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
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.