Natural Compound Could Counter Opioid Addiction Without Sacrificing Pain Relief
Boosting the endocannabinoid 2-AG within the mind can counteract opioid dependancy whereas preserving their ache reduction, a Weill Cornell Medicine research finds. This method, examined in mice utilizing the chemical JZL184, could result in safer remedies for ache administration.
The pure enhancement of chemical compounds produced by the body, referred to as endocannabinoids, could mitigate the addictive properties of opioids like morphine and oxycodone whereas preserving their pain-relieving results, in line with researchers from Weill Cornell Medicine in collaboration with The Center for Youth Mental Health at NewYork-Presbyterian. Endocannabinoids work together with cannabinoid receptors discovered all through the body, which play a task in regulating features corresponding to studying and reminiscence, feelings, sleep, immune response, and urge for food.
Opioids prescribed to regulate ache can develop into addictive as a result of they not solely uninteresting ache, but additionally produce a way of euphoria. The preclinical research, revealed just lately within the journal Science Advances, could result in a brand new sort of therapeutic that might be taken with an opioid routine to solely scale back the reward facet of opioids.
In 2023, opioid abuse or overuse was chargeable for greater than 80,000 deaths, fueling a nationwide disaster, in line with the U.S. Centers for Disease Control and Prevention. Illegally obtained medication have been finally chargeable for many deaths, however not all of them. “When someone has surgery and is taking opioids for pain management, there’s always a risk of developing a dependence on these drugs,” stated senior writer Dr. Francis Lee, chair of the Department of Psychiatry at Weill Cornell Medicine and psychiatrist-in-chief at New York-Presbyterian/Weill Cornell Medical Center.
The co-senior writer is Dr. Anjali Rajadhyaksha, adjunct professor of neuroscience analysis in pediatrics at Weill Cornell Medicine and director of the Center for Substance Abuse Research at Lewis Katz School of Medicine at Temple University. The first writer, Dr. Arlene Martinez-Rivera, was an teacher in Dr. Rajadhyaksha’s lab on the time of the research and is now an assistant professor on the Katz School of Medicine.
A Different Perspective
None of the researchers have been finding out opioids once they started this challenge. Dr. Lee was investigating the position of endocannabinoids in concern and anxiousness. Next door, Dr. Rajadhyaksha was finding out mouse fashions of cocaine dependancy. They determined to work collectively when stories within the literature recommended that the opioid system may probably work together with the endocannabinoid system’s advanced community of chemical compounds and receptors.
Just as opioids stimulate the mind’s reward system to launch dopamine, so do the naturally occurring endocannabinoids and associated medication, corresponding to tetrahydrocannabinol (THC), the substance in marijuana that produces a “high.” Although they’ve comparable results, endocannabinoids and THC each act via cannabinoid receptors and opioids work together with totally different receptors.
Surprisingly, the findings additionally upend the central dogma within the opioid subject that combining endocannabinoids and opioids ought to exacerbate addictive behaviors in a synergistic manner. “By both of us not being members of the opioid field, we came up with the counterintuitive idea that one system might actually block the other system from having effects on reward,” stated Dr. Lee, who can be a professor of neuroscience on the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
Surprising Interaction of Reward Systems
Running with that concept, Dr. Martinez-Rivera examined elevating the 2 essential endocannabinoids— first, anandamide (AEA) after which 2-AG—in mice. “We got lots of negative results initially while studying AEA, and we were actually going to give up on the project,” she stated. “But then we switched to 2-AG and got positive findings.” Increasing the degrees of 2-AG counteracts the rewarding properties of opioids, dampening behaviors related to opioid dependancy, but nonetheless controlling ache in a mouse mannequin.
The researchers used a chemical referred to as JZL184 that stops 2-AG from breaking down thereby growing the extent of this endocannabinoid within the mind. In separate assays, the crew discovered much less addiction-associated habits when mice have been handled with a low dose of JZL184 earlier than being given morphine or oxycodone.
In ache assays, mice handled with JZL184 nonetheless appeared to expertise the pain-relieving results of morphine and oxycodone. “This suggests that endocannabinoids and opioids may not act together in areas of the brain and spinal cord involved in analgesia,” Dr. Rajadhyaksha stated. “In contrast, their interaction in brain regions is involved in decreasing reward and dependence.”
Additional experiments confirmed that 2-AG exerts its impact via the CB1 cannabinoid receptor within the ventral tegmental space, a gaggle of neurons within the midbrain that performs a key position in reward and motivation. Elevating 2-AG ranges additionally lowered dopamine signaling, a key ingredient of the reward system.
“This is one of the first examples showing that engaging the endocannabinoid system can have an antagonistic effect on another reward system—in this case, the opioid system,” Dr. Rajadhyaksha stated.
Potential medication like JZL184 are at the moment being examined in scientific trials as doable remedies for anxiousness problems, so Dr. Lee is optimistic concerning the timeline for testing them together with opioids for ache administration in people. “We’re thinking about this methodically and working toward translating these preclinical findings to help patients,” Dr. Lee stated.
Reference: “Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia” by Arlene Martínez-Rivera, Robert N. Fetcho, Lizzie Birmingham, Jin Xu, Ruirong Yang, Careen Foord, Diego Scala-Chávez, Narmin Mekawy, Kristen Pleil, Virginia M. Pickel, Conor Liston, Carlos M. Castorena, Joshua Levitz, Ying-Xian Pan, Lisa A. Briand, Anjali M. Rajadhyaksha and Francis S. Lee, 29 November 2024, Science Advances.
DOI: 10.1126/sciadv.adq4779
This work was supported by the National Institutes of Health via grant numbers DA054368, MH123154, DA029122, R01 DA053261, R01 MH125006, R01 MH118934, R01 DA050454, DA042888, DA051529, DA042943, DA048635, DA047851, MH109685, MH118451, DA047265, DA049837, 5F30MH115622, and by The Center for Youth Mental Health at NewYork-Presbyterian, the Gelband Family Foundation, The Paul Fund, the Pritzker Neuropsychiatric Disorders Research Consortium, a Rohr Family Research Scholar Award, an Irma T. Hirschl/Monique Weill-Caulier Research Award, the Hope for Depression Research Foundation, the Rita Allen Foundation and the National Science Foundation via grant quantity GRFP #2139291.
