Painkiller Discovery Separates Pain from Inflammation

Mij

Senior Member (Voting Rights)
Researchers at New York University (NYU) Pain Research Center have identified a new target that can block pain without interfering with inflammation.

“Inflammation and pain are usually thought to go hand in hand. But being able to block pain and allow inflammation—which promotes healing—to proceed is an important step in improved treatment of pain,” said Nigel W. Bunnett, PhD, professor and chair of the department of molecular pathobiology at NYU College of Dentistry and a faculty member in the NYU Pain Research Center.

The most commonly used type of painkillers are non-steroidal anti-inflammatory drugs (NSAIDs), a class of drugs that block the enzymes that produce prostaglandins. These hormone-like compounds are involved in a wide range of biological functions, including pain, inflammation and blood clotting, which can lead NSAIDs to induce a variety of unwanted side effects and long-term toxicity in the gastrointestinal tract, cardiovascular system, kidneys and liver.

These issues have pushed the search for effective alternatives to NSAIDs, but options are still limited for those in need for pain management solutions. In particular, identifying painkillers that don’t interfere with inflammation has long remained a challenge because of how closely linked both processes are at the cellular and molecular level.

“Inflammation can be good for you—it repairs and restores normal function,” said Pierangelo Geppetti, MD, adjunct professor at the NYU Pain Research Center, professor emeritus at the University of Florence, and former director of the Headache Center of Careggi University Hospital. “Inhibiting inflammation with NSAIDs may delay healing and could delay recovery from pain. A better strategy to treat prostaglandin-mediated pain would be to selectively reduce the pain without affecting inflammation’s protective actions.”
 
Nature Communications: September 25, 2025

Targeting prostaglandin E2 Receptor 2 in Schwann cells inhibits inflammatory pain but not inflammation

Abstract​

Analgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE2 receptor 2 (EP2) in Schwann cells via adeno-associated viral vectors abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PGE2-mediated persistent inflammatory pain but not PG-dependent protective inflammation.

 
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