# Neuropeptidergic Inhibition of Spinal Pain Transmission

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $482,428

## Abstract

Neuropathic pain (NP) is a debilitating disease that is difficult to manage. Current treatments are only partially
effective, in a small subset of patients. The development of effective analgesics for NP is stalled by our
incomplete understanding of its underlying mechanisms. An important clue comes from our progress on this
project over the past 20 years with studies of the neurobiology of neuropeptide Y (NPY) and its inhibitory
actions at excitatory interneurons (IN) in the dorsal horn of the spinal cord that express the NPY Y1 receptor
(Y1). Our long-term goal is the development of Y1 agonists that will engage and inhibit precise
subpopulations of Y1-INs and thus reduce NP. To this end, we confirmed that Y1-INs co-express either
cholecystokinin (Cck), gastrin-releasing peptide (Grp), or Neuropeptide FF (Npff) mRNA, and that
chemogenetic inhibition or ablation of Y1-IN blocked multiple signs of NP in mice with peripheral nerve injury.
Similarly, chemogenetic inhibition of protein kinase C type γ interneurons (PKCγ-INs) reversed touch-evoked
allodynia. Our central hypothesis is that nerve injury recruits a pronociceptive dorsal horn microcircuit that
includes excitatory presynaptic input from PKCγ-IN onto the subpopulations of Y1-INs that facilitate
neuropathic pain. Specific Aim 1 will use patch clamp dorsal horn slice electrophysiology to record
postsynaptic currents, and high-resolution confocal microscopy to measure appositions between pre and
postsynaptic elements of synapse, at Y1eGFP neurons. We predict that nerve injury will produce a net ratio
increase not only in presynaptic excitatory vs inhibitory drive, but also in the number of excitatory vs inhibitory
synapses, leading to a potentiation of neuronal activation in the CCK, GRP and/or Npff subpopulations of Y1-
INs. Specific Aim 2 tests the hypothesis that Y1-INs are necessary and sufficient for neuropathic pain. We
predict that wireless in vivo optogenetic activation of spinal Npy1rcre (Y1cre) neurons will produce nocifensive
and aversive behaviors in normal mice, while optogenetic inhibition will reverse mechanical and cold allodynia
in nerve-injured mice. Specific Aim 3 tests the hypothesis that nerve injury recruits a pronociceptive PKCγ 
Y1-IN chronic pain circuit. We predict that chemogenetic or optogenetic activation of PKCγCreERT2 neurons will
increase pERK+ immunoreactivity (a proxy for in vivo neuronal activity) and excitatory postsynaptic currents
(EPSCs) in Y1eGFP reporter mice, while genetic inhibition of PKCγCreERT2 or pharmacological inhibition of PKCγ
will prevent or reduce SNI potentiation of touch-evoked neuronal activation, spontaneous EPSCs and/or
stimulus-evoked action potentials in Y1eGFP neurons. Specific Aim 4 will determine which subpopulations of
excitatory Y1-INs are necessary for the antiallodynic actions of intrathecal Y1 agonists. We predict that
conditional deletion of Y1 receptors in Lbx1cre spinal cord neurons as well as CckCre, GrpCre, and/or NpffCr...

## Key facts

- **NIH application ID:** 10782458
- **Project number:** 5R01NS045954-19
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** BRADLEY K. TAYLOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $482,428
- **Award type:** 5
- **Project period:** 2002-09-10 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10782458

## Citation

> US National Institutes of Health, RePORTER application 10782458, Neuropeptidergic Inhibition of Spinal Pain Transmission (5R01NS045954-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10782458. Licensed CC0.

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