# Mechanisms of cAMP signaling that drive spontaneous activity in nociceptors

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $445,662

## Abstract

Project Summary:
Chronic pain caused by injury to the peripheral or central nervous system (neuropathic pain) is
notoriously resistant to treatment, while the mechanisms that drive and/or maintain chronic pain remain
unclear. We have shown that chronic nociceptor hyperexcitability after severe injury is maintained by
cAMP signaling through multiple cAMP effectors, including PKA, EPAC and HCN channels. These
pathways are enhanced by AKAP-mediated complex formation with AC and show significant cross-talk
with Ras/MAPK signaling. Activation of cAMP- and Ras-mediated pathways initiate at the plasma
membrane (PM) and are uniquely sensitive to clustering of lipids within the PM. We have also shown
that spinal cord injury reduces AC inhibition by Gαi, resulting in reduced potency of opioids in DRG
neurons. This reduced sensitivity can be mimicked in DRG neurons from naïve animals by overnight
exposure to neurotrophic factors or by a 5 min, modest depolarization that approaches the firing
threshold of DRG neurons after severe injury. Importantly, nociceptor hyperexcitability and reductions
in opioid potency, induced by either injury, neurotrophic factors or acute depolarization, can be
reversed by inhibition of Ras-dependent signaling or reorganization of lipids in the plasma membrane.
We hypothesize that the sustained depolarization that occurs in many injury models drives alterations
in PM lipid organization, leading to increased ERK signaling and decreased opioid responses. Release
of neurotrophic factors reinforce these pathways and, in conjunction with cAMP signaling, drives
nociceptor hyperexcitability and a chronic pain state. To address these hypotheses, we propose three
Aims. 1) Determine the mechanism for reduced MOR-Gαi inhibition of AC by C-Raf, 2) Define the
mechanism of Ras activation and nociceptor hyperexcitability by depolarization and SCI, and 3) Define
functional consequences of interactions among depolarization and cell signaling by cAMP, C-Raf, and
ERK. Importantly, our model identifies multiple FDA-approved drugs that could simultaneously enhance
endogenous opioid responses and block nociceptor hyperexcitability after severe injury.

## Key facts

- **NIH application ID:** 10121682
- **Project number:** 2R01NS091759-06
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Carmen W. Dessauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,662
- **Award type:** 2
- **Project period:** 2015-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121682

## Citation

> US National Institutes of Health, RePORTER application 10121682, Mechanisms of cAMP signaling that drive spontaneous activity in nociceptors (2R01NS091759-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121682. Licensed CC0.

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