Differential regulation of Cav3.2 and Cav2.2 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 mu M) 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 mu M) 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.

Automated summary

Cannabinoids are a potential therapy for chronic pain, but their analgesic efficacy is often not reported in clinical trials. This study found that cannabinoids can produce analgesia by inhibiting voltage gate calcium channels, and different cannabinoids target different types of channels through distinct mechanisms. The cannabinoid CBD binds to and occludes the pore of the Ca(v)3.2 channel, alleviating inflammatory and neuropathic pain.