# Mrgs as New Target for the Treatment of Neuropathic Pain

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $358,203

## Abstract

PROJECT SUMMARY
 Understanding the role of human MrgX1 in pain is a critical step to developing new therapy for pain
treatment. However, the function of MrgX1 cannot be fully inferred from studying of its rodent ortholog MrgC.
The cross-species variation in Mrg receptor function and agonist activity has presented a daunting challenge
for the study of MrgX1 in animal models. To solve these problems, we have generated novel MrgX1:Mrg-/-
mice that selectively express MrgX1 in DRG neurons, developed MrgX1-specific agonists and positive
allosteric modulators (PAMs), and acquired a human neuronal HC-1 cell line. Using these new tools, we will
examine the roles and mechanisms of MrgX1 in pain modulation and morphine analgesia for the first time. In
Aim 1, we will determine the effects of MrgX1 agonists and PAMs on neuropathic pain-related
behavior in MrgX1:Mrg-/- mice. We will characterize the analgesic properties of MrgX1 agonists (BAM8-22,
JHU23) and two leading PAMs (891 and 179) in MrgX1:Mrg-/- mice after nerve injury. We will further examine
if PAMs potentiate MrgX1 agonist-induced pain inhibition. Aim 1 will provide proof of principle for the
therapeutic utility of using MrgX1 agonists and PAMs to treat neuropathic pain. In Aim 2, we will examine
novel mechanisms of pain inhibition by MrgX1 agonists and PAMs in MrgX1:Mrg-/- mice and human
neuronal HC-1 cells. We will test the hypothesis that neuronal inhibition by MrgX1 agonists involves
Gαi/o-dependent inhibitions of downstream high-voltage-activated (HVA) Ica and cAMP production. We will
then examine if 179 and 891 potentiate the inhibition of HVA Ica by MrgX1 agonists in DRG neurons and in
human neuronal HC-1 cells. Finally, we will determine whether PAMs also enhance MrgX1 inhibition of spinal
nociceptive transmission. Aim 2 will provide important knowledge about neurophysiologic mechanisms for
pain inhibition by MrgX1 agonists and PAMs. In Aim 3, we will examine the interaction between MrgX1/C
and mu-opioid receptor (MOR) and its implication in morphine analgesia. In HEK293T cells, native
DRG neurons, and HC-1 cells, we will test the hypothesis that MrgX1/C can interact physically with MOR.
Furthermore, activation of MrgX1/C leads to co-internalization and sorting of MORs into the recycling
pathway. We will examine if MrgX1 agonists enhance morphine inhibition of cAMP, potentiate morphine
analgesia, and reduce morphine tolerance under neuropathic pain conditions. Aim 3 will uncover the physical
and functional interplay between MrgX1/C and MOR, which may help improve morphine analgesia. Findings
from the proposed studies will help us to conceptualize the biological basis of pain inhibition by MrgX1, and
offer potential clinical translatability for the use of MrgX1 agonists and PAMs as novel pain therapies.

## Key facts

- **NIH application ID:** 9955331
- **Project number:** 5R01NS070814-10
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Yun Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $358,203
- **Award type:** 5
- **Project period:** 2011-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955331

## Citation

> US National Institutes of Health, RePORTER application 9955331, Mrgs as New Target for the Treatment of Neuropathic Pain (5R01NS070814-10). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9955331. Licensed CC0.

---

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