Differential regulation of Ca v 3.2 and Ca v 2.2 calcium channels by CB 1 receptors and cannabidiol.

Background and Purpose: Cannabinoids are a promising therapeutic avenue for chronic pain. However, clinical trials often fail to report analgesic efficacy of cannabinoids. Inhibition of voltage gate calcium (Ca _v ) channels is one mechanism through which cannabinoids may produce analgesia. We hypothesized that cannabinoids and cannabinoid receptor agonists target different types of Ca _v channels through distinct mechanisms.
Experimental Approach: Electrophysiological recordings from tsA-201 cells expressing either Ca _v 3.2 or Ca _v 2.2 were used to assess inhibition by HU-210 or cannabidiol (CBD) in the absence and presence of the CB ₁ receptor. Homology modelling assessed potential interaction sites for CBD in both Ca _v 2.2 and Ca _v 3.2. Analgesic effects of CBD were assessed in mouse models of inflammatory and neuropathic pain.
Key Results: HU-210 (1 μM) inhibited Ca _v 2.2 function in the presence of CB ₁ receptor but had no effect on Ca _v 3.2 regardless of co-expression of CB ₁ receptor. By contrast, CBD (3 μM) produced no inhibition of Ca _v 2.2 and instead inhibited Ca _v 3.2 independently of CB ₁ receptors. Homology modelling supported these findings, indicating that CBD binds to and occludes the pore of Ca _v 3.2, but not Ca _v 2.2. Intrathecal CBD alleviated thermal and mechanical hypersensitivity in both male and female mice, and this effect was absent in Ca _v 3.2 null mice.
Conclusion and Implications: Our findings reveal differential modulation of Ca _v 2.2 and Ca _v 3.2 channels by CB ₁ receptors and CBD. This advances our understanding of how different cannabinoids produce analgesia through action at different voltage-gated calcium channels and could influence the development of novel cannabinoid-based therapeutics for treatment of chronic pain.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)