New pain-relief approach targets pain signals without suppressing inflammation, study finds

A new study from NYU Langone Pain Center identifies a way to block pain signals by targeting a specific prostaglandin receptor, a move that could eventually reduce reliance on nonsteroidal anti-inflammatory drugs (NSAIDs) and transform chronic-pain treatment. The research focuses on prostaglandin E2 (PGE2) and its receptors, aiming to separate the body’s pain response from its inflammatory response. If proven effective in humans, the approach could pave the way for medications that relieve pain without dampening the inflammation the body needs to heal and fight infections. The study, published in Nature Communications, examined how PGE2 operates in Schwann cells—cells located outside the brain in the peripheral nervous system that are implicated in migraine pain and other nociceptive signals.

Researchers found that PGE2 interacts with four receptors, with EP2 singled out as the driver of pain, while EP4 appears more closely tied to inflammation. In a series of preclinical experiments, they used drugs not yet available to the public to selectively block the EP2 receptor in mice. The result was a marked reduction in pain behaviors without dampening inflammatory processes. Pierangelo Geppetti, study author and adjunct professor at the NYU Pain Research Center, said: "Inflammation can be good for you - it repairs and restores normal function." He added that inhibiting inflammation with NSAIDs can potentially delay healing and recovery from pain, and that a strategy targeting prostaglandin-mediated pain while preserving protective inflammation could be a better approach. The researchers emphasized that the work is early and primarily preclinical, but they see potential for developing selective EP2 antagonists that could replace or reduce NSAID use in the future.

The findings come as the medical community weighs competing views on acetaminophen, the active ingredient in Tylenol. President Donald Trump has tied acetaminophen to autism in discussions this week, a claim that rests on inconclusive evidence and has sparked debate about the drug’s safety during pregnancy. The study’s authors and other researchers note that acetaminophen operates via different mechanisms than NSAIDs and that the current work does not address acetaminophen directly. Still, the study highlights the broader pursuit of pain-relief options that avoid compromising the body’s normal healing and defense processes. The NYU team conducted experiments on human Schwann cells to identify which receptors to target and then tested the approach in mouse models. While the results are promising, the researchers cautioned that specific drugs used in the study are not yet approved for public use, and more research is needed to assess safety and efficacy in humans.

If selective EP2 receptor antagonists prove safe in humans and effective in broader trials, they could reduce the reliance on NSAIDs—an estimated 30 billion doses are used in the United States each year. NSAIDs act by blocking COX-1 and COX-2 enzymes, lowering prostaglandin production and dampening pain signals. However, this broad reduction in prostaglandins also diminishes beneficial inflammation, which can slow healing and increase the risk of gastrointestinal and kidney problems over long-term use. Prostaglandins help maintain the stomach’s protective mucus lining, and NSAIDs can reduce blood flow to the GI tract, hindering the lining’s ability to repair itself. They can also affect kidney function over time. The researchers stressed that a targeted approach—especially one that limits systemic exposure—could offer pain relief without the collateral damage associated with widespread prostaglandin suppression. Geppetti noted that selective EP2 antagonists could be very useful, but emphasized the need for further studies on potential side effects, particularly with systemic administration. He suggested that localized delivery, such as to a specific joint area like the knee, might offer a practical path forward while minimizing broader risks.

The research represents a step forward in understanding how to dissociate pain from inflammation at the molecular level. While the findings are encouraging, experts caution that translating preclinical success into safe, effective human therapies will require careful, large-scale clinical testing. The study itself does not name any commercially available EP2-targeting drugs, and it remains to be seen how quickly such therapies could move from the lab to the clinic. In the meantime, physicians and researchers will continue evaluating new strategies to mitigate chronic pain while preserving the body’s natural ability to heal and defend against illness. The study’s authors and independent experts alike view this work as a foundational step toward a new generation of analgesics that could reshape how pain is treated in the years ahead.