# Neuropeptidergic Inhibition of Spinal Pain Transmission

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $451,345

## Abstract

Nerve injury dramatically increases NPY expression in sensory neurons and NPY receptor-mediated
analgesia, yet this is underappreciated as a potential pain relief mechanism that might prevent the transition
from acute to chronic pain. Among 35 original research articles, reviews, and a book published during the
previous funding cycle (28 as first or senior authors), our work published in PNAS discovered that intrathecal
NPY receptor antagonists or conditional genetic NPY depletion reinstated hyperalgesia, even when applied
months after nerve injury or inflammation. Our overall hypothesis is that injury induces a sustained release of
NPY and activation of NPY Y1 receptor signaling that opposes the transition to a chronic state of lasting pain
vulnerability. However, whether tissue- or nerve-injury induced increases in spinal NPY Y1 receptor (Y1R)
signaling is associated with a tonic increase in the releasable pool of NPY has been difficult to determine. To
address this gap, we developed a new in situ assay of functional NPY release (Y1R internalization). Our new
data indicate that Y1R internalization is greater with nerve injury after high frequency electrical stimulation of
dorsal horn slices or after in vivo non-noxious stimulation of the hindpaw. Specific Aim 1 will use this novel
method to test the hypothesis that non-noxious stimulus-evoked release of NPY from A-fibers will remain
primed for weeks and even months after nerve injury. We now report that NPY produces an outward current
and inhibits action potentials evoked by dorsal root stimulation (DRS) in Y1-EGFP labeled neurons. To test the
hypothesis that injury increases synaptic inhibition by NPY, Specific Aim 2A will patch-clamp lamina II
neurons and conduct Fura-2 [Ca2+]i imaging at peak of hyperalgesia after injury. We predict that Y1R agonists
will inhibit stimulus-evoked responses and their concentration-response curves will be left-shifted by injury. Our
progress with NPY saporin-conjugated neurotoxin indicates that Y1R-expressing dorsal horn neurons
contribute to neuropathic pain, and new double-label immunohistochemistry and patch-clamp
electrophysiology data in Y1R-EGFP mice support the concept that Y1R-positive neurons are excitatory. To
test the hypothesis that Y1R-expressing neurons maintain LS after inflammation or nerve injury, but are held in
check by NPY, Specific Aim 2B will evaluate the effects of Y1 receptor antagonists on [Ca2+]i mobilization and
NMDA or AMPA receptor currents in Y1R-expressing neurons upon dorsal root stimulation or laser-directed
NMDA/AMPA uncaging. Specific Aim 3 will then use an intrathecal pharmacology approach to determine
whether NPY silences pronociceptive GluN AC1 Epac signaling on Y1R-expressing dorsal horn neurons
and TRPA1 TRPV1 signaling on central afferents terminals. Completion of this project will bring us closer to
our long-term goal of alleviating chronic pain by either: a) facilitating endogenous NPY analgesia, thus
restricting pa...

## Key facts

- **NIH application ID:** 9852555
- **Project number:** 5R01NS045954-15
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** BRADLEY K. TAYLOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,345
- **Award type:** 5
- **Project period:** 2002-09-10 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852555

## Citation

> US National Institutes of Health, RePORTER application 9852555, Neuropeptidergic Inhibition of Spinal Pain Transmission (5R01NS045954-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9852555. Licensed CC0.

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