# T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2023 · —

## Abstract

Pain-sensing sensory neurons of the dorsal root ganglion (DRG) and dorsal horn (DH) can become sensitized
(hyperexcitable) in response to the tissue injury. Because of insufficient knowledge about the mechanisms for
this sensitization, current treatment for postoperative pain has been limited to somewhat non-specific systemic
drugs (opioids) having significant side effects or potential for abuse. Recent studies in our laboratory have
established that CaV3.2 (T-type) calcium-channels voltage-gated calcium channels make a previously
unrecognized contribution to sensitization of pain responses by enhancing excitability of peripheral nociceptors
in the setting of surgically induced tissue injury. Despite the established role of CaV3.2 channels in the
pathogenesis of peripheral sensitization of pain responses, the role of multiple isoforms of T-channels (CaV3.1,
CaV3.2 and CaV3.3) in central (spinal) sensitization of pain responses is not well studied. We previously showed
that the blockade of CaV3.2 currents in nociceptive DRG neurons by an endogenous compound and dietary
supplement a lipoic acid (ALA) underlies its potent peripheral anti-nociceptive effects. Our new data demonstrate
that ALA displays excellent analgesia in a rat model of post-surgical pain resulting from paw skin incisions, and
that CaV3.1 isoform of T-channels is also important for the development of hyperalgesia in a mouse model of
paw incision. Thus, we propose that ALA may represent a safer class of analgesics having desirable analgesic
properties in post-operative period by targeting T-channels in pain pathway, as well as being able to reduce the
risk for the opioid addiction.
In Aim 1, we will study the roles of CaV3.1 and CaV3.2 channels in ALA-induced analgesia using a clinically
relevant rodent model of skin and deep tissue incision.
In Aim 2, we will define the role of ALA in modulating synaptic transmission and neuronal excitability of
nociceptive DH neurons. In this Aim, we will also test the hypothesis that ALA may reverse hyperexcitability in
the identified nociceptive DH neurons in the rats following plantar skin incision. These studies will define the
whole-cell neurophysiological effects of ALA in the major nociceptive pathway. Finally, we will also use electron
microscopy to study cellular and subcellular localization of CaV3.1 and CaV3.2 channels in nociceptive DH
neurons. The proposed work is innovative and medically significant because we anticipate that our preclinical
studies will identify novel therapies for perioperative pain that may greatly decrease the need for narcotics and
potential for drug abuse.

## Key facts

- **NIH application ID:** 10618859
- **Project number:** 5I01BX004763-04
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Slobodan M. Todorovic
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618859

## Citation

> US National Institutes of Health, RePORTER application 10618859, T-type calcium channel inhibitors and alpha lipoic acid as novel therapies for treating pain post-surgery (5I01BX004763-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10618859. Licensed CC0.

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