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  • Although it is well documented that FAAH substrates

    2022-05-26

    Although it is well documented that FAAH substrates can elicit analgesic effects [for review see [47,48] and that systemic poly I:C administration induces mechanical allodynia in rats [14], to our knowledge this is the first study to demonstrate that enhancing FAAH substrate levels can modulate TLR3-mediated allodynia. Systemic administration of URB597 has been shown to reverse thermal hyperalgesia via CB1 receptor activation [32] and mechanical hyperalgesia via CB1 and CB2 receptors [31] following intraplantar TLR4 activation. Thus, it is possible that enhanced FAAH substrate levels at peripheral nociceptive terminals following the systemic administration of URB597 may have modulated nociceptive input resulting in the attenuation of TLR3-induced mechanical and cold allodynia. However, previous data from our group have indicated that the systemic administration of URB597 fails to modulate TLR-induced inflammatory responses peripherally, but potently reduces neuroinflammatory tone [8,9]. Furthermore, microinjection of IL-1β and PGE2 into the preoptic area of the PKI-402 receptor has been shown to induce thermal hyperalgesia [49,50] and systemic LPS-induced thermal hyperalgesia was abolished by the administration of a COX-2 inhibitor into the preoptic area of the hypothalamus [51]. Thus, it is possible that the attenuation of TLR3-mediated microglial activation and neuroinflammation in key supraspinal sites such as the hypothalamus may mediate, at least in part, the anti-nociceptive effects of URB597 observed in the current study. In addition to the attenuation of TLR3-mediated fever and allodynia, the current study demonstrates that URB597 also attenuates TLR3-associated anxiety-like behaviour, without significantly altering anhedonia or stress-coping behaviour (FST). The effects of URB597 on TLR3-induced anxiety-related behaviour were not confounded by effects on locomotor activity as URB597 did not alter the locomotor activity of poly I:C treated rats in the homecage, OFT or EPM. Recent work by our group has shown that FAAH inhibition attenuates TLR4-mediated anhedonia, but not sickness-like behaviour [30]. Thus, taken together the data indicate that enhancing FAAH substrate levels can elicit differential physiological and behavioural effects in response to TLR3 vs. TLR4 stimulation. Furthermore, individual FAAH substrates may have specific effects on the neuroinflammatory and/or behavioural effects observed following TLR stimulation. For example, OEA and PEA, have been shown to attenuate TLR4-mediated neuroinflammatory responses, however only OEA, but not PEA, attenuated the associated anhedonia [28]. Future studies will determine if the effects of URB597 on TLR3-mediated neuroinflammation and behavioural alterations observed in the current study are mediated by one or a combination of FAAH substrates. Acute systemic administration of URB597 has been previously shown to reduce anxiety-like behaviour in the EPM [20,21,[23], [24], [25],52] and OFT [21]. However, the anxiolytic-like effects of FAAH inhibitors in these paradigms are primarily evaluated at a time when FAAH substrate levels would be maximally enhanced (30 min - 2 h post administration) and to our knowledge no studies have investigated the effect of a single acute administration of URB597 on anxiety-like behaviour in the EPM and OFT at time points beyond 2 h. Accordingly, the current study demonstrated that acute systemic administration of URB597 does not alter anxiety-like behaviour in the EPM 24 hs post administration, however TLR3-mediated increases in anxiety-like behaviour were found to be attenuated at this time point. As highlighted earlier, TLR3-mediated acute neuroinflammation is followed by longer term changes in microglia/macrophage activation, activation of the kynurenic pathway, reduced BDNF and altered neuronal activity [17,44]. Thus, it is likely FAAH substrate-induced attenuation of acute TLR3-mediated neuroinflammation results in the inhibition of these longer term changes in neuronal and glial activity in key brain areas that underlie anxiety-, but not depressive-, like behavioural responses. This hypothesis is supported by the data demonstrating that systemic administration of URB597 is associated with an attenuation of the early expression of TLR3-mediated increases in IRF3- and NFκB-related inflammatory mediators in the brain [8,9], an effect we have now shown to be accompanied by a later suppression of CD11b and CD68 expression (markers of M1 microglia/macrophage activation) 24 hs post TLR3 activation.