# Identification of cells and signaling mechanisms underlying opioid analgesia and side effects

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $349,875

## Abstract

Opioids are used extensively to relieve pain but also produce detrimental effects, including opioid-induced
hyperalgesia (OIH) and analgesic tolerance. OIH and tolerance reduce opioid efficacy and drive dose escalation,
which worsens other deleterious effects such as respiratory depression, and transition to addiction. These effects
dramatically impact the quality of life of pain patients. Until now it has not been possible to dissociate the
analgesic from the OIH and tolerance effects, because the receptors and cells on which opioids act to cause
OIH and tolerance have not been identified. In contrast to the current model of opioids acting on CNS microglia
to initiate antinociceptive tolerance and OIH, we found in RNA-sequencing experiments that the mu opioid
receptor (MOR) is not expressed by microglia, and that OIH is lost, but microglia activation intact, in MOR global
knockout mice. Furthermore, we generated new mutant mice that lack MOR only in dorsal root ganglion (DRG)
nociceptors, but have intact MOR function in the CNS, and found that these mice show intact morphine
antinociception, but no OIH or tolerance. These preliminary studies open the possibility of dissociating opioid
analgesia from side effects, and lead to the following hypothesis: MORs in CNS underlie opioid analgesia, while
MOR signaling and maladaptive neuroplasticity in DRG is responsible for OIH and tolerance. In Aim 1, we will
use mouse genetics and viruses to delete MOR only in DRG of mice with chronic pain and treated with opioids,
and submit these mice to behavioral assays to measure opioid analgesia, analgesic tolerance, and OIH,
including with measures of pain affect and spontaneous pain. We will also block peripheral MORs with FDA-
approved peripherally restricted antagonist methylnaltrexone bromide. We predict that deleting or blocking MOR
in DRG will reduce morphine tolerance and OIH without impacting analgesia. In Aim 2, we will resolve the
maladaptive synaptic mechanisms that underlie OIH and tolerance. Opioids induce pronociceptive long-term
potentiation (LTP) at the synapse between DRG and spinal neurons. We will combine optogenetics and
electrophysiological analysis to determine whether activation of presynaptic MORs in DRG initiates maladaptive
LTP. In Aim 3, we will use RNA-sequencing on individual DRG nociceptors and PZM21, a novel Gi-biased MOR
agonist, to determine the MOR effectors present in identified nociceptors, the relevance to tolerance/OIH of Gi
versus beta-arrestin signaling in DRG neurons, and how opioids alter the expression of the genes controlling
DRG neuron excitability and neurotransmission. This research will transform our understanding of the
mechanisms of action of opioids by identifying MOR in DRG as the target of opioids for OIH and tolerance. This
research also has the potential to transform clinical practice, as MNB, or other drugs acting on targets identified
by RNA-sequencing, might be used to treat pain at lower opioid dosage. I...

## Key facts

- **NIH application ID:** 10165682
- **Project number:** 5R01DA044481-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gregory Scherrer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $349,875
- **Award type:** 5
- **Project period:** 2020-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165682

## Citation

> US National Institutes of Health, RePORTER application 10165682, Identification of cells and signaling mechanisms underlying opioid analgesia and side effects (5R01DA044481-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165682. Licensed CC0.

---

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