# Spatiotemporal signaling and trafficking of the mu-opioid receptor

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $613,700

## Abstract

SUMMARY
Opioids are the most effective analgesics but are associated with severe side effects including respiratory
depression, tolerance, and addiction. These factors helped cause the opioid abuse epidemic in the US, making
drug overdose the leading cause of accidental death in the US. Thus, the identification of safer analgesics with
diminished side effects and abuse potential is critical to address the ongoing crisis. Clinically used opioids
predominantly exert both their analgesic and adverse effects through their action on the µ-opioid receptor (MOR).
While several approaches were taken towards safer analgesics, these efforts are limited by a lack of
understanding the complex biochemical networks engaged and activated by MOR in response to ligand binding.
This proposal builds on recent evidence suggesting that (1) MOR signaling is dependent on the interplay between
subcellular localization and membrane trafficking in a ligand-specific manner and (2) MOR shows ligand-
dependent effects on its protein interaction network and the signaling pathways it activates. Thus, delineating
the MOR-initiated signaling pathways for endogenous peptides and addictive opioids and how these are
coordinated by receptor location and trafficking provides potential new strategies for therapeutic modalities and
safer analgesics. The overarching goal of this proposal is to combine quantitative proteomics, functional
genomics, and opioid receptor biology to systematically discover and characterize regulators of MOR signaling
and trafficking in human induced pluripotent stem cell-derived neurons. We will combine proximity labeling mass
spectrometry and quantitative phosphoproteomics to systematically delineate interaction networks that MOR
engages and map the signaling pathways it activates. To study the functional role of proteomic targets in MOR
signaling and trafficking, we will develop and apply reporter assays for receptor signaling and trafficking in
CRISPRi gene regulation screens. Finally, we will test mechanistic hypotheses from proteomic and genetic
screens on how novel regulators of trafficking and signaling fine tune the cellular response of MOR activation.
Our proposed approach will yield mechanistic insights into MOR-initiated signaling pathways and how these are
regulated by receptor trafficking. Identifying key regulators of MOR activation will fill a critical gap for designing
safer, pathway selective analgesics and treatments for opioid addiction.

## Key facts

- **NIH application ID:** 10489609
- **Project number:** 1R01DA056354-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ruth Huttenhain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $613,700
- **Award type:** 1
- **Project period:** 2022-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489609

## Citation

> US National Institutes of Health, RePORTER application 10489609, Spatiotemporal signaling and trafficking of the mu-opioid receptor (1R01DA056354-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10489609. Licensed CC0.

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