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  • In conclusion the data reported in this study


    In conclusion, the data reported in this study have demonstrated an important role for FAAH substrates in the Lubiprostone receptor in the modulation of TLR4-induced neuroinflammatory and associated anhedonic responses, but not acute sickness behaviour. Such potent neuroimmunomodulatory effects were shown to be likely due to the inhibition or delayed activation of inflammation-induced glial activation and subsequent NFκB activation. Evaluating the possible receptor mechanisms revealed that the effects are independent of central cannabinoid receptors (CB1, CB2, and GPR55) or PPARs (PPAR-α/γ) but rather demonstrate for the first time a role for central TRPV1 in partially mediating FAAH substrate-mediated modulation of TLR4-induced neuroinflammation. Overall, these findings support an important immunomodulatory role for FAAH substrates within the brain, and may have implications for the development of novel treatments for neuroinflammatory disorders.
    Conflicts of interest
    Acknowledgments The authors would like to gratefully acknowledge funding received from the Science Foundation Ireland Research Frontiers Programme (Grant no.), The Research Office and College of medicine, Nursing and Health Sciences National University of Ireland Galway. The authors would also like to thank Patricia Calcagno for technical assistance during this study.
    Cannabis, endocannabinoids, and anxiety Cannabis is one of the most widely used drugs in the world, with historical records dating use in Eastern cultures back millennia [1]. Cannabis and its derivatives have profound effects on a wide variety of behavioral and neural functions, ranging from feeding and metabolism to pain and cognition [2]. However, epidemiological studies have indicated that the most common self-reported reason for using cannabis is rooted in its ability to reduce feelings of stress, tension, and anxiety [3]. Significant numbers of people may be self-medicating with cannabis in an attempt to reduce excessive anxiety 4, 5 (even though cannabis use can also cause paranoia and heightened anxiety in certain situations and predisposed individuals, depending on the dose [6]). Furthermore, studies in controlled clinical settings confirm that administration of synthetic variants of delta-9-tetrahydrocannabinol (THC), the psychoactive constituent of cannabis, can reduce anxiety in patients with anxiety disorders 7, 8. Finally, the anxiety-reducing properties of THC extend to preclinical rodent assays and models [9], demonstrating that the anxiolytic properties of cannabinoids are well conserved across species. Many of the neural and behavioral effects of exogenously administered cannabinoids can be traced directly to activation of the ‘endocannabinoid’ (ECB) system [10] – a set of neurochemicals and cognate receptors densely expressed throughout the brain [11]. The discovery of the ECB system raised the possibility that ECBs could be important modulators of anxiety, and might contribute to individual differences in anxious temperament and risk for anxiety disorders. It also led Lubiprostone receptor to the notion that targeting components of the ECB system could represent a novel therapeutic approach to developing effective anxiolytic medications devoid of the unwanted effects of cannabis (e.g., cognitive impairment, abuse liability) 4, 12 (Box 1). That is, selective alleviation of symptoms could be produced by increasing levels of endogenously activated ECBs and avoiding widespread behavioral effects caused by exogenously applied, ubiquitously activating cannabinoid receptor type 1 (CB1R) agonists. A substantial amount of research has been undertaken over the past decade to test these ideas. As a result, understanding the role of ECBs in controlling stress, fear, and anxiety has grown considerably in recent years, with some targets already having been advanced to preliminary clinical trials in patients. The broader literature on this topic has been covered in many excellent, comprehensive reviews [13] and will not be reiterated here. The focus of the current article is on one of the most rapidly moving developments in the field – the stress and anxiety-related role of a major modulatory component of the ECB system, known as fatty acid amide hydrolase (FAAH).