heightened inflammatory tone. The FAAH substrates AEA, OEA and PEA have been shown to modulate TLR4-induced thermoregulatory changes and hypophagia [, , ], most likely mediated via modulation of hypothalamic cytokine expression . A recent study from our group demonstrated that FAAH inhibition modulated TLR4-mediated neuroinflammatory responses in the hippocampus and frontal cortex, an effect which was accompanied by an attenuation of TLR4-mediated anhedonia, but not sickness behaviour . Furthermore, FAAH inhibition has been demonstrated to reverse TLR4-mediated mechanical allodynia , thermal hyperalgesia and paw oedema . Collectively, these results demonstrate a role for FAAH substrates in the modulation of behavioural responses following TLR4 activation, although there are no studies to date examining if similar responses occur following activation of other TLRs such as TLR3. Thus, the aim of the present study was to examine the effect of enhancing FAAH substrate levels on TLR3-mediated neuroimmune activation and resulting physiological and behavioural responses.