NIH-funded research team develops new drug targeting pain-sensing pathway

A research team funded by the National Institutes of Health (NIH) has developed a drug that shows promise in treating acute and chronic pain. The drug, known as VIP36, targets the body's cannabinoid receptor type 1 (CB1). It has been shown to be effective in three different animal models for pain and does not appear to cause the harmful side effects that have thwarted other efforts to target CB1. These findings improve understanding of how to design safer and more effective drugs that target cannabinoid receptors and are an important step toward developing new, non-addictive pain treatments.

CB1 receptors can be found throughout the body and are particularly dense in the brain's pain circuits. They have long been considered a potential target for non-opioid pain treatment; however, previous attempts to target this pathway have faced two challenges. First, repeated exposure to a drug leads to tolerance, which limits its effectiveness. Second, the dose required to reduce peripheral pain tends to be high enough for the drug to penetrate the central nervous system. In humans, this can cause unwanted changes in mood, cognition, or emotional state.

To overcome these problems, the researchers used computer modeling of the CB1 receptor to design molecules that interact better with CB1, much like a key fitting into a lock. The new drug, VIP36, is more "peripherally restricted" than previous drugs, meaning that much less of it leaks into the central nervous system where it can cause unwanted side effects. VIP36 also interacts with CB1 differently than previously tested treatments and in a way that reduces tolerance.

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CB1 is part of a broad class of receptors known as G-protein-coupled receptors, which are involved in countless functions throughout the body, including smell, vision, mood regulation, immune system responses, autonomic nervous system responses such as blood pressure and heart rate, and the growth and metastasis of certain tumors. In addition to their implications for pain treatment, the results of this study could also help spur the development of other drugs that target similar receptors involved in other pathologies.

This research was funded by the Initiative NIH's Helping to End Addiction Long-term®, or NIH HEAL Initiative®, an NIH-wide effort to accelerate science-based solutions to the overdose epidemic, including opioid and stimulant use disorders, and the chronic pain crisis.Who

Julia Bachman, Ph.D., HEAL Program Manager, NIH

Article

Rangari VA et al. “A cryptic pocket in CB1 drives peripheral and functional selectivity”

Nature. March 5, 2025. DOI: 10.1038/s41586-025-08618-7 About the National Institute of Neurological Disorders and Stroke (NINDS):

The NINDS is the nation's largest funder of brain and nervous system research. NINDS's mission is to seek fundamental knowledge about the brain and nervous system and to use this knowledge to reduce the burden of neurological disease. About the National Institutes of Health (NIH):