Researchers at the NYU Pain Research Center have pinpointed a specific receptor within prostaglandins—the hormone-like compounds that common pain relievers target—which triggers pain signals without contributing to inflammation. These groundbreaking results, detailed in the prestigious journal Nature Communications, hold the potential to guide the creation of highly targeted medications for pain management that minimize unwanted side effects.
Typically, inflammation and pain are viewed as inseparable companions in the body’s response to injury. However, the ability to suppress pain while permitting inflammation—a process that actively supports tissue repair and recovery—to continue unabated represents a significant advancement in pain therapy strategies, according to Nigel Bunnett, the lead study author. Bunnett serves as professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and is also affiliated with the NYU Pain Research Center.
Non-steroidal anti-inflammatory drugs (NSAIDs) rank among the world’s most widely used medications, with approximately 30 billion doses consumed annually in the United States alone. These remedies are readily accessible over the counter, such as ibuprofen and aspirin, or through prescriptions for stronger formulations. Regrettably, prolonged use of the majority of NSAIDs poses substantial health risks, including erosion of the stomach lining, heightened risk of bleeding, and potential complications affecting the cardiovascular system, kidneys, and liver.
The mechanism of NSAIDs involves inhibiting enzymes responsible for prostaglandin synthesis, which in turn lowers prostaglandin levels, curbs inflammation, and alleviates pain. Prevailing scientific consensus has long held that diminishing inflammation is the primary way these drugs combat pain. Yet, inflammation itself, as the immune system’s natural reaction to trauma or infection, often serves a beneficial purpose in safeguarding and healing the body.
Far from being inherently harmful, inflammation plays a constructive role by facilitating the repair of damaged tissues and restoring optimal physiological function, explained Pierangelo Geppetti, another key author on the study. Geppetti holds positions as an adjunct professor at the NYU Pain Research Center, professor emeritus at the University of Florence, and former director of the Headache Center at Careggi University Hospital. He cautioned that suppressing inflammation through NSAIDs might inadvertently prolong the healing process and extend the duration of pain experienced by patients. A superior approach for addressing pain linked to prostaglandins would involve selectively targeting the pain pathway alone, thereby preserving the protective benefits of inflammation.
For this investigation, the team zeroed in on prostaglandin E2 (PGE2), widely recognized as a primary driver of pain associated with inflammation, particularly within Schwann cells. These specialized cells reside in the peripheral nervous system, beyond the brain’s protective barriers, and are crucially involved in conditions like migraines as well as various other pain disorders.
PGE2 interacts with four distinct receptor types. Earlier research by Geppetti had implicated the EP4 receptor as a key player in inflammatory pain generation. Nevertheless, employing a refined, precision-based methodology in the current Nature Communications publication, the scientists discovered that the EP2 receptor bears the primary responsibility for pain transmission. By administering drugs directly to the site to inhibit solely the EP2 receptor in Schwann cells, the team successfully eliminated pain responses in experimental mice while leaving inflammation entirely unaffected.
The results were astonishing: silencing the EP2 receptor in Schwann cells completely eradicated the pain induced by prostaglandins, yet the inflammatory process unfolded as it normally would. This achievement effectively separated pain from inflammation, allowing each to be addressed independently, Geppetti remarked.
Further experiments conducted on both human and mouse Schwann cells reinforced these observations. Stimulating the EP2 receptor triggered signaling cascades that prolonged pain sensitivity via a mechanism wholly distinct from those governing inflammation, solidifying EP2’s specific role in pain mediation without inflammatory involvement.
Bunnett emphasized that developing antagonists for this accessible ‘druggable’ receptor could effectively manage pain while sidestepping the troublesome side effects commonly associated with traditional NSAIDs.
The research team is now advancing pre-clinical trials to evaluate the therapeutic potential of EP2 receptor-targeted drugs for treating chronic pain conditions such as arthritis, which are conventionally managed with NSAIDs.
Geppetti expressed optimism about selective EP2 antagonists, noting their potential utility. Although additional investigations into side effects are essential—particularly for systemic delivery methods like oral tablets—localized delivery to specific sites, such as a painful knee joint, appears particularly promising.
Joining Bunnett and Geppetti from NYU were co-authors Raquel Tonello, Chloe Peach, Dane Jensen, and Brian Schmidt. The study also involved collaborations with Romina Nassini, Francesco De Logu, Lorenzo Landini, and Matilde Marini from the University of Florence; Jin Zhang from the University of California, San Diego; and Giulia Brancolini from FloNext, a venture co-founded by Geppetti.
Funding for this work came from multiple sources, including grants from the National Institutes of Health (NS102722, DE026806, DK118971, DE029951, R01 DK073368, R35 CA197622), the US Department of Defense (W81XWH1810431, W81XWH2210239), the European Research Council, and the European Union—Next Generation EU, National Recovery and Resilience Plan. The views expressed herein are those of the authors alone and do not necessarily reflect the positions of the funding agencies.
