21: The Opposing Roles of ASIC3 in Distinct DRG neurons After Peripheral Nerve Injury

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Electrophysiology, Genetics and Epigenetics, Behavioral studies

Background and Aims: Chronic constriction injury (CCI) triggers neuronal hyperexcitability via ion channel remodeling. TTX-S Na+ currents increase immediately in small-diameter DRG neurons at week 2; however, the specific Nav channels that dominate during chronic phase remain unknown. TTX-R Na+ currents exhibit broader action potentials, facilitating calcium influx and suggesting sustained signaling transduction. ASIC3 is a Na+-permeable ion channel that is expressed abundantly in large-diameter DRG neurons. We previously revealed that ASIC3 deletion relieves CCI-induced mechanical allodynia from week 8 (chronic phase). Therefore, I wonder (1) which Nav channels mediate chronic phase and (2) whether ASIC3 regulates Nav channels to relieve chronic pain.

Methods: I cultured DRG neurons at specific time points (naïve 0, 2, 8, and 14 weeks) post CCI from Asic3+/+ or Asic3-/- mice and injected with a series of increasing currents to measure rheobase. Further, the action potential pattern from rheobase can be roughly categorized into TTX-S or TTX-R sodium currents based on the differential waveform.

Results: CCI induces sensitization of small-diameter neurons (<30 µm). TTX-S sodium currents play a role in initiation at week 2; we then first demonstrated that TTX-R sodium currents dominate during chronic sensitization at week 8, which might mediate neuronal plasticity via signaling transduction. Surprisingly, ASIC3 deficiency switches to regulate large-diameter neurons (>30 µm), lowering the firing membrane threshold by modulating TTX-S and TTX-R sodium currents compared to wild type at week 2. In the chronic phase, ASIC3-deficient large-diameter neurons exhibit a higher TTX-S distribution with a higher rheobase by week 8, indicating decreased neuronal sensitivity.

Conclusions: In conclusion, deletion of ASIC3 shifts the sensitization of large-diameter neurons by initially upregulating TTX-S and TTX-R sodium currents. This upregulation of TTX-R sodium currents may contribute to neuronal plasticity, which subsequently reduces TTX-S sodium currents and abolishes chronic pain following peripheral nerve injury.

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Presenting Author: Jia-Yun Hsu
Submitting Author: Jia-Yun Hsu

Senior Author: Wei-Hsin Sun

IASP 2026 Global Year theme of Neuropathic Pain: Yes