# Mechanisms in nociceptors driving ongoing activity and ongoing pain.

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $33,010

## Abstract

Project Summary
Management of ongoing pain not only improves patient comfort but also accelerates postoperative recovery and
diminishes the likelihood of developing chronic pain, ultimately reducing the cost of care. Many types of pain at
rest (spontaneous or ongoing pain) are likely driven by ongoing activity (OA) in nociceptors that occurs in the
absence of a discrete stimulus. In a model of neuropathic pain, nociceptive OA is produced by a prolonged
depolarization of resting membrane potential, reduction of the action potential threshold, and an increased
incidence of large depolarizing spontaneous fluctuations (DSFs) of the membrane potential. A low dose of the
inflammatory mediator serotonin (5-HT), when combined with artificial depolarization, strongly potentiates the
generation of large DSFs and OA in probable nociceptors from uninjured rats, showing that DSFs can also be
enhanced acutely to promote OA. A variety of 5-HT receptors are expressed in sensory neurons, and it is
unknown which of these receptor types and downstream pathways are important for 5-HT potentiation of DSFs.
Previous studies demonstrate that AKAP-scaffolded PKA activity is important for maintenance of OA in
nociceptors after spinal cord injury. The T-type voltage-gated Ca2+ channel Cav3.2 is stimulated by PKA and by
Gs-coupled 5HT7 receptor activity, and PKA-dependent internalization of Slack KNa channels induces nociceptor
hyperexcitability. These and other observations led to the hypothesis that peripheral 5-HT modulates specific
Ca2+ (T-type), and K+ (KNa) conductances via PKA to generate large DSFs that promote OA in nociceptors
and ultimately ongoing pain. This hypothesis will be tested in three specific aims. In Aim 1, we will determine
the receptors and cell signaling mechanisms mediating 5-HT potentiation of DSFs and OA. Using available
pharmacological tools along with patch clamp and high content microscopy techniques, we will test the
hypothesis that 5-HT enhancement of DSFs is mediated largely by PKA activation downstream of Gs-coupled 5-
HT receptors. In Aim 2, the specific conductances important for 5-HT-dependent generation of large DSFs and
OA will be defined. Using patch clamp recording and pharmacology, we will probe the necessity and sufficiency
of increased T-type Ca2+ and TRPC channel conductances and inhibition of KNa channel conductance for
generation of large DSFs. Our mechanistic model for enhancement of the generation of large DSFs and OA may
be particularly relevant to deep tissue incision pain in which platelet aggregates release 5-HT at and near a
wound. Deep tissue incision has been shown to induce both OA in nociceptors and spontaneous pain behavior
for a few days after injury. It is unknown whether 5-HT or PKA at or near the incision site plays a role in the OA
and ongoing pain following incision. In Aim 3, we will determine whether peripheral 5-HT and PKA contribute to
pain behavior in a model of postoperative pain. This proposed study w...

## Key facts

- **NIH application ID:** 9930441
- **Project number:** 5F31GM133203-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Elia Rose Lopez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,010
- **Award type:** 5
- **Project period:** 2019-06-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930441

## Citation

> US National Institutes of Health, RePORTER application 9930441, Mechanisms in nociceptors driving ongoing activity and ongoing pain. (5F31GM133203-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9930441. Licensed CC0.

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