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

Abstract

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.

• Authors: Erika K Harding, Annemarie Dedek, Robert P Bonin, Michael W Salter, Terrance P Snutch, Michael E Hildebrand
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 178 Issue 17 Pg. 3517-3532 (09 2021) ISSN: 1476-5381 [Electronic] England
• PMID: 33871884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Calcium Channel Blockers
• Calcium Channels, T-Type
• Piperidines
• Z944

Topics

• Animals
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, T-Type
• Female
• Male
• Pain (drug therapy)
• Piperidines
• Rats
• Spinal Cord Dorsal Horn