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Recent acceleration in discoveries on the “endocannabinoid signaling system” and its role in physiological and pathological conditions offers a promising polypharmacological approach to future treatment of chronic pain and inflammation.After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ9-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s. Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the “endocannabinoid signaling system,” its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity. The way researchers look at this system has thus rapidly evolved towards the idea of the “endocannabinoidome,” that is, a complex system including also several endocannabinoid-like mediators and their often redundant metabolic enzymes and “promiscuous” molecular targets. These peculiar complications of endocannabinoid signaling have not discouraged efforts aiming at its pharmacological manipulation, which, nevertheless, now seems to require the development of multitarget drugs, or the re-visitation of naturally occurring compounds with more than one mechanism of action. In fact, these molecules, as compared to “magic bullets,” seem to offer the advantage of modulating the “endocannabinoidome” in a safer and more therapeutically efficacious way. This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation.