# Neuron vasculature interactions in pain

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2024 · $629,503

## Abstract

Neuropathic spontaneous pain, a main symptom of neuropathic pain, is often a particularly intractable clinical
problem. While much has been done to understand the sensory sensitization to evoked pain, the mechanisms
underlying neuropathic spontaneous pain are less understood and believed to be different from evoked pain
mechanisms. Our collaborator Dr. Xinzhong Dong’s lab in Johns Hopkins University created Pirt-GCaMP6 mice,
mice in which a genetically encoded Ca²+ indicator GCaMP6 is specifically expressed in >95% of dorsal root
ganglion (DRG) neurons under the control of the Pirt promoter. With these mice, we were able to examine DRG
neuronal activity in vivo, still in its original environment and spatial arrangement. We found that after nerve injury,
spatially clustered neurons with sporadic spontaneous activity formed within the DRG (Zheng et al., Neuron,
2022). Mice that displayed increased spontaneous pain behavior after nerve injury were found to highly correlate
with presence of these ectopic ‘cluster’ neurons. We further discovered that cluster firing of DRG neurons and
neuropathic spontaneous pain could be triggered by sympathetic activation - effects blocked by both α- and β-
adrenergic antagonists. However, the main target of sympathetic activation is not clear since adrenoceptors are
expressed in sensory neurons as well as the blood vessels in the DRGs. Results from our preliminary studies
show that cluster firing and spontaneous pain behaviors are enhanced by local or systemic administration of
vasoconstrictors (e.g., phenylephrine or angiotensin II), and that evoked and spontaneous cluster firing as well
as spontaneous pain are decreased by blocking the Piezo2 mechanoreceptors in the DRG pharmacologically or
genetically. We thus hypothesize that neuropathic spontaneous pain and cluster firing of sensory neurons after
peripheral nerve injury are triggered by the mechanical movement (i.e., vasoconstriction and/or vasodilation,
blood vessel displacement) of the blood vessels within the DRGs. The somata or axons of all neurons in the
clusters are physically associated with branches of blood vessels supplying the DRG. We further hypothesize
that Piezo2 receptors expressed in the majority of hyperexcitable DRG neurons mediate such effects. The
above-mentioned findings that sympathetically evoked cluster firing and spontaneous pain can be blocked by
both α- and β-adrenergic antagonists support our hypothesis since blocking α- and β-adrenoceptors would block
vasoconstriction and vasodilation, respectively, and both would result in stabilization of blood vessel movement.
In this application, using established mouse and rat neuropathic pain models, we propose to test the hypothesis
in 3 Specific Aims (SA). SA1 will characterize the role of local vascular movement in triggering neuropathic
spontaneous pain. SA2 will determine how mechanoreceptors in sensory neurons contribute to vascular
movement-evoked spontaneous pain. SA3 is to identify ad...

## Key facts

- **NIH application ID:** 10979939
- **Project number:** 1R01NS135157-01A1
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Jun-Ming Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $629,503
- **Award type:** 1
- **Project period:** 2024-09-09 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979939

## Citation

> US National Institutes of Health, RePORTER application 10979939, Neuron vasculature interactions in pain (1R01NS135157-01A1). Retrieved via AI Analytics 2026-07-20 from https://api.ai-analytics.org/grant/nih/10979939. Licensed CC0.

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