# Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $447,865

## Abstract

Signaling Mechanisms of Opioid-induced Hyperalgesia and Tolerance
Project Summary
The major objective of this project is to identify key signaling mechanisms responsible for the development of
opioid-induced hyperalgesia and analgesic tolerance (OHT). Opioid drugs remain indispensable for treating
severe pain caused by surgery, trauma, and cancer. However, acute and repeated administration of μ-opioid
receptor (MOR) agonists often cause OHT, the major obstacle to adequate pain relief with opioids. OHT can
also lead to unsafe opioid dose escalation, resulting in dependence, addiction, and even overdose death. Opioid
signaling is complex and has been studied mostly in vitro, but the functional significance and relevance of various
opioid signaling components to OHT are poorly understood. N-methyl-D-aspartate receptors (NMDARs) are a
clinically validated target for treating OHT, and extracellular signal-regulated kinase (ERK) is stimulated by MOR
activation and is involved in opioid-induced NMDAR hyperactivity at the spinal cord level and in OHT. At present,
little is known about the upstream signaling mechanism leading to stimulation of ERK at the spinal cord level
during OHT. Although BRAF, a serine/threonine-specific protein kinase, is a crucial upstream signal for ERK
activation, its role in OHT has not been recognized previously. In our preliminary studies, we found that repeated
treatment with opioids increased BRAF activity in the spinal cord. Furthermore, BRAF inhibition or knockdown
at the spinal cord level substantially attenuated OHT and rescued the synaptic trafficking and expression of
MORs and NMDARs in the spinal cord altered by opioid treatment. These initial findings suggest that BRAF-
dependent signaling plays a key role in the control of synaptic MOR and NMDAR plasticity in the development
of OHT. Therefore, in this competing renewal application, we will test the overall hypothesis that repeated
treatment with opioids, through the BRAF-mediated signaling axis, induces (1) analgesic tolerance by inhibiting
expression and activity of MORs at primary afferent central terminals and (2) hyperalgesia by promoting
trafficking and activity of NMDARs at primary afferent terminals synapsing with spinal cord excitatory neurons.
To test this hypothesis, we will use a multidisciplinary approach, including protein biochemistry,
electrophysiological recordings in spinal cord slices, and targeted gene knockout and knockin. Our proposed
studies are expected to advance our understanding of the fundamental signaling mechanisms highly relevant to
the development of OHT. Our project also has important clinical implications and could lead to new strategies
(e.g., using FDA-approved BRAF inhibitors) for improving opioid analgesic efficacy in patients with severe pain.

## Key facts

- **NIH application ID:** 10531344
- **Project number:** 2R01DA041711-05A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shao-Rui Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $447,865
- **Award type:** 2
- **Project period:** 2017-03-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531344

## Citation

> US National Institutes of Health, RePORTER application 10531344, Signaling Mechanisms of Opioid-Induced Hyperalgesia and Tolerance (2R01DA041711-05A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10531344. Licensed CC0.

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