Ca_v3.2 T-type calcium channels in chronic pain: Structural insights, pharmacological advances and challenges in...

The clinical management of chronic pain has long relied on conventional medications, including drugs such as opioids, anti-inflammatory drugs and anticonvulsants, which are universally associated with inadequate efficacy and prominent adverse effects. This highlights an urgent need for novel therapeutic strategies targeting the underlying mechanisms of pain. Recent studies have demonstrated that T-type calcium channels play a pivotal role in the pathogenesis and progression of neuropathic and inflammatory pain, with their expression and function being significantly up-regulated in neurons of the dorsal root ganglion (DRG) and spinal dorsal horn neurons, emerging as a highly promising yet clinically unvalidated analgesic target. However, the development of blockers directly targeting the Ca_v3.2 subtype is still confronted with major translational challenges, such as low subtype selectivity, as well as adverse effects in the central nervous system and cardiovascular system. Repeated clinical setbacks of candidate drugs like ABT-639 have highlighted the gap between preclinical potential and clinical efficacy, and to date, no ideal clinical candidate has been identified. This review integrates structural biology insights, lessons from clinical failures and pharmacological advances to guide the research and development of safe, highly selective Ca_v3.2-targeted analgesic agents.