# Peripheral and Central Pathways of α3 Glycine Receptors as Non-Opioid Molecular Targets to Treat Pain

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $582,214

## Abstract

Over 100 million Americans experience some forms of physical pain, a quarter of whom
struggle daily to cope with chronic and persistent pain conditions. One of the risks associated with
existing analgesic drugs, beyond some manageable side effects, is the potential for drug
dependence and abuse. Glycinergic inhibition plays a pivotal role in spinal nociception. Enhancing
glycine receptor (GlyR) activities by positive allosteric modulators (PAMs) has been recognized
as a promising alternative to opioids for treating chronic pain. By combining structural biology,
electrophysiology, and in vivo studies, we discovered a novel drug binding site in the human
GlyRs that mediates marijuana’s analgesic action independent of its psychoactive side effects.
We further discovered a new molecular scaffold that potentiates GlyRs with little cross reactivity
with opioid receptors and other psychotropic receptors. A lead drug candidate from this scaffold
was found to be specific positive allosteric modulators for α3-containing GlyRs and have higher
potencies than morphine in suppressing neuropathic and inflammatory pain in rodents. Using
RNAscope for in situ hybridization, we also discovered abundant colocalization of α3GlyR with a
special group of projection neurons in the midbrain. These intriguing findings led us to
hypothesize that α3GlyRs in the superficial layer of the spinal dorsal horn and in the midbrain
play a dual role as important targets for analgesia and as inhibitory regulators for the reward
circuits, respectively. We have collected ample preliminary data to support the following three
specific aims: Aim 1: Investigate the role of spinal α3GlyR as an effective molecular target to
alleviate mechanical and thermal hypersensitivity in neuropathic and inflammatory pain; Aim 2:
Understand α3GlyR’s regulation of the midbrain projection neurons as a key cellular target for
antinociception and anti-psychomotor stimulation; and Aim 3: Elucidate the coupling of glycinergic
and dopaminergic signaling pathways to harness the dual action of selective positive allosteric
modulation of α3GlyRs for both analgesia and reduction of reward-seeking behavior, focusing on
drug-seeking and instrumental learning of self-administration tests. These mechanism-guided
investigations will complement and further enhance the discovery of new α3GlyR-targeting drugs
for safe and effective pain treatment.

## Key facts

- **NIH application ID:** 10824344
- **Project number:** 5R01NS122830-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** YAN XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,214
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824344

## Citation

> US National Institutes of Health, RePORTER application 10824344, Peripheral and Central Pathways of α3 Glycine Receptors as Non-Opioid Molecular Targets to Treat Pain (5R01NS122830-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10824344. Licensed CC0.

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