A research team funded by the National Institutes of Health (NIH) has developed a promising new medication for treating both acute and chronic pain. The drug, designated VIP36, targets the body's cannabinoid receptor type 1 (CB1) and has demonstrated efficacy in three different animal pain models without the harmful side effects that have plagued previous attempts to target this pathway.
The breakthrough, published March 5 in Nature, represents a significant advancement in the development of non-addictive pain treatments and could help address the ongoing opioid crisis by providing alternative pain management options.
Overcoming Previous Challenges in CB1 Targeting
CB1 receptors are abundant throughout the body, with particularly high concentrations in the brain's pain circuitry. While these receptors have long been considered promising targets for non-opioid pain treatments, previous development efforts have encountered two major obstacles.
First, patients typically develop tolerance to CB1-targeting drugs, limiting their long-term effectiveness. Second, the doses required to reduce peripheral pain have historically been high enough to cause drug penetration into the central nervous system, resulting in unwanted psychological effects including alterations in mood, cognition, and emotional state.
Dr. Julia Bachman, HEAL Program Manager at NIH, explained: "The challenge has always been finding a way to harness the pain-relieving potential of the cannabinoid system without triggering the central effects that limit clinical utility."
Innovative Design Approach
To overcome these limitations, the research team employed sophisticated computer modeling of the CB1 receptor to design molecules with improved receptor interaction. This precision engineering approach resulted in VIP36, which demonstrates two critical advantages over previous candidates.
First, VIP36 is more "peripherally restricted," meaning significantly less of the drug crosses into the central nervous system where it could cause unwanted side effects. Second, the drug interacts with CB1 through a novel mechanism that substantially reduces tolerance development, potentially allowing for sustained efficacy with continued use.
"We essentially created a better key for a very specific lock," noted the study's lead author, Dr. Vikram Rangari. "By understanding the detailed structure of CB1, we were able to design a molecule that fits precisely where we want it to, activating pain relief pathways while minimizing off-target effects."
Broader Implications for Drug Development
The significance of this research extends beyond pain management. CB1 belongs to the G-protein-coupled receptor (GPCR) family, which is involved in numerous physiological functions including sensory perception, mood regulation, immune responses, and cardiovascular control. Some GPCRs also play roles in tumor growth and metastasis.
The structural insights and design principles established in this study could accelerate the development of drugs targeting other GPCRs involved in various conditions, potentially impacting treatment approaches across multiple therapeutic areas.
Part of a Broader Initiative
This research was funded through NIH's Helping to End Addiction Long-term Initiative (HEAL Initiative), a comprehensive effort to address the overdose crisis and improve pain management. The initiative aims to speed scientific solutions to the opioid epidemic and the challenges of chronic pain treatment.
"This work exemplifies the HEAL Initiative's mission," said Dr. Bachman. "By developing novel, non-addictive approaches to pain management, we hope to reduce reliance on opioids while still providing effective relief to those suffering from pain conditions."
Next Steps in Development
While the current findings are based on animal models, the research team is preparing for the next phases of development. Preclinical safety studies will be necessary before any human trials can begin, but the researchers are optimistic about VIP36's potential.
If successful in human trials, VIP36 could represent a significant addition to the pain management arsenal, particularly for patients with chronic pain conditions who currently have limited effective treatment options without substantial side effects or addiction risks.
The study details were published in Nature under the title "A cryptic pocket in CB1 drives peripheral and functional selectivity" (DOI: 10.1038/s41586-025-08618-7).
