Rising the degrees of chemical substances naturally produced within the physique known as endocannabinoids could thwart the extremely addictive nature of opioids corresponding to morphine and oxycodone whereas sustaining the medicine’ capability to alleviate ache, in keeping with Weill Cornell Medication investigators working with researchers from The Middle for Youth Psychological Well being at NewYork-Presbyterian. Endocannabinoids bind to cannabinoid receptors all through the physique that regulate actions, corresponding to studying and reminiscence, feelings, sleep, immune response and urge for food.
Opioids prescribed to manage ache can grow to be addictive as a result of they not solely boring ache, but in addition produce a way of euphoria. The preclinical examine, printed Nov. 29 in 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 keeping with the U.S. Facilities for Illness Management and Prevention. Illegally obtained medicine had been in the end chargeable for many deaths, however not all of them.
When somebody has surgical procedure and is taking opioids for ache administration, there’s all the time a threat of growing a dependence on these medicine.”
Dr. Francis Lee, senior creator, chair of the Division of Psychiatry at Weill Cornell Medication and psychiatrist-in-chief at New York-Presbyterian/Weill Cornell Medical Middle
The co-senior creator is Dr. Anjali Rajadhyaksha, adjunct professor of neuroscience analysis in pediatrics at Weill Cornell Medication and director of the Middle for Substance Abuse Analysis at Lewis Katz Faculty of Medication at Temple College. The primary creator, Dr. Arlene Martinez-Rivera, was an teacher in Dr. Rajadhyaksha’s lab on the time of the examine and is now an assistant professor on the Katz Faculty of Medication.
A unique perspective
Not one of the researchers had been learning opioids once they began this undertaking. Dr. Lee was investigating the function of endocannabinoids in concern and anxiousness. Subsequent door, Dr. Rajadhyaksha was learning mouse fashions of cocaine habit. They determined to work collectively when experiences within the literature instructed that the opioid system might doubtlessly work together with the endocannabinoid system’s complicated community of chemical substances and receptors.
Simply as opioids stimulate the mind’s reward system to launch dopamine, so do the naturally occurring endocannabinoids and associated medicine, corresponding to tetrahydrocannabinol (THC), the substance in marijuana that produces a “excessive.” Though 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 means. “By each of us not being members of the opioid subject, we got here up with the counterintuitive concept that one system may truly block the opposite system from having results on reward,” stated Dr. Lee, who can be a professor of neuroscience on the Feil Household Mind and Thoughts Analysis Institute at Weill Cornell Medication.
Shocking interplay of reward techniques
Working with that concept, Dr. Martinez-Rivera examined elevating the 2 fundamental endocannabinoids— first, anandamide (AEA) after which 2-AG—in mice. “We obtained a number of destructive outcomes initially whereas learning AEA, and we had been truly going to surrender on the undertaking,” she stated. “However then we switched to 2-AG and obtained constructive findings.” Rising the degrees of 2-AG counteracts the rewarding properties of opioids, dampening behaviors related to opioid habit, but nonetheless controlling ache in a mouse mannequin.
The researchers used a chemical known as JZL184 that forestalls 2-AG from breaking down thereby rising the extent of this endocannabinoid within the mind. In separate assays, the group discovered much less addiction-associated conduct when mice had 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 implies that endocannabinoids and opioids could not act collectively in areas of the mind and spinal wire concerned in analgesia,” Dr. Rajadhyaksha stated. “In distinction, their interplay in mind areas is concerned in lowering reward and dependence.”
Extra 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 function in reward and motivation. Elevating 2-AG ranges additionally lowered dopamine signaling, a key component of the reward system.
“This is among the first examples displaying that partaking the endocannabinoid system can have an antagonistic impact on one other reward system—on this case, the opioid system,” Dr. Rajadhyaksha stated.
Potential medicine like JZL184 are presently being examined in medical trials as doable therapies for anxiousness problems, so Dr. Lee is optimistic in regards to the timeline for testing them together with opioids for ache administration in people. “We’re occupied with this methodically and dealing towards translating these preclinical findings to assist sufferers,” Dr. Lee stated.
Supply:
Journal reference:
Martínez-Rivera, A., et al. (2024). Elevating ranges of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward however not analgesia. Science Advances. doi.org/10.1126/sciadv.adq4779.
