# Neuropeptide Y1 Receptor-Expressing Neurons in the Dorsal Horn and Neuropathic Pain

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $45,520

## Abstract

PROJECT SUMMARY
 Chronic pain affects millions of patients worldwide, costing over 600 billion dollars annually for the
United States alone. Neuropathic pain is a form of chronic pain that arises as a direct consequence of a lesion
or diseases affecting the somatosensory system and is very difficult to treat as the underlying mechanisms of
this disease are poorly understood. A stronger excitatory tone in the delicate balance between excitatory and
inhibitory interneurons in the dorsal horn of the spinal cord has been strongly implicated in the mechanical and
thermal hypersensitivities seen in patients that suffer from neuropathic pain. Exactly how nerve injury disrupts
this balance to generate a net pronociceptive tone, however, remains unclear. Promising preliminary data
within our laboratory has implicated one specific excitatory interneuron population, those expressing the
neuropeptide Y (NPY) Y1 receptor. First, selective lesioning of Y1 receptor-expressing interneurons (Y1Rs)
reduces behavioral signs of neuropathic pain. Second, intrathecal administration of a Y1 agonist dose-
dependently reduces mechanical and cold hypersensitivity after nerve injury. Third, chemogenetic activation of
Y1Rs induces both mechanical and thermal hypersensitivities. These observations provide the premise for my
central hypothesis that nerve injury increases the excitability of Y1R interneurons in response to
peripheral input, ultimately leading to neuropathic pain. The overarching goals of the following three
specific aims are to increase our understanding of how nerve injury increases the excitability of Y1Rs and
provide rationale for targeting Y1Rs as a novel approach to treat neuropathic pain.
Specific Aim 1 will test the hypothesis that nerve injury will favor the anatomical expression of excitatory, as
compared to inhibitory, synaptic contacts onto Y1Rs. I will utilize high-throughput synapse quantification tools
to quantify both putative-excitatory and putative-inhibitory synapses onto Y1Rs after spared nerve injury (SNI).
I predict that nerve injury will increase the number of excitatory inputs and/or decrease the number of inhibitory
inputs onto Y1Rs.
Specific Aim 2 will test the hypothesis that nerve injury increases presynaptic excitatory drive and/or decreases
inhibitory drive onto Y1Rs in dorsal horn. Npy1rGFP mice will undergo SNI or sham surgery followed 14 days
later by whole-cell voltage-clamp recordings in spinal cord slices. I will measure both excitatory and inhibitory
miniature postsynaptic currents of Y1Rs in sham and SNI slices in order to assess physiological changes in
pre- or postsynaptic activity to Y1Rs after injury.
Specific Aim 3 will test the hypothesis that spinal Y1Rs are necessary for neuropathic pain and sufficient to
produce pain hypersensitivity. I will use innovative optogenetic spinal LED implants to optogenetically inhibit
Y1Rs in naïve and nerve injured mice and excite Y1Rs in naïve mice in order to understand the behavior...

## Key facts

- **NIH application ID:** 9992063
- **Project number:** 1F31NS117054-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Tyler Scott Nelson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-07-08 → 2021-07-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992063

## Citation

> US National Institutes of Health, RePORTER application 9992063, Neuropeptide Y1 Receptor-Expressing Neurons in the Dorsal Horn and Neuropathic Pain (1F31NS117054-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9992063. Licensed CC0.

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