# Molecular genetic mechanisms of opioid receptor signaling

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2020 · $425,000

## Abstract

Summary
Opioid drugs are the most widely used analgesics in the clinic and are also some of the most widely abused
substances. The adverse actions of these drugs, including peripheral side effects, dependence and tolerance,
severely limit their utility for long term pain management. The µ-opioid receptor (MOR) is the primary target of
the analgesic and rewarding effects of opioids. Thus, efforts aimed at developing safer and more effective opioid
treatments will require a much deeper understanding of MOR signaling.
 Our long-term goal is to use unbiased forward genetics to dissect the molecular organization of the
MOR signaling network using whole-animal behavioral responses to opioids as a phenotypic readout. Towards
this goal, we developed a transgenic MOR model (tgMOR), in which mammalian MOR is expressed in the
nervous system of the nematode C. elegans. We found that tgMOR animals gain the ability to respond to opioids
and exhibit all the cardinal behavioral hallmarks of opioid responses seen in higher organisms including acute
depressant effects, desensitization and tolerance. We further demonstrated key known molecular players that
control opioid responsiveness in mammals play conserved functions in tgMOR worms. Using this novel tgMOR
model, we have completed an unbiased, forward genetic screen for modifiers of behavioral opioid sensitivity,
and isolated a large number of mutants with altered opioid responses. We have developed a pipeline for
discovery, identification and validation of genes responsible for phenotypes using a combination of whole
genome sequencing, mapping and targeted CRISPR/Cas9 gene editing. Using this approach, we uncovered
several known and novel genes that regulate opioid responsiveness in worms and confirmed their effects on
MOR signaling using cell-based assays with cultured mammalian cells.
 Our findings suggest an elaborate, largely unknown, network of players exists to regulate MOR signaling.
Thus, the main effort of this project focuses on identifying and characterizing these players by analyzing tgMOR
mutants isolated from our unbiased, forward genetic screen. Our first aim will be to identify the genes
responsible for 1) hypersensitivity, 2) hyposensitivity, and 3) impaired tolerance to opioid drugs by pursuing a
subset of mutants from each phenotypic category. In the second aim, we will validate and perform mechanistic
studies on identified, conserved regulators of MOR signaling using a comprehensive platform of cell-based
assays that monitor various aspects of MOR signaling. The third aim will focus on exploring the
pharmacogenomics by which MOR impacts behavior. To do so, we analyze interactions between genetic MOR
variants found naturally in the human population, FDA-approved opioid drugs, and different genetic backgrounds
using a humanized tgMOR C. elegans platform. It is anticipated that these studies will advance our understanding
of how opioids act thereby paving the way for the development of safer op...

## Key facts

- **NIH application ID:** 10321847
- **Project number:** 7R01DA048036-03
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** Brock Grill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,000
- **Award type:** 7
- **Project period:** 2020-12-31 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321847

## Citation

> US National Institutes of Health, RePORTER application 10321847, Molecular genetic mechanisms of opioid receptor signaling (7R01DA048036-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10321847. Licensed CC0.

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