Targeting Pain Without Inhibiting Healing: New Research on Prostaglandin Receptors
Traditional nonsteroidal anti-inflammatory drugs (nsaids), commonly used for pain relief – available both over-the-counter (like aspirin) and by prescription – carry meaningful long-term risks, including gastrointestinal damage, increased bleeding, and potential harm to the heart, kidneys, and liver. New research suggests a pathway to pain relief that avoids these drawbacks by focusing on a specific receptor involved in pain signaling, rather than broadly suppressing inflammation.
Scientists have long believed that reducing inflammation is key to treating pain, as NSAIDs work by blocking enzymes that produce prostaglandins, thereby reducing both inflammation and pain. Though, inflammation is a natural immune response that plays a crucial role in healing and restoring normal function. Inhibiting this process with NSAIDs may actually delay recovery.
A recent study, led by Pierangelo Geppetti of NYU Pain Research Center and the University of Florence, investigated the role of prostaglandin E2 (PGE2) and its receptors in pain signaling within Schwann cells – cells found in the peripheral nervous system that are critically important in conditions like migraine. while previous research pointed to the EP4 receptor as the primary driver of inflammatory pain, this study revealed a different picture.
Using a targeted approach, researchers found that the EP2 receptor, rather than EP4, was largely responsible for mediating pain responses in Schwann cells. Blocking the EP2 receptor in these cells in mice eliminated pain without impacting the natural inflammatory process. Further studies, conducted on both human and mouse Schwann cells, confirmed that activating the EP2 receptor triggered a pain response autonomous of inflammation.
“To our great surprise, blocking the EP2 receptor…abolished prostaglandin-mediated pain but the inflammation took its normal course,” explained Geppetti. “We effectively decoupled the inflammation from the pain.”
This discovery suggests that developing drugs specifically targeting the EP2 receptor - “antagonists” – could offer effective pain control without the adverse effects associated with traditional NSAIDs. Researchers are now conducting pre-clinical studies to explore the potential of these targeted therapies for conditions like arthritis, currently managed with NSAIDs.
While acknowledging the need for further research into potential side effects, particularly with systemic management, Geppetti notes that localized delivery of EP2 antagonists – for example, directly into a knee joint – shows significant promise.
The research was supported by funding from the National Institutes of Health, the US Department of Defense, the European Research Council, and the European Union – Next Generation EU, National Recovery and Resilience Plan.
