While opioids are effective pain relievers, they are also highly rewarding and overuse of them often leads to addiction. Despite great efforts to minimize the use of opioids, they are still the mainstay of treatment for acute pain. While there was an approximate 20% decrease in deaths due to opioid drug overdoses last year, it remains one of the leading causes of death in Americans under 50 years of age.
In collaboration with researchers from Temple University –Anjali Rajadhyaksha, PhD, and Arlene Martinez-Rivera, PhD – and The Center for Youth Mental Health at NewYork-Presbyterian, Francis Lee, MD, PhD, psychiatrist-in-chief at NewYork-Presbyterian and Weill Cornell Medicine, has been studying the potential role that endocannabinoids could play in opioid addiction.
Below, Dr. Lee discusses his results from a recent preclinical study suggesting that we may be able to blunt the rewarding properties of opioids while retaining the analgesic effects by enhancing endocannabinoid levels in the brain.
Research Background
Historically, my primary area of research is not opioids or cannabinoids but rather focused on how the brain can contend with various types of stressors and environmental challenges. Endogenous cannabinoids in the brain act similarly to exogenous cannabinoids, binding to the same receptor in many ways. These endogenous cannabinoids are involved in various neuronal functions and act like plasticity factors, making neurons adaptable to different scenarios.
I was doing foundational research investigating the role of endocannabinoids in fear and anxiety when we made an interesting discovery that there might be some crosstalk between the cannabinoid system and the opioid system. This led to the question of whether there is an additive, synergistic, or antagonistic relationship between these two major systems in the brain.
Research Methods
The purpose of our study was to test the biological impact of increasing endocannabinoids on opioid reward behavior. Two endocannabinoids exist in the brain, including 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide). The endogenous levels of these endocannabinoids are regulated by two catabolic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). To increase the half-life of the endocannabinoids, we pharmacologically inhibited MAGL and FAAH.
We used the FAAH inhibitor PF-3485 and the MAGL inhibitor JZL184 in a standard opioid reward behavioral paradigm. This included a self-administration paradigm, which is the closest to IV self-administration in humans, where mice are trained to lever press for IV injections of oxycodone. We also measured brain dopamine transmission using fiber photometry with fluorescent sensors.
We were able to blunt opioid reward while preserving the analgesic properties of the opioids, upending what the prevailing theory about endocannabinoids and opioids.
— Dr. Francis Lee
Key Findings
The prevailing theory is that combining endocannabinoids and opioids should exacerbate addictive behaviors synergistically. However, we were able to blunt opioid reward while preserving the analgesic properties of the opioids, upending what the prevailing theory about endocannabinoids and opioids While we found that anandamide did not affect opioid behavior, enhancing levels of 2-AG significantly inhibited two forms of opioid reward behavior, including substantially reducing lever pressing for oxycodone. We also found that enhancement of 2-AG substantially decreased dopamine transmission, suggesting that we had been able to affect the reward circuit specifically. In addition, there were no effects of the MAGL inhibitor on opioid-induced analgesia.
This confocal microscope image shows midbrain neurons (red) co-expressing the mu-opioid receptor (Oprm1, white) and cannabinoid receptor 1 (Cnr1, green). The interaction of these two reward pathways in brain regions may be involved in decreasing the reward effects of opioids. Credit: Rajadhyaksha Lab
The endogenous system is much more powerful than we thought. It can actually blunt exogenous agents that have previously been so powerful in overtaking the reward system.
— Dr. Francis Lee
In the brain, there are relatively low levels of endocannabinoids. Despite that, these small amounts of endocannabinoids are having substantial effects on exogenous oxycodone. This tells us that the endogenous system is much more powerful than we thought. It can actually blunt exogenous agents that have previously been so powerful in overtaking the reward system.
Future Directions
There is a mystery that we must work on going forward: Why is it that the distribution of the opioid receptors and cannabinoid receptors seems to be in the right ratio so that endocannabinoids can blunt the opioid reward system, but in the pain pathways, that doesn't seem to be true?
Dr. Rajadhyaksha, who is a neuroscientist at Temple University and an adjunct professor of neuroscience research in pediatrics at Weill Cornell Medicine, and I received a 5-year National Institute on Drug Abuse (NIDA) grant to expand on our findings to understand the underlying mechanism of how we separate the rewarding versus the analgesic properties. As a psychiatrist and a physician-scientist, I'm also intensely interested in how we can translate this foundational basic neuroscience finding into the clinic.
Further, the fact that we already have MAGL inhibitors in phase two clinical trials for other indications suggests that the compounds are safe. Ultimately, you can imagine a strategy where you use these MAGL inhibitors as adjunctive agents that you would take along with opioids for acute pain control to reduce the risk of addiction substantially.
