Importantly both genetic deletion and

Importantly, both genetic deletion and pharmacological inhibition of FAAH also reduced NTG-induced neuronal hyperactivity in the trigeminal nucleus, which receives sensory input from craniofacial deep tissues. NTG is known to evoke the robust neuronal activation, as evidenced by the induction of the immediate early gene c-Fos induction, in this particular region (Bates et al., 2010, Greco et al., 2010), thus providing a physiological readout of NTG effects that is independent from behavioral measurements. Although the effect of FAAH inhibition on c-Fos activity in brain has not well studied yet, it was reported that either FAAH deficiency or FAAH inhibition can modulate the Fos-related neuronal activity is several CNS regions including hypothalamus and spinal cord (Clapper et al., 2010, Murillo-Rodriguez et al., 2007, Soria-Gomez et al., 2007). Exogenously administered AEA also reduced NTG-evoked neuronal hyperactivity on several brain regions in the rat, including nucleus trigeminalis caudalis (Greco et al., 2010). Taken together, increased level of AEA induced by inhibition of FAAH activity significantly attenuates the neuronal hyperactivity evoked by NTG-induced vasodilation.
Role of funding source This research was supported by the Deutsche Forschungsgemeinschaft (FOR926 SP6 and CP2). C.N. was supported by a grant from the Medical Faculty of the University of Bonn (BONFORO-178.0012). C.N. and A.Z. are member of the DFG Cluster of Excellence ImmunoSensation. The sponsors had no further role in (1) study design (2) collection, analysis and interpretation of data (3) the writing of the report and (4) the decision to submit the paper for publication.
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Fatty Alisol A amide hydrolase (FAAH) is a membrane-associated, intracellular enzyme that degrades endocannabinoids, including anandamide (-arachidonoyl ethanolamine), by amide hydrolysis. Inhibition of FAAH induces cannabinoid (CB) receptor-dependent analgesia in rodents, often without causing the full tetrad of symptoms (anti-nociception, hypothermia, hypolocomotion, catalepsy) associated with direct CB receptor agonists. This is thought to be due to the localized action of endocannabinoids, which are only synthesized as-needed in those regions of the body where they are required. As a result, inhibitors of FAAH have been aggressively pursued as a potentially new class of drugs for pain relief. Although many potent and selective FAAH inhibitors have been reported in the literature, the first phase II clinical trial with one such inhibitor, PF-04457845, was terminated early due to a lack of efficacy in treating osteoarthritis pain compared with naproxen. This, in spite of a greater than 10-fold excess of anandamide in the blood of patients treated with the inhibitor and pre-clinical data showing potent analgesic effects in rodent models. A number of reasons for the lack of observed efficacy have been proposed, including the possibility that, in humans, CB-mediated anti-nociception by anandamide and other fatty acid amides may be negated by the concomitant initiation of pro-nociceptive pathways by the same molecules., Such signaling may include activation of transient receptor potential vanilloid type 1 (TRPV1) receptors. Like capsaicin, the pain-evoking component of ‘hot’ chili peppers, anandamide is also an agonist of TRPV1, a ligand-gated calcium channel associated with thermal pain perception and inflammation-induced hyperalgesia. Antagonists of TRPV1 have been shown to reduce pain in humans and other animals, as well as in pain models that are refractory to NSAIDs (non-steroidal anti-inflammatory drugs). Furthermore, anandamide may be converted to the pro-inflammatory prostamide F by cyclooxygenase 2 (COX2)., Thus, in order to harness the therapeutic potential of the endocannabinoid system, a multi-modal approach may be required.