# Molecular genetic mechanisms of opioid receptor signaling

> **NIH NIH R01** · SCRIPPS FLORIDA · 2020 · $216,882

## Abstract

Summary
Opioid drugs are the most widely used analgesics in 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 as prescription analgesics 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.
Taking advantage of this model, we 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 by pursuing a
subsets 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 to the development of s...

## Key facts

- **NIH application ID:** 10016286
- **Project number:** 5R01DA048036-02
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Brock Grill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $216,882
- **Award type:** 5
- **Project period:** 2019-09-15 → 2020-10-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016286

## Citation

> US National Institutes of Health, RePORTER application 10016286, Molecular genetic mechanisms of opioid receptor signaling (5R01DA048036-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016286. Licensed CC0.

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