# Central glutamate signaling in postoperative pain regulation

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $212,175

## Abstract

PROJECT SUMMARY
Postoperative pain is a major morbidity, and persistent opioid use after surgery has contributed to an epidemic.
An improved mechanistic understanding of how pain is regulated within the brain can lead to novel non-opioid
analgesic development. The long-term goal of this proposal is to understand the central regulation of
postoperative pain. The objective of the current application is to define the role of prelimbic cortex (PL) and
anterior cingulate cortex(ACC), two key components of the prefrontal cortexin rodents, in the regulation of acute
and chronic postoperative pain. The PL is homologous to human dorsolateral prefrontal cortex that is known to
undergo synaptic changes with chronic pain, and the ACC is a well-described region for processing affective
component of pain across species. Our central hypothesis is that an imbalance in neural activities in the PL and
ACC contributes to symptoms of postoperative pain and thus forms a therapeutic target. Our hypothesis is
supported by the current literature showing that the PL has a pain-inhibitory role, whereas the ACC enhances
pain aversion, and that chronic pain causes increased excitability in the ACC and hypo-excitability in the PL. It
is also supported by our recent results demonstrating that AMPAkines and ketamine, drugs that alter glutamate
signaling and shape cortical circuits, reduce pain. In Aim 1, we will test the hypothesis that an imbalance in ACC
and PL activities contributes to postoperative pain in awake freely behaving rats. We will use paw incision (PI)
to mimic acute reversible incisional pain, and spared nerve injury (SNI) to model chronic pain after intraoperative
nerve damage. We will first correlate imbalanced prefrontal activities with pain, by showing a concurrent loss of
nociceptive response in the PL and gain of response in the ACC as pain behavior persists, and the resolution of
such neural changes as pain resolves, using simultaneous in vivo extracellular recordings of the PL and ACC.
Further, to test the causal effect of this imbalance on pain, we will show that optogenetic PL activation, or ACC
inhibition, reverses postoperative pain behaviors. Next, we will use optrode recordings to dissect a local pain-
regulatory circuit fromthe PL to the ACC. Further, we will use an unbiased supervised machine learning analysis
to validate the relationship between the imbalance in PL and ACC activities and the chronicity of postoperative
pain. In Aim 2, We will test the hypothesis that pharmacologic and electrical neuromodulation can target
imbalanced PL/ACC activities in the postoperative pain state. We will show that AMPAkines and ketamine
increase PL outputs and reduce ACC activities to inhibit pain and optimize the timing and dosing regimens for
these drugs and test therapeutic synergy. We will also optimize invasive and non-invasive electrical stimulation
protocols in the PL to treat pain. This project is innovative because it applies a new systems neuroscie...

## Key facts

- **NIH application ID:** 10385965
- **Project number:** 3R01GM115384-07S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $212,175
- **Award type:** 3
- **Project period:** 2015-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385965

## Citation

> US National Institutes of Health, RePORTER application 10385965, Central glutamate signaling in postoperative pain regulation (3R01GM115384-07S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10385965. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*