# REST-mediated regulation of opioid receptors in chronic pain mouse models

> **NIH NIH R61** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $411,960

## Abstract

Project Summary
Chronic neuropathic pain (CNP) is usually caused by disease or damage involving the somatosensory nervous
system, adversely affecting millions of Americans. It is difficult to treat and remains a major clinical problem.
Opioids, acting through opioid receptors (ORs: MOR for µ, KOR for κ, DOR for δ, NOP for nociceptin), trigger a
complex signaling system and function as powerful analgesics. However, chronic opioid treatment causes
hyperalgesia/analgesic tolerance and addiction, which have resulted in an opioid epidemic in the U.S. The
opioid-induced hyperalgesia /analgesic tolerance (OIH/AT) and addiction can be modulated by many factors
including OR expression levels and heteromer formation with different ORs (for example, MOR-DOR) or with
other receptors such as the cannabinoid receptor (CNR1). Our long-term goal is to develop new strategies to
enhance opioid analgesic effects and reduce opioid consumption for treatment of CNP. REST is a major
epigenetic regulator. We and others have found that overexpression (OE) of REST in the dorsal root ganglion
(DRG), causing repression of the MOR gene oprm1, is linked to the onset and maintenance of CNP. Our
recent studies indicate that peripheral nerve injury in fact reduces opioid analgesia via the REST corepressor
G9a-mediated chromatin repression of oprm1. Further, our preliminary studies suggest that MORs in DRG
neurons are essential for OIH/AT. This would suggest that the REST-MOR axis in DRG neurons is a major
mechanism regulating both CNP and OIH/AT. However, although the discovery of oprm1 as a REST target
using a gene-by-gene approach is useful, it is unclear whether REST regulates the impacts of opioid analgesia
in CNP or in OIH/AT by controlling the expression of other ORs or CNR1 or both of these processes. Our
preliminary results suggest that REST differentially regulates expression of these receptors in DRG neurons.
While it causes a decrease in the expression of MOR and DOR, it causes an increase in the expression of
NOP and CNR1, perhaps by repressing the expression of an inhibitor of these genes such as a miRNA. To
begin to generate comprehensive insights into the role of REST in CNP, we have now developed an innovative
experimental system consisting of Rest conditional knock-out (cKO) mice and REST conditional OE (cOE)
mice. Preliminary results indicate that whereas DRG-specific Rest cKO mice show attenuated pain
hypersensitivity after nerve injury, DRG-specific REST cOE mice exhibit pain hypersensitivity even without
nerve injury. Thus, the two contrasting mouse models recapitulate the chronic pain transition and provide a
robust system in which to study mechanisms governing OR expression in primary sensory neurons in CNP and
in OIH/AT. Here we propose to test the central hypothesis that REST in DRG neurons is involved in regulating
opioid analgesia in CNP and in OIH/AT by governing ORs/CNR1 expression through epigenomic regulation of
these genes. Thus, manipulation of R...

## Key facts

- **NIH application ID:** 10205014
- **Project number:** 5R61DA049334-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** SADHAN MAJUMDER
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,960
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10205014

## Citation

> US National Institutes of Health, RePORTER application 10205014, REST-mediated regulation of opioid receptors in chronic pain mouse models (5R61DA049334-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10205014. Licensed CC0.

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