# Cholinergic modulation of Descending Pain Control Pathways

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2021 · $438,712

## Abstract

Chronic pain conditions plague more than 20% of adults in the United States, emphasizing the need for a more
comprehensive understanding of pain control mechanisms and better pain therapies. This need is amplified
further by the current opioid crisis, which killed 47,600 Americans in 2018. While opioids are remarkably
effective treatments for acute and chronic pain, adverse side effects, including abuse liability and tolerance to
the analgesic effects with repeated use, highlight the need for novel non-opioid pain therapies. This need
motivates our investigations of pain modulation by acetylcholine (ACh) and its receptors (AChRs) in the
ventrolateral periaqueductal gray (vlPAG). Ascending pain signaling from periphery to central nervous system
is modulated by the descending pain pathway, including the vlPAG and its projections to rostral ventromedial
medulla (RVM) and locus ceruleus (LC). This descending pain pathway is a key site of action of opioids and
endogenous pain control. While much is known about this circuitry, the pain modulatory effects of cholinergic
inputs to vlPAG are understudied. Our preliminary data show that optogenetic stimulation of cholinergic
projections from the pedunculopontine tegmental nucleus (PPTg) to vlPAG is antinociceptive in acute pain.
Using cell- and circuit-specific optogenetic approaches, we will test the effect of stimulating cholinergic
projections to vlPAG on nociception in a chronic neuropathic pain model, identify the cholinergic receptors
mediating these antinociceptive effects, and explore possible interactions between cholinergic signaling and
the opioid system.
 In Aim 1, we will use optogenetic approaches to test antinociceptive effects of stimulating cholinergic
PPTg neurons projecting to vlPAG in mice experiencing chronic neuropathic pain. We will also assay affective
pain relief of stimulating these projections using a real-time place preference assay. In Aim 2, we will identify
cholinergic receptor(s) mediating synaptic communication between PPTg and vlPAG neurons, using high-
throughput fluorescence in situ hybridization assay to visualize mRNA expression of muscarinic and nicotinic
AChRs on vlPAG neurons. After identifying candidate AChR(s) based on mRNA expression, we will test
functional role of these receptors in synaptic communication, using slice electrophysiology and ex vivo
optogenetics. Finally, we will test the causal role of identified AChRs in antinociception in vivo using
optogenetics and pharmacology in neuropathic pain assays. In Aim 3, we will explore possible interactions
between these cholinergic mechanisms and the opioid system, by testing the efficacy of cholinergic analgesia
in morphine-tolerant mice and during naloxone precipitated withdrawal from chronic morphine treatment.
These studies will employ histological, electrophysiological, optogenetic and pharmacological approaches to
advance our knowledge of cholinergic modulation of descending pain pathways, to ultimately hel...

## Key facts

- **NIH application ID:** 10317942
- **Project number:** 1R21NS120582-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Daniel S McGehee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,712
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317942

## Citation

> US National Institutes of Health, RePORTER application 10317942, Cholinergic modulation of Descending Pain Control Pathways (1R21NS120582-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10317942. Licensed CC0.

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