R01DA054368

Circuit and Synaptic Mechanisms of Endocannabinoid-Opioid Crosstalk - Project Summary

For the past decade, the use of opioids has risen dramatically in the United States. The disproportionate increase in opioid dependence and overdose deaths 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.

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 of opioids while preserving their powerful analgesic properties.

The 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.

Temple University-Of The Commonwealth System Of Higher Education

NOT APPLICABLE

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Philadelphia, Pennsylvania 191404106 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 341% from $786,660 to $3,472,531.