# Regulated trafficking and compartmentalized signaling of opioid receptors

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $461,789

## Abstract

This proposal addresses an exciting aspect of the biology of the delta opioid receptor (DOR), a prototypical
and clinically relevant G protein-coupled receptor (GPCR) that has long been considered a promising target for
treating pain and opioid addiction - two highly prevalent and comorbid diseases. Pain, one of the most common
symptoms presented at hospitals, is currently managed primarily by opioid analgesics that target the mu-opioid
receptor. While effective, their use is highly limited due to extensive side effects and a high potential for addiction.
DOR activation is a promising alternate strategy to reduce pain without causing addiction as the receptor is not
expressed much in the reward pathway. While the contribution of DOR-expressing neurons to distinct modalities
of pain is being heavily explored, the critical problem with this strategy is that effectively targeting DOR in vivo
has been difficult. DOR agonists activate the receptor and signal efficiently in isolated systems, but they show
poor analgesic responses in vivo. Centrally acting DOR agonists can inhibit pain at high doses in animal models,
but they also induce convulsions which preclude their use. This low analgesic effectiveness in vivo, which is a
critical limiting factor in developing analgesics targeting DOR, is being studied at various levels including at the
pharmacological and neural circuit level. However, we still do not fully understand the mechanisms underlying
this low effectiveness. Interestingly, DOR is unique when compared to many other GPCRs in that it localizes
mostly to intracellular compartments, with very little expressed on the cell surface. Our proof of mechanism
experiments showing that relocating DOR to the neuronal surface increases the effectiveness of DOR agonists,
suggesting the exciting idea that this intracellular location is what contributes to the low analgesic potency.
Understanding how and why DOR is intracellular in neurons is therefore critical to understand opioid physiology
and to develop DOR as a target for pain management. This proposal addresses the mechanisms and
consequences of DOR localization to intracellular compartments in neurons. We hypothesize that sequence-
specific interactions of DOR mediate retention of newly synthesized DOR in intracellular compartments in
neurons and allow compartment-specific signaling. We will test our hypothesis by determining the mechanisms
of DOR intracellular retention and testing the role of these mechanisms in compartment-specific DOR signaling.
Specifically, we will follow two aims, 1) To determine the mechanisms regulating DOR localization in intracellular
compartments, and 2) To investigate compartment-specific DOR signaling from intracellular membranes. We
will use focused candidate-based and unbiased genome-wide approaches to pursue these aims. Completion of
this project will validate a novel and physiologically relevant model for how DOR is localized to intracellular
compartments in neurons...

## Key facts

- **NIH application ID:** 10886036
- **Project number:** 5R01DA055026-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Manojkumar A Puthenveedu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $461,789
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886036

## Citation

> US National Institutes of Health, RePORTER application 10886036, Regulated trafficking and compartmentalized signaling of opioid receptors (5R01DA055026-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10886036. Licensed CC0.

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