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 CB CB, 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.

FAAH, but not MAGL, inhibition modulates acute TLR3‐induced neuroimmune signaling in the rat, independent of sex

“…Taken together, the data indicate that the effects of FAAH inhibition on TLR3‐induced inflammatory gene expression are most likely mediated at the level of the brain. Furthermore, we and others have demonstrated that FAAH substrates also potently attenuate TLR4‐induced neuroinflammatory responses in several brain regions, including the hypothalamus (Henry et al, ; Kerr et al, ; Sayd et al, ). Thus, FAAH substrates play an important role in modulating TLR3‐ (and TLR4‐) induced neuroinflammatory responses in both males and females.…”

“…Both in vitro and in vivo studies have demonstrated that enhancing endocannabinoid tone modulates inflammatory mediators following TLR4 activation (for detailed review, see Henry et al, ). For example, recent studies from our group have demonstrated that inhibition of FAAH and subsequent increases in AEA levels result in an attenuation of TLR4‐induced proinflammatory cytokine responses in several brain regions, including the hypothalamus (Henry et al, ; Kerr et al, ). Furthermore, FAAH substrates, including AEA, have been demonstrated to modulate TLR4‐induced temperature changes and hypophagia (Hollis, Jonaidi, Lemus, & Oldfield, ; Sayd et al, ; Steiner et al, ).…”

FAAH inhibition attenuates TLR3-mediated hyperthermia, nociceptive- and anxiety-like behaviour in female rats

“…As previously described [30], animals were singly housed and presented with two drinking bottles in their home cage, one containing tap water and the other containing a 1% (w/v) sucrose solution for 3 days prior to the experiment and for 24hrs following poly I:C/saline injection.…”

“…In order to evaluate the effect of URB597 on TLR3-induced neuroinflammation, the expression of CD11b and GFAP were examined in the hypothalamus 24hrs post poly I:C, as markers of microglia/macrophage and astrocyte activation [17,30]. The hypothalamus was selected as it is a key brain region involved in the inflammatory and sickness response to infection, including the viral TLR3-mediated response.…”

“…The FAAH substrates AEA, OEA and PEA have been shown to modulate TLR4-induced thermoregulatory changes and hypophagia [27][28][29], most likely mediated via modulation of hypothalamic cytokine expression [28]. 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 [30]. Furthermore, FAAH inhibition has been demonstrated to reverse TLR4-mediated mechanical allodynia [31], thermal hyperalgesia and paw oedema [32].…”