# Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $667,788

## Abstract

Project Summary
For the past decade, the use of opioids has risen dramatically in the United States and the disproportional
increase in opioid dependence and overdose death has led to the current opioid crisis. Although different
measures have been taken to reduce opioid overutilization for pain management, opioid use in clinics continues
leading to dependence and overdose. In
there is a compelling need for non-opioid
use
of
pharmacological
addition, for the significant number of people with opioid use disorder,
pharmacological therapies to complement current treatments for opioid
disorder. A major challenge is to develop new treatment strategies that can attenuate the rewarding aspects
opioids while preserving their powerful analgesic properties.
 endocannabinoid (eCB) system serves as a potential target for the development of new
 treatments as a complement to opioid based treatments. Several lines of evidence suggest
The
functional interaction between the opioid and the eCB system at the level of neurochemical, neuroanatomical
and molecular pathways. Our preliminary results find that indirectly enhancing levels of the endocannabinoid 2-
AG levels through pharmacological inhibition of its catabolic enzyme, monoacylglycerol lipase (MAGL),
attenuates the rewarding effects of morphine, while maintaining its analgesic effects. In this proposal we will
dissect at a circuit, synaptic and molecular level how elevated 2-AG attenuates opioid reward.
 Recent studies have underscored the role of local GABAergic neuronal inputs from the rostromedial
tegmental nucleus (RMTg) in regulating the ventral tegmental area (VTA), a key dopaminergic brain region
involved in opioid reward. Opioids are thought to act by disinhibiting RMTg inhibition onto VTA dopamine neurons
by activating presynaptic mu opioid receptors (MOR), subsequently increasing dopamine cell firing and nucleus
accumbens (NAc) activity that drives reward. However, little is known about how cannabinoid receptors (CB1R)
and MORs signal and crosstalk at these key synapses. Aim 1 will examine 2-AG mechanisms in the VTA on
opioid reward behavior and its effect on NAc dynamics. Aim 2 will examine the role of CB1R and MOR in the
RMTg→VTA projection on opioid reward behavior and NAc dynamics. Aim 3 will examine synaptic and molecular
mechanisms of CB1R and MOR crosstalk to determine how enhancing 2-AG levels leads to blunted opioid
reward.

## Key facts

- **NIH application ID:** 10864004
- **Project number:** 5R01DA054368-04
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Francis Sang Yong Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $667,788
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864004

## Citation

> US National Institutes of Health, RePORTER application 10864004, Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk (5R01DA054368-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10864004. Licensed CC0.

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