TRP channels as novel targets for endogenous ligands: focus on endocannabinoids and nociceptive signalling.

The endocannabinoid system is gaining steadily increasing research interest as its important role in the regulation of many fundamental physiological processes becomes more and more evident. One area which received particularly significant attention concerns targeting the endocannabinoid system as a useful strategy in pain control, especially in refractory, difficult to treat cases of chronic pain. Apart from the classical targets of cannabinoids, the CB1 and CB2 receptors, several members of the large TRP family of Ca2+-permeable cation channels have been designated as “ionotropic cannabinoid receptors” to highlight their role in cannabinoid signalling. The most notable in this connection are TRPV1-4, TRPA1 and TRPM8 channels. Intriguingly, all of them are also important for the detection of noxious stimuli of various origin and pain transduction. Thus, the aim of this review was to summarise the current knowledge of the endocannabinoid system, including its components, and its physiological and pathophysiological roles with focus on synaptic transmission and pain, then progress to an overview of “painful” TRPs with focus on their targeting by cannabinoids, and finally to discuss possible cellular mechanisms linking nociceptive and cannabinoid signalling with TRP channels. We conclude that several TRP subtypes not only function as an integral part of the endocannabinoid system, but also represent promising molecular constituents for pain alleviation with the use of endo- and phytocannabinoids, especially when these channels are upregulated/sensitized under inflammatory conditions.

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