# Adenylyl cyclase signaling in persistent pain

> **NIH NIH R01** · UNIVERSITY OF NEW ENGLAND · 2022 · $459,865

## Abstract

Chronic pain affects more than 50 million Americans per year, resulting in extraordinary
personal and societal costs. Adding to the dilemma, deaths involving prescription opiate
analgesics have almost quadrupled in the last ten years. The clinical challenge of pain
management is underscored by evidence that chronic pain is mechanistically distinct from acute
pain, therefore a thorough understanding of the molecular and cellular mechanisms underlying
the transition to chronic pain is fundamental to improving and expanding treatment options.
Hyperalgesic priming is a compelling model of the transition to chronic pain in which an initial
injury resolves, but leaves the animal in a primed state in which a second insult induces a
greatly prolonged pain response. While previous studies have explored the development of
sustained mechanical hypersensitivity, we have adapted this model to examine sustained
hypersensitivity mediated by nociceptors expressing the heat-gated ion channel TRPV1, which
can drive pain in a range of inflammatory and neuropathic conditions. Experiments proposed
here will test the contribution to heat hyperalgesic priming of adenylyl cyclase isoform AC2,
which has not been previously characterized in sensory neurons, and which is insensitive to
inhibition by Gi/o-coupled receptors such as opioid receptors. Preliminary analysis indicates that
AC2 is highly expressed in TRPV1-expressing neurons and required for the manifestation of
heat hyperalgesic priming. Specific Aim 1 will examine the impact of AC2 gene deletion and
pharmacological inhibition on behavioral nociceptive thresholds at baseline, in acute
hyperalgesia and in the setting of hyperalgesic priming. Specific Aim 2 will determine whether
AC2 and the downstream effector Epac are functionally coupled through AKAP family member
scaffolding proteins by co-immunoprecipitation-mass spectrometry, and will determine the
impact of deleting identified AKAP genes on Epac signaling and nociceptor function in vitro
using a CRISPR/Cas9-based approach. Specific Aim 3 will determine the consequences for
Epac function of AC2 and AKAP gene deletion through Epac-dependent PKC phospho-
substrate profiling and behavioral assessment of heat hyperalgesia. This proposal will use
innovative approaches to explore novel mechanisms contributing to the development of
persistent hyperalgesia.

## Key facts

- **NIH application ID:** 10418657
- **Project number:** 5R01NS109936-04
- **Recipient organization:** UNIVERSITY OF NEW ENGLAND
- **Principal Investigator:** DEREK C MOLLIVER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $459,865
- **Award type:** 5
- **Project period:** 2019-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418657

## Citation

> US National Institutes of Health, RePORTER application 10418657, Adenylyl cyclase signaling in persistent pain (5R01NS109936-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418657. Licensed CC0.

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