Since the 1990s, deaths due to opioid overdoses have become a leading cause of death for Americans under age 50. While a portion of these deaths are due to recreational use of opioids, many others can be traced to people who became dependent after being prescribed FDA-approved opioid-based drugs, typically for the relief of acute or chronic pain.

Now, a team including BBRF Scientific Council member and three-time BBRF grantee Francis S. Lee, M.D., Ph.D., of Weill Cornell Medicine, and collaborators Anjali Rajadhyaksha, Ph.D., and Arlene Martinez-Rivera, Ph.D., now at Temple University, report finding a way to significantly blunt the rewarding properties of opioids while preserving their analgesic (i.e., pain-relieving) properties. The new research appears in the journal Science Advances and could indicate a potentially new therapeutic strategy for opioid-related pain treatments. Four other BBRF grantees were members of the team.

The widespread prevalence of opioid use disorder and the high mortality associated with opioid misuse in connection with medical treatment for pain “has highlighted the urgent need to develop non-opioid analgesic alternatives,” write Dr. Lee and colleagues. But “an additional strategy,” they note, “is to develop adjunctive treatments that can specifically attenuate the rewarding but not the analgesic properties of opioids.”

The team tested its approach in mice undergoing various behavioral tasks tied to opioid rewards. The team’s approach was to pharmacologically enhance the brain’s endocannabinoid system. This system, which is naturally occurring, helps regulate a wide range of functions in the body ranging from cognition to appetite, mood, memory, and pain, among others. Two endocannabinoid compounds, neuromodulators usually referred to by their chemical abbreviations 2-AG and AEA, interact with cannabinoid receptors called CB1 in cells throughout the body. These receptors are widespread in the central nervous system and play key roles in regulating the release of neurotransmitters such as dopamine.  

One key place in the brain where 2-AG and AEA interact with CB1 receptors is in the circuit linking the ventral tegmental area (VTA) and the nucleus accumbens (NAc), which are central to the brain’s reward system. This circuit is at the core of the opioid reward response. When a person (or mouse) ingests an opioid, dopamine levels in the NAc increase markedly, an action that has been directly linked with the feeling of reward that occurs after taking the drug.        

Much research has been devoted to understanding how the endocannabinoid system works, and how it is perturbed by chronic or acute drug use. Cannabis from plants targets the CB1 receptor. Abuse of cannabis is thought to dysregulate the body’s endocannabinoid system, with various potential impacts including dependency.  

Studies of the interplay between the endocannabinoid system and opioid reward has mainly focused on two enzymes (called catabolic enzymes) that tightly regulate the level of the two endocannabinoid molecules, 2-AG and AEA. One of these enzymes, called MAGL, breaks down 2-AG. Another, called FAAH, breaks down AEA. Previous research has indicated that inhibiting these two enzymes has distinct and sometimes opposing effects on opioid reward, highlighting the complexity of these systems.  

Drs. Martinez-Rivera, Rajadhyaksha, and Lee set out to systematically study and clarify the specific impact of raising 2-AG and AEA levels in the brain upon the rewarding effect of opioid intake. Using a MAGL inhibitor called JZL184, the team conducted experiments throughout the mouse system as well as in a specific brain region. They found that raising levels of 2-AG greatly reduced opioid reward in various opioid reward tests, including in mice trained to self-administer oxycodone intravenously. Interestingly, using a different compound to raise levels of the other endocannabinoid, AEA, had no effect on morphine reward.  

Further experiments focused on the circuitry known to be involved in reward. When the researchers blocked MAGL in the mouse brain’s VTA, they found that the rewarding effects of morphine were reduced. They also observed that a decrease in reward was linked to lower activity of the NAc and lower levels of dopamine.  

In short, the experiments demonstrated that 2-AG selectively dampens the rewarding effects of opioids—by disrupting signaling between the VTA and NAc. Equally important, while JZL184 substantially reduced opioid reward, two separate tests demonstrated that it had no effect on the analgesic properties of the opioids tested.  

For this reason, the team concluded that their findings “provide a compelling rationale for developing a new class of adjunctive endocannabinoid-based treatments that could dissociate the rewarding and analgesic properties of opioids.”  In other words, they say, it may be possible to develop a drug similar to JZL184 that can be taken alongside an opioid to treat chronic or acute pain while greatly reducing (or even eliminating) the risk of addiction.  

Developing a drug treatment that alleviates pain without the addictive side effects of opioids could be a major step toward addressing one key component of the opioid crisis, the team said. “By targeting the brain’s reward system without affecting pain relief, we may be able to create a treatment that provides the benefits of opioids while avoiding their addictive potential--an exciting step forward,” said Dr. Rajadhyaksha.

The team also included Conor Liston, M.D., Ph.D., 2013 BBRF Young Investigator; Virginia M. Pickel, Ph.D., 2001 BBRF Distinguished Investigator; Lisa A. Briand, Ph.D. 2015 BBRF Young Investigator; and Kristen Pleil, Ph.D., 2017 BBRF Young Investigator.  Dr. Lee, in addition to being a member of the BBRF Scientific Council, is a 2010 BBRF Independent Investigator and 2005 and 2002 Young Investigator.