Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia

Abstract

Despite the wealth of information on cannabinoid-induced peripheral antihyperalgesic and antinociceptive effects in many pain models, the molecular mechanism(s) for these actions remains unknown. Although metabotropic cannabinoid receptors have important roles in many pharmacological actions of cannabinoids, recent studies have led to the recognition of a family of at least five ionotropic cannabinoid receptors (ICRs). The known ICRs are members of the family of transient receptor potential (TRP) channels and include TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1. Cannabinoid activation of ICRs can result in desensitization of the TRPA1 and TRPV1 channel activities, inhibition of nociceptors and antihyperalgesia and antinociception in certain pain models. Thus, cannabinoids activate both metabotropic and ionotropic mechanisms to produce peripheral analgesic effects. Here, we provide an overview of the pharmacology of TRP channels as ICRs.

Figure 1

Mechanisms for cannabinoid cross-desensitization of TRPV1 and TRPA1. Cannabinoids desensitize TRPV1 via activation of calcineurin and dephosphorylation of the ion channel. Homologous desensitization of TRPV1 can occur by application of TRPV1-selective cannabinoids (e.g. ACEA), and heterologous desensitization of TRPV1 can occur by administration of TRPA1-selective cannabinoids (e.g. WIN55212). Cannabinoids desensitize TRPA1 via activation of a calcium-independent pathway. Abbreviations: DAG, diacylglycerol; IP₃, inositol (1,4,5)-trisphosphate; PHD, pleckstrin homology domain; PIP₂, phosphatidylinositol (4,5)-bisphosphate; PLC, phospholipase C.

Figure 2

Proposed mechanisms for the peripherally mediated antihyperalgesic effects of cannabinoids. (a) Hypothesis 1 proposes that cannabinoids produce peripheral antihyperalgesia by activation of both MCRs and ICRs. (b) Hypothesis 2 proposes that different pain models (or routes of drug injection) selectively activate either MCR or ICR pathways. (c) Hypothesis 3 proposes that the net effect of cannabinoids on modulating nociception is due to activation of MCRs and/or ICRs located on multiple cell types that are capable of interacting. (d) Hypothesis 4 proposes that MCRs and ICRs interact in the same cell leading to desensitization of activity. Note that the selective involvement of MCR and/or ICR in each hypothesis is for illustrative purposes only.