# Mechanisms in primary nociceptors that drive ongoing activity and ongoing pain

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $420,773

## Abstract

Project Summary
The long-term objective of this project is to discover novel, highly targeted approaches for treating ongoing
pain by defining critical mechanisms of ongoing activity (OA) in primary nociceptors that drive this pain. Recent
discoveries revealed that the OA generated spontaneously in probable nociceptors and linked to ongoing pain
after spinal cord injury (SCI) is associated with all three electrophysiological alterations that, in principle, can
promote OA. These are depolarization of resting membrane potential (RMP), reduced voltage threshold for
action potentials (APs), and increased frequency of large, transient, depolarizing spontaneous fluctuations
(DSFs). Two extrinsic mediators related to inflammation, serotonin (5-HT) and capsaicin (mimicking
endogenous TRPV1 activators), also promote OA, in large part by enhancing DSFs. Virtually nothing is known
about mechanisms underlying large DSFs. Three specific aims will test hypotheses about DSF generation and
potentiation, employing whole cell patch recording, stimulation by Ca2+ uncaging, pharmacological and
transgenic approaches, in vivo recording, and behavioral tests. Aim 1 will define ion conductance and cell
signaling (Ca2+ and cAMP) contributions to the acute generation of large DSFs, taking advantage of the ability
of 5-HT, forskolin, and capsaicin to rapidly stimulate large DSFs, using naïve rats and transgenic mice. The
focus will include HCN channels, T-type Ca2+ channels, and Nav1.8 channels. Special attention will be paid to
TRPC4/5 channels, which are important for OA and have unusual properties that account for unique features
of large DSFs. Aim 2 will define ion conductances and cell signals that promote large DSF generation in
chronic SCI and in a subacute peripheral inflammation model (hindpaw injection of complete Freund's adjuvant
- CFA). The channels found in Aim 1 to be important for large DSFs will be tested for altered contributions and
expression in each model. Alterations promoting OA are predicted to be shared in these models (and thus to
potentially drive many forms of ongoing pain). Aim 3 will test the prediction that combined interventions
selectively blocking large DSFs and elevating AP threshold will reduce ongoing pain. A novel analgesic
strategy will be tested, which combines a drug that prevents large DSF generation (a TRPC4/5 blocker) with a
drug that selectively elevates AP threshold in nociceptors (a Nav1.8 blocker). The combination should
efficiently suppress nociceptor OA and consequent ongoing pain at doses lower than required to observe any
effect on ongoing pain from either drug alone. This prediction will be tested in vivo both on C-fiber OA recorded
from dorsal roots of anesthetized rats and on ongoing pain in SCI rats and in rat and mouse CFA models. This
targeted approach could lay the foundation for new treatments for severe ongoing pain that have relatively few
side effects and provide an alternative to opioids, with their attendant ...

## Key facts

- **NIH application ID:** 9908192
- **Project number:** 5R01NS111521-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** EDGAR T. WALTERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,773
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908192

## Citation

> US National Institutes of Health, RePORTER application 9908192, Mechanisms in primary nociceptors that drive ongoing activity and ongoing pain (5R01NS111521-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908192. Licensed CC0.

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