The T‐type calcium channel antagonist, Z944, reduces spinal excitability and pain hypersensitivity

BACKGROUND AND PURPOSE: T‐type voltage‐gated calcium channels are an emerging therapeutic target for neurological disorders including epilepsy and pain. Inhibition of T‐type channels reduces the excitability of peripheral nociceptive sensory neurons and reverses pain hypersensitivity in male rodent pain models. However, administration of peripherally restricted T‐type antagonists failed to show efficacy in multiple clinical and preclinical pain trials, suggesting that inhibition of peripheral T‐type channels alone may be insufficient for pain relief. EXPERIMENTAL APPROACH: We utilized the selective and CNS‐penetrant T‐type channel antagonist, Z944, in electrophysiological, calcium imaging and behavioural paradigms to determine its effect on lamina I neuron excitability and inflammatory pain behaviours. KEY RESULTS: Voltage‐clamp recordings from lamina I spinal neurons of adult rats revealed that approximately 80% of neurons possess a low threshold T‐type current, which was blocked by Z944. Due to this highly prevalent T‐type current, Z944 potently blocked action‐potential evoked somatic and dendritic calcium transients in lamina I neurons. Moreover, application of Z944 to spinal cord slices attenuated action potential firing rates in over half of laminae I/II neurons. Finally, we found that intraperitoneal injection of Z944 (1–10 mg·kg(−1)) dose‐dependently reversed mechanical allodynia in the complete Freund's adjuvant model of persistent inflammatory pain, with a similar magnitude and time course of analgesic effects between male and female rats. CONCLUSION AND IMPLICATIONS: T‐type calcium channels critically shape the excitability of lamina I pain processing neurons and inhibition of these channels by the clinical stage antagonist Z944 potently reverses pain hypersensitivity across sexes.