# Mechanistic Study of Pain Inhibition by Activation of Non-nociceptive Afferent Fibers

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $487,574

## Abstract

PROJECT SUMMARY
 Electrical stimulation (ES) of low-threshold Aβ-nerve fibers is a clinical strategy for treating chronic pain
that is refractory to pharmacotherapies, including opiates. However, the mechanisms underlying pain
inhibition by Aβ-fiber activation remain elusive, limiting further clinical and technological improvements. Our
major goal is to uncover spinal neuronal and non-neuronal mechanisms of pain inhibition by Aβ-ES, and to
identify targets for rationally selecting adjuvant drugs to enhance pain inhibition and avoid side effects. In Aim
1, by using animal models of neuropathic pain, we will first delineate spinal neuronal mechanisms by which
Aβ-ES inhibits pain transmission. Electrophysiology studies will uncover how different forms of Aβ-ES
modulate functionally distinct subsets of superficial dorsal horn neurons (e.g., inhibitory vs. excitatory
neurons), and further differentiate the underlying receptor mechanisms. We postulate that the excitatory
neuron-preferred inhibition may enable Aβ-ES to be used together with low-dose adjuvant drugs for
circuitry-specific enhancement of pain inhibition. We will test whether limiting endogenous adenosine
degradation or GABA reuptake during Aβ-ES specifically enhances the inhibition of dorsal horn excitatory
and projection neurons and increases the net inhibition of pain transmission. In Aim 2, we will then unveil a
non-neuronal pain gating mechanism activated by Aβ-ES. By conducting high-throughput GCaMP6 imaging
and electrophysiology recording, we will examine whether Aβ-ES activates spinal astrocytes to induce
inhibition of spinal nociceptive transmission, and whether this process is attenuated by nerve injury. Since
pain inhibition by dorsal column stimulation (DCS) is intrinsically linked with activation of Aβ-fibers, DCS will
be used as a proof-of-principle for studying Aβ-ES in vivo. We will examine whether DCS changes astrocyte
reactive markers, affects the levels of pro-inflammatory mediators, and promotes microglial polarization from
M1 to M2 state after nerve injury. We will further test whether glia-derived adenosine inhibits excitatory or
projection neurons and enhances Aβ-ES–induced inhibition of these neurons. Our findings in Aims 1 and 2
will help us to develop new strategies of enhancing pain inhibition by Aβ-ES in Aim 3. We will test whether
inhibition of neuropathic pain-related behavior by DCS can be enhanced by limiting degradation of
endogenous adenosine and inhibiting GABA reuptake in the spinal cord. Owing to use-dependent and
circuitry-specific features, we expect that the treatment will not induce side effects. Our findings will reveal
new mechanisms underlying pain inhibition by Aβ-ES, and will provide important rationales and drug targets
for future translational studies aimed at using low-dose adjuvant drugs to improve the efficacy and specificity
of pain inhibition by Aβ-ES therapies.

## Key facts

- **NIH application ID:** 10112977
- **Project number:** 5R01NS110598-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Yun Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $487,574
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112977

## Citation

> US National Institutes of Health, RePORTER application 10112977, Mechanistic Study of Pain Inhibition by Activation of Non-nociceptive Afferent Fibers (5R01NS110598-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112977. Licensed CC0.

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