# Neuronal and glial interactions of neuropathic pain

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $488,534

## Abstract

Mounting evidences suggests that cancers such as melanoma produce programmed death protein-1 ligand 1
(PD-L1) to suppress T cell activation and immunity via interaction with PD-1 (receptor of PD-L1). Emerging
immune therapies such as anti-PD1 and anti-PD-L1 treatments have shown great success in treating cancers,
such as melanoma and head and neck cancers. However, the unique role of PD-L1/PD-1 in pain regulation is
unknown. Our work in progress has demonstrated the presence of anatomical and functional PD-1 in primary
sensory neurons and identified PD-L1 as a novel pain inhibitor, produced not only by cancer cells but also by
normal neural tissues. We hypothesize that PD-L1 masks cancer pain and inhibits baseline pain and
neuropathic pain via silencing PD-1 expressing nociceptive neurons. We also hypothesize that PD-L1 can inhibit
somatic and trigeminal neuropathic pain via suppressing microglial and T-cell activation in the spinal cord and
brain stem. Of interest recent studies have shown that microglia and T cells in the spinal cord contribute to
neuropathic pain in a sex-dependent manner. Consistently, our pilot study shows that intrathecal inhibition of
caspase-6 and p38 signaling inhibits nerve injury-induced mechanical allodynia in male but not female mice. We
further hypothesize that PD-L1 inhibits microglial and T-cell activation in a sex-dependent manner. The overall
goal of this application is to investigate how the PD-L1/PD-1 pathway can mask cancer pain and also suppress
neuropathic pain via regulating the function of neurons, microglia, and T-cells. We will use mouse melanoma
and neuropathic pain models of both sexes to test our hypotheses by accomplishing the following 3 specific
aims: Aim 1. Test the hypothesis that the PD-L1/PD-1 pathway can mask skin cancer pain, suppress somatic
and trigeminal neuropathic pain, and inhibit baseline pain; Aim 2. Test the hypothesis that activation of the PD-
L1/PD-1 pathway can suppress neuronal excitability in mouse and human DRG/TG neurons and inhibit synaptic
plasticity in mouse spinal cord neurons; Aim 3. Test the hypothesis that the PD-L1/PD-1 pathway can inhibit
pain via suppressing microglial and T-cell activation in a sex-dependent manner. This project will identify PD-L1
as a novel endogenous pain inhibitor and provide new insights into neuron-glia, neuron-immune, and neuron-
cancer interactions. Manipulation of PD-L1/PD-1 signaling may lead to the development of novel analgesics.

## Key facts

- **NIH application ID:** 10214589
- **Project number:** 5R01DE017794-16
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Thomas Buchheit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $488,534
- **Award type:** 5
- **Project period:** 2006-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214589

## Citation

> US National Institutes of Health, RePORTER application 10214589, Neuronal and glial interactions of neuropathic pain (5R01DE017794-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10214589. Licensed CC0.

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