# CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2021 · $517,184

## Abstract

Despite significant limitations, opioids remain a mainstay for the treatment of severe acute and chronic pain.
Two clinically significant limitations that accompany the long-term therapeutic use of opioids are: (1) The
development of tolerance (requiring escalating doses of opioid to maintain the desired therapeutic benefit or
leading to diminished benefit with constant dose) and (2) Physical dependence (withdrawal symptoms on
cessation of opioid use, which are very unpleasant, and seeking their avoidance may increase the risk for
opioid addiction). Currently, there are no practical approaches for decreasing opioid tolerance or suppressing
the development of physical dependence. However, in exploring potential interactions between CB2
cannabinoid receptor (CB2R) and mu opioid receptor (MOR) signaling, we made the exciting discovery that
certain CB2 agonists effectively prevented the development of tolerance to opioid-induced anti-allodynic
efficacy in a murine neuropathic pain model, while also blunting the physical dependence that accompanies
chronic morphine exposure. These findings, if they can be translated to humans, hold the promise to
significantly improve the clinical use of opioids. On the path to translating these findings, we will complete
three specific aims to better understand how CB2 and mu opioid receptor agonists interact to suppress opioid
tolerance and dependence:
Aim 1: Identify the CB2-expressing cells engaged by LY28282360 to prevent opioid tolerance. We will
delineate the cell types responsible for the ability of LY2828360 to block development of morphine tolerance
and identify site of action using both pharmacological manipulations and a conditional deletion approach.
Separate studies will target primary afferent nociceptors vs. microglia.
Aim 2: Define the conditions under which CB2 agonists suppress opioid-induced physical dependence.
We will delineate the cell types responsible for the effects of LY2828360 on opioid dependence, as measured
using naloxone precipitated opioid withdrawal, using both pharmacological manipulations and a conditional
deletion approach. Separate studies will target primary afferent nociceptors vs. microglia.
Aim 3: Mechanistic characterization of CB2R/MOR interaction. We will characterize CB2 ligands for their G
protein/arrestin signaling bias as well as their kinetics of G protein activation. We will also determine if the slow
activation of G protein signaling by LY2828360 and related CB2 agonists is due to the kinetics of receptor
binding. Finally, if the results of Aims 1 or 2 suggest that MOR and CB2R are interacting in the same cell, we
will characterize the differences in CB2R/MOR crosstalk between slowly and rapidly signaling CB2 agonists.
Completion of these aims will fully characterize interactions between CB2 and opioid receptors in preclinical
and cell-based models. These studies will help define the clinical settings where CB2 agonists may be useful in
countering two major limitatio...

## Key facts

- **NIH application ID:** 10117221
- **Project number:** 5R01DA047858-03
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Andrea Grace Hohmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,184
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117221

## Citation

> US National Institutes of Health, RePORTER application 10117221, CB2 Cannabinoid Mechanisms for Suppressing Opioid Tolerance and Dependence (5R01DA047858-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10117221. Licensed CC0.

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