# Chemical biology tools for illuminating cannabinoid signaling pathways in opioid use disorder.

> **NIH NIH DP1** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $421,200

## Abstract

Project Summary/Abstract
The opioid epidemic is a persistent public health crisis in the United States and abroad, historically dominated
by the misuse of prescription opioids and heroin; however, those illicit substances have been overtaken by a
surge in the synthetic opioid fentanyl. Fentanyl’s unmatched potency and addictiveness makes it more difficult
to treat with pharmaceuticals that act on opiate receptors directly; as a result, opioid overdose deaths in the
U.S. skyrocketed to more than 80,000 in 2021. Novel therapeutic approaches to manage this crisis are
urgently needed, making understanding basic opiate signaling mechanisms in the brain critically important.
 A potential target to mitigate opioid use disorder (OUD) are the cannabinoid receptors (CBRs), which are
co-expressed alongside opiate receptors in the brain’s reward centers. Recent studies indicate that CBRs can
modulate opioid-reward behaviors; however, our understanding is challenged by multiple CBR subtypes that
have dynamic and overlapping expression in the brain. Antibodies for CBRs can be nonspecific and provide
only a snapshot of receptor localization, and conventional approaches to manipulate CBRs have poor spatial
and temporal resolution: Genetic knock-outs are prone to compensation, while microinjection or wash-on of
hydrophobic cannabinoid ligands suffer from poor kinetics and don’t distinguish between CBRs on overlapping
circuits. To delineate the role(s) of CBRs in opioid reward and as a potential therapeutic target for OUD, there
is a critical need for new tools to probe their localization and manipulate their signaling with high resolution.
The long-term goal of my lab is to build chemical tools for deconvoluting the molecular components of
substance use disorder, and I have pioneered several chemical biology technologies to study CBRs with
enhanced spatiotemporal precision. In collaboration with Erick Carreira’s lab, we developed fluorescent probes
that label CB1 and CB2 cannabinoid receptors with a fluorophore. These overcome the poor selectivity of
antibodies and can be applied to live-cell imaging experiments. We also developed chemical photoswitches
allowing acute reversible optical manipulation of CB1 and CB2, which permits control of downstream signaling
by a precise optical stimulus. The objective of this proposal is to expand our cannabinoid chemical biology
toolkit towards the atypical cannabinoid receptor GPR55, and then apply these tools in ex vivo and in vivo
models of opioid administration. We will explore the interactions between cannabinoid and opiate receptors in
the ventral tegmental area (VTA), a critical hub in the brain’s reward system. This proposal has a strong
scientific premise built on our published studies, preliminary data, and a careful review of the literature. It is
innovative because it applies our state-of-the-art tools to illuminate basic signaling mechanisms relevant to
opioid reward and could generate novel therapeutic avenues f...

## Key facts

- **NIH application ID:** 10903650
- **Project number:** 1DP1DA060496-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** James Allen Frank
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,200
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903650

## Citation

> US National Institutes of Health, RePORTER application 10903650, Chemical biology tools for illuminating cannabinoid signaling pathways in opioid use disorder. (1DP1DA060496-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903650. Licensed CC0.

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