Contribution of T-Type Calcium Channels to Spinal Cord Injury-Induced Hyperexcitability of Nociceptors.

Autor:	Lauzadis J; Graduate Program in Molecular and Cellular Pharmacology, Department of Pharmacology, Stony Brook Medicine, Stony Brook, NY 11794., Liu H; Department of Anesthesiology, HSC L4-076, Stony Brook Medicine, Stony Brook, NY 11794., Lu Y; Department of Anesthesiology, HSC L4-076, Stony Brook Medicine, Stony Brook, NY 11794., Rebecchi MJ; Department of Anesthesiology, HSC L4-076, Stony Brook Medicine, Stony Brook, NY 11794., Kaczocha M; Department of Anesthesiology, HSC L4-076, Stony Brook Medicine, Stony Brook, NY 11794., Puopolo M; Department of Anesthesiology, HSC L4-076, Stony Brook Medicine, Stony Brook, NY 11794 michelino.puopolo@stonybrook.edu.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2020 Sep 16; Vol. 40 (38), pp. 7229-7240. Date of Electronic Publication: 2020 Aug 24.
DOI:	10.1523/JNEUROSCI.0517-20.2020
Abstrakt:	A hyperexcitable state and spontaneous activity of nociceptors have been suggested to play a critical role in the development of chronic neuropathic pain following spinal cord injury (SCI). In male rats, we employed the action potential-clamp technique to determine the underlying ionic mechanisms responsible for driving SCI-nociceptors to a hyperexcitable state and for triggering their spontaneous activity. We found that the increased activity of low voltage activated T-type calcium channels induced by the injury sustains the bulk (∼60-70%) of the inward current active at subthreshold voltages during the interspike interval in SCI-nociceptors, with a modest contribution (∼10-15%) from tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In current-clamp recordings, inhibition of T-type calcium channels with 1 μm TTA-P2 reduced both the spontaneous and the evoked firing in response to current injections in SCI-nociceptors to a level similar to sham-nociceptors. Electrophysiology in vitro was then combined with the conditioned place preference (CPP) paradigm to determine the relationship between the increased activity of T-type channels in SCI-nociceptors and chronic neuropathic pain following SCI. The size of the interspike T-type calcium current recorded from nociceptors isolated from SCI rats showing TTA-P2-induced CPP (responders) was ∼6 fold greater than the interspike T-type calcium current recorded from nociceptors isolated from SCI rats without TTA-P2-induced CPP (non-responders). Taken together, our data suggest that the increased activity of T-type calcium channels induced by the injury plays a primary role in driving SCI-nociceptors to a hyperexcitable state and contributes to chronic neuropathic pain following SCI. SIGNIFICANCE STATEMENT Chronic neuropathic pain is a major comorbidity of spinal cord injury (SCI), affecting up to 70-80% of patients. Anticonvulsant and tricyclic antidepressant drugs are first line analgesics used to treat SCI-induced neuropathic pain, but their efficacy is very limited. A hyperexcitable state and spontaneous activity of SCI-nociceptors have been proposed as a possible underlying cause for the development of chronic neuropathic pain following SCI. Here, we show that the increased activity of T-type calcium channels induced by the injury plays a major role in driving SCI-nociceptors to a hyperexcitable state and for promoting their spontaneous activity, suggesting that T-type calcium channels may represent a pharmacological target to treat SCI-induced neuropathic pain. (Copyright © 2020 the authors.)
Databáze:	MEDLINE
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