TRP Channels as Novel Targets for Endogenous Ligands: Focus on Endocannabinoids and Nociceptive Signalling

Abstract

Background: Chronic pain is a significant clinical problem and a very complex pathophysiological phenomenon. There is growing evidence that targeting the endocannabinoid system may be a useful approach to pain alleviation. Classically, the system includes G protein-coupled receptors of the CB1 and CB2 subtypes and their endogenous ligands. More recently, several subtypes of the large superfamily of cation TRP channels have been coined as "ionotropic cannabinoid receptors", thus highlighting their role in cannabinoid signalling. Thus, the aim of this review was to explore the intimate connection between several "painful" TRP channels, endocannabinoids and nociceptive signalling.

Methods: Research literature on this topic was critically reviewed allowing us not only summarize the existing evidence in this area of research, but also propose several possible cellular mechanisms linking nociceptive and cannabinoid signaling with TRP channels.

Results: We begin with an overview of physiology of the endocannabinoid system and its major components, namely CB1 and CB2 G protein-coupled receptors, their two most studied endogenous ligands, anandamide and 2-AG, and several enzymes involved in endocannabinoid biosynthesis and degradation. The role of different endocannabinoids in the regulation of synaptic transmission is then discussed in detail. The connection between the endocannabinoid system and several TRP channels, especially TRPV1-4, TRPA1 and TRPM8, is then explored, while highlighting the role of these same channels in pain signalling.

Conclusion: There is increasing evidence implicating several TRP subtypes not only as an integral part of the endocannabinoid system, but also as promising molecular targets for pain alleviation with the use of endo- and phytocannabinoids, especially when the function of these channels is upregulated under inflammatory conditions.

Keywords: Endocannabinoid; GABA receptor; TRP channel; calcium signalling; cannabinoid receptor; pain.

Fig. (1)

Schematic illustration of various interactions between the endocannabinoid signalling system and ‘painful’ TRP channels in pain control. Acidic ‘inflammatory soup' represents peptides, such as bradykinin and cytokines, various lipid messengers, such as prostaglandins, neurotransmitters (serotonin, and ATP) and neurotrophic factors, such as NGF. These various factors acting in synergy can strongly sensitize sensory nerve endings by altering the activation threshold and sensitivity of several TRPs to thermal and mechanical stimuli, thus leading to hyperalgesia. Several mechanisms that can, with the involvement of the endocannabinoid system, counteract these effects are listed below. See text for details of the mechanisms involved.