# Adaptations following chronic opioid treatment and withdrawal

> **NIH NIH F30** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary
 Opioids such as morphine and fentanyl effectively relieve acute and post-operative pain but long-term
use is problematic due to their abuse liability. Long-term opioid use causes cellular and circuit level adaptations
that can lead to addiction, but the precise mechanisms are not fully understood. Furthermore, withdrawal from
opioids unmasks these adaptive changes facilitating increased drug intake and promoting relapse. This
proposal will use an optogenetic approach to isolate glutamate projection from both opioid sensitive (thalamic)
and insensitive (cortical) terminals coming into the striatum in mice. Whole-cell electrophysiological recordings
in brain slices will be used to investigate the mechanisms mediating adaptive changes following chronic opioid
treatment and withdrawal.
 Receptor phosphorylation is a key cellular event mediating acute desensitization and long-term
tolerance in cell-body specific µ-opioid receptors (MORs), but little is known about the role of phosphorylation
in mediating signaling in presynaptic terminal MORs. Experiments in Aim 1 will therefore elucidate the role of
phosphorylation in mediating acute sensitivity and long-term tolerance to both morphine and fentanyl after
chronic treatment in terminal MORs. Furthermore, adaptations following chronic treatment go beyond the
receptor level and can influence downstream second messengers like adenylyl cyclase. Adenylyl cyclase can
be metabolized to adenosine in central nervous system synapses to modulate glutamate release. Experiments
in Aim 2 will therefore focus on the mechanisms underlying release and regulation of adenosine in striatal
synapses, specifically the role of MORs in mediating adenosine concentration after chronic opioid treatment.
The overall hypothesis is that MOR phosphorylation is a key signaling event that establishes both acute
sensitivity and long-term tolerance to opioids, and activation of MORs plays a critical role in mediating the
concentration of adenosine in striatal synapses.
 Ultimately, the results from this study will address the role of phosphorylation in terminal MOR signaling
and determine receptor and cellular adaptations that result from chronic opioid treatment and withdrawal. By
looking at the effects of both morphine (a partial agonist) and fentanyl (a full agonist), a comprehensive
understanding of the role of receptor phosphorylation on synaptic transmission after chronic opioid exposure
will be established. Understanding the key receptor and cellular changes that mediate synaptic activity after
chronic opioid treatment is a crucial first step in identifying novel therapeutic targets to treat opioid use
disorder.

## Key facts

- **NIH application ID:** 9989501
- **Project number:** 1F30DA051117-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Sweta Adhikary
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989501

## Citation

> US National Institutes of Health, RePORTER application 9989501, Adaptations following chronic opioid treatment and withdrawal (1F30DA051117-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989501. Licensed CC0.

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