Chronic pain affects millions worldwide and is one of the major causes of disability. However, almost all the current treatments for chronic pain have severe drawbacks — opioids carry addiction risks, while non-opioid alternatives often lack effectiveness.
In a recent study published in Nature, a research team from the United States (U.S.) introduced a potential breakthrough in chronic pain treatment — a novel peripherally restricted cannabinoid receptor 1 (CB1) agonist that provides pain relief without the psychoactive side effects or tolerance issues associated with previous cannabinoid-based drugs.
Study: A cryptic pocket in CB1 drives peripheral and functional selectivity. Image Credit: Perfect Wave/Shutterstock.com
Chronic Pain Treatment
Chronic pain is a widespread and debilitating condition that affects more than 10% of the U.S. population. Opioids have long been a primary treatment, but their risks, including dependence and overdose, have fueled an ongoing opioid crisis.
On the other hand, non-opioid alternatives such as gabapentinoids and antidepressants offer limited relief, underscoring the need for better solutions.
Cannabinoid receptor 1 (CB1) has emerged as a promising target for pain management. This receptor is found throughout the nervous system and modulates pain perception. However, drugs that activate CB1 also produce unwanted effects, including psychoactivity, sedation, and rapid tolerance, which has limited their clinical utility.
Moreover, past attempts to develop CB1 agonists that avoid non-target impacts on the central nervous system function have fallen short.
The Current Study
In the present study, scientists identified a novel approach of targeting a rarely accessed cryptic pocket within CB1 to create a safer and more effective analgesic that minimizes central side effects while preserving therapeutic benefits.
They designed new molecules derived from the potent CB1 agonist MDMB-Fubinaca, an indazole-based synthetic cannabinoid, to develop this new analgesic.
Using computational modeling, they identified a cryptic binding pocket within the CB1 receptor that could be selectively targeted to reduce side effects while maintaining pain relief properties.
Their goal was to engineer a drug that would remain peripherally restricted, acting on pain pathways outside the central nervous system while minimizing engagement with the arrestin signaling pathway, which contributes to tolerance.
The team synthesized a series of novel compounds featuring a positively charged functional group to prevent the drug from crossing the blood-brain barrier. They then optimized these compounds to engage with the newly identified cryptic pocket, hypothesizing that this interaction would enhance peripheral selectivity and bias signaling towards G-protein pathways, reducing side effects.
To test the efficacy of their lead compound, VIP36, the researchers conducted cryo-electron microscopy experiments to confirm its binding mechanism. They also performed in vitro pharmacological assays to assess its selectivity and molecular interactions.
Finally, they evaluated the analgesic effects of VIP36 in three different mouse models of pain: inflammatory pain, neuropathic pain, and migraine pain.
By comparing VIP36 to existing CB1 agonists, the study also assessed its ability to provide pain relief without causing sedation, hypothermia, or tolerance.
Primary Findings
The study found that VIP36 effectively reduced pain across multiple models while minimizing common side effects associated with CB1 activation. Unlike previous CB1 agonists, which caused psychoactivity, sedation, and rapid tolerance, VIP36 maintained its analgesic efficacy without significant non-target engagement of other central nervous system functions.
The researchers observed that VIP36 provided substantial pain relief in all three mouse models of pain. Furthermore, it achieved these effects at doses that were 100 times lower than the threshold required to induce side effects such as sedation and hypothermia. This suggested a far wider therapeutic window compared to other CB1 agonists.
At the molecular level, the study showed that VIP36’s design allowed it to selectively bind to a newly discovered cryptic pocket in CB1, stabilizing a receptor conformation that favored G-protein signaling over arrestin recruitment.
Because arrestin signaling is linked to tolerance, VIP36 maintained its pain-relieving effects even after repeated use, unlike other CB1-targeting drugs that lose efficacy over time.
One of the study’s major insights was that peripheral CB1 activation was sufficient for strong analgesic effects, challenging the assumption that central CB1 activation is necessary for pain relief.
This finding also has broad implications for drug development as it suggests that peripherally restricted CB1 agonists could be a safer class of analgesics.
Despite these promising results, the researchers acknowledged some limitations. The long-term safety and efficacy of VIP36 in humans remain unknown, as the findings were based on animal models. Further clinical trials are needed to confirm whether these benefits translate to human patients.
Conclusions
In summary, this study presented a novel approach to chronic pain management by designing a peripherally restricted CB1 agonist that effectively reduces pain without the common drawbacks of cannabinoids and opioids. By selectively targeting a cryptic pocket in CB1, the novel CB1 agonist VIP36 minimizes tolerance and psychoactive effects while maintaining strong analgesic properties.
If future clinical trials confirm its efficacy, VIP36 could offer a breakthrough in safe, non-opioid pain relief, also offering a potential solution to the growing opioid crisis.
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