Differential regulation of Ca_v 3.2 and Ca_v 2.2 calcium channels by CB₁ 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 CB₁ 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 CB₁ receptor but had no effect on Ca_v 3.2 regardless of co-expression of CB₁ receptor. By contrast, CBD (3 μM) produced no inhibition of Ca_v 2.2 and instead inhibited Ca_v 3.2 independently of CB₁ 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 CB₁ 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.