IU researchers potentially discover new way to block brain’s 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. Their findings were published in the journal Pharmacological Research.

The opioid epidemic has 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.

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 GAT358 to reduce the signaling of a protein called cannabinoid receptor 1, or CB1, to successfully block opioid reward while maintaining its therapeutic benefits and avoiding negative side effects. Other drug candidates that directly block CB1 signaling exist, but they have negative side effects including depression, anxiety and suicidality.

“Our results support the therapeutic potential of GAT358 and other CB1 negative allosteric modulators as novel drug candidates aimed at preventing opioid reward and treating opioid abuse while avoiding unwanted side effects,” Hohmann said.

CB1 is part of the endocannabinoid system, which was discovered by scientists in the 1990s. They found that the human body naturally produces chemicals like those found in cannabis on its own, without the need to take any external substances.

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.

“Think of the problem as if you’re trying to parallel park in a really tight spot,” said Iyer, who is the first author on the study. “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 really tight spot between pain and addiction, he said the researchers’ findings suggest that the easiest option may be to just to park somewhere else.

“We have this really fascinating endocannabinoid system which is within all of us,” Iyer said. “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.

Other IU researchers on the study include Claudia Rangel-Barajas, Taylor J. Woodward, Jonathon D. Crystal, Ken Mackie and George V. Rebec. Northeastern University researchers on the study include Abhijit Kulkarni, Lucas Cantwell and Ganesh Thakur.