January 25, 2023 - Podcast

Episode 340 — Blocking the reward response to opioids

Indiana University researchers have potentially discovered a new way to block the brain’s reward response to opioids, reducing their potential for addiction without reducing their therapeutic aspects.

The opioid epidemic profoundly increased drug overdose deaths globally – an increase that has been further exacerbated by the COVID-19 pandemic. While opioid therapy is effective for short-term pain management, its long-term use for chronic pain management is limited by adverse side effects, including addiction, tolerance and physical dependence.

Despite recent changes in prescribing guidelines, opioids continue to be used in patients at elevated risk for abuse, says Andrea Hohmann, a Linda and Jack Gill Chair of Neuroscience and Professor of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. This highlights the urgent need to identify novel therapeutic strategies to circumvent opioid abuse liability while sparing therapeutic efficacy.

Led by Hohmann, the researchers collaborated with Northeastern University chemists, who previously developed a drug candidate called GAT358 to treat alcohol addiction, but it had never been tested with opioids. In a preclinical study in rodents, Hohmann’s team demonstrated that they could use the drug to successfully block opioid reward while maintaining its therapeutic benefits and avoiding negative side effects. Other drug candidates which directly block the signaling of a protein called cannabinoid receptor 1 exist, or CB1, but they have negative side effects including depression, anxiety and suicidality. GAT358 potentially avoids these side-effects by selectively reducing the signaling of CB1.

Hohmann says the results support the therapeutic potential of these novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side effects.

Opioid reward and reinforcement, which can lead to addiction, requires communication between the brain’s endocannabinoid system and endogenous opioid system, which regulates pain, reward and addictive behaviors.

Vishakh Iyer, a former postdoctoral and graduate student researcher in Hohmann’s lab who graduated from IU in December 2021 with a Ph.D. in neuroscience and psychology, said most research to date has focused on the endogenous opioid system.

Iyer says to think of the problem as if you’re trying to parallel park in a tight spot. The car in front of you is pain. The car behind you is addiction. You’re constantly checking front and back to make sure you don’t hit either car.

But instead of trying to squeeze into this tight spot between pain and addiction, Iyer says the researchers’ findings suggest that the easiest option may be to just to park somewhere else.

Humans have a fascinating endocannabinoid system which is within them, says Iyer. Harnessing this system could potentially be a way of overcoming opioid addiction and avoiding unwanted side effects.

The team said more research is needed to study how GAT358 affects other aspects of opioid use and addiction, such as tolerance and withdrawal symptoms.