The role of the dual fatty acid amide hydrolase/TRPV1 blocker, n-arachidonoyl-serotonin, in inflammation and hyperalgesia
Since the discovery that the cannabinoid CB1 agonist anandamide (AEA) could also activate TRPV1, a barrage of investigations has focused on the relationship between these receptors, particularly in C-fibers, in which activation of TRPV1 and CB1 receptor lead to nociceptive and antinociceptive effects, respectively. Consistent with the requirement for their close anatomical localization to enable a functional crosstalk, many studies reported a high level of coexpression of CB1 and TRPV1 in DRG and CNS neurons. The hypothesis raised from many studies is that the crosstalk between the endocannabinoid and endovanilloid system can be pharmacologically suitable to develop drugs therapeutically effective in the field of pain and inflammation. The development of TRPV1 antagonists for acute and inflammatory pain have resulted in some unwanted side effects including increasing body temperature and some uncertainty in such antagonists for drug development. Similarly, the therapeutic employment of cannabinoid system modulators has been less simply than expected from the preclinical studies data. Although TRPV1 is a promiscuous channel, such complimentary pathways may lead to novel pharmaceutical targets. The endogenous cannabinoid system may be one such pathway that when attenuated may result in the inhibition of some types of inflammatory pain. On this basis, we tested the hypothesis that one possible strategy to retain/ameliorate the beneficial properties of cannabinoid system modulators and TRPV1 antagonists with a simultaneous decrease in the potential unwanted effects may be the employment of a molecule in which is concentrate the capability to interfere both with the cannabinoid and vanilloid system. The example showing in this presentation is the effect of the dual fatty acid amide hydrolase/TRPV1 blocker, N-arachidonoylserotonin, in inflammation and hyperalgesia. Consistent with the efficacy of this approach we report for the first time that the systemic administration of this dual blocker prevented the development of carrageenan-induced oedema and hyperalgesia. In conclusion, by combining the features of FAAH inhibitors and TRPV1 channel antagonists, we obtained a molecule that exhibits notable anti-inflammatory and anti-hyperalgesic activity in preclinical model of acute inflammation, that lacks of main side effects and that, in due turn, could be used as a pillar to evolve new drugs.
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