Scientists Discover Schwann Cell EP2 Receptor That Separates Pain from Protective Inflammation

For decades, nonsteroidal anti-inflammatory drugs, or NSAIDs, have been the main treatment for inflammatory pain. They work by blocking cyclooxygenase enzymes and lowering prostaglandin production, which reduces both inflammation and pain. That dual action explains their effectiveness, but it is also the root of two major problems. First, systemic prostaglandin blockade produces serious side effects, including gastrointestinal, renal, and cardiovascular toxicity. Second, because inflammation is a protective process that aids tissue healing, bluntly suppressing inflammation can delay the natural resolution of pain and tissue repair. In short, current drugs often trade pain relief for collateral harm.

What if pain and inflammation could be uncoupled? That is the question the Florence, New York University, and collaborating groups set out to answer in a carefully controlled set of experiments that combine genetics, pharmacology, optogenetics, and live-cell imaging. Their answer points to a druggable receptor located not on neurons but on Schwann cells, the glial cells that envelop peripheral nerve fibers.

The problem the researchers tackled

Prostaglandin E2, or PGE2, is a well known mediator of inflammatory pain. It can excite sensory neurons and produce both an immediate spontaneous pain response and a longer-lasting mechanical hypersensitivity, commonly called allodynia. But previous attempts to pin down which PGE2 receptor subtype and which cell types are responsible for these different pain behaviors have produced mixed results, in part because many pharmacological tools lack perfect selectivity and because systemic manipulations confound peripheral and central actions. The researchers sought a focused, cell-type specific answer: which PGE2 receptor, acting in which cell type, sustains the persistent mechanical pain produced by inflammatory stimuli, and can that signaling be interrupted without suppressing inflammation?

What the team did, in plain terms

At a high level, the investigators combined three complementary approaches.

1. Cell-selective silencing in vivo. They used adeno-associated viral vectors to deliver short hairpin RNAs that selectively reduce expression of the four known PGE2 receptors (EP1–EP4) in either Schwann cells or dorsal root ganglion (DRG) sensory neurons. Cell-selective promoters and Cre-dependent constructs allowed them to target Schwann cells (using a Plp-CreERT driver) or sensory neurons (using an Advillin-Cre driver) and then test behavioral responses in the injected hindpaw.
2. Pharmacology and inflammatory models. They combined selective agonists and antagonists for EP2 and EP4, and they used prototypical inflammatory stimuli such as carrageenan and complete Freund’s adjuvant (CFA), as well as agents that evoke endogenous prostaglandin release. Behavioral endpoints included transient spontaneous nociception (lifting and licking), sustained mechanical allodynia measured with von Frey filaments, and the mouse grimace scale for spontaneous pain. Inflammation was assessed by paw edema, myeloperoxidase activity, and cytokine assays, so the team could compare effects on pain versus measurable inflammatory markers.
3. Cell signaling and optogenetics. To map the intracellular signaling, they used cultured human and mouse Schwann cells with genetically encoded cAMP and PKA biosensors, and optogenetic tools that produce cAMP when illuminated (bPAC), including membrane-targeted versions (Lyn11-bPAC) and compartmentalized phosphodiesterases that can be turned on with red light to degrade cAMP in specific nanodomains. These experiments probed where inside the Schwann cell the cAMP/PKA signal is generated and which scaffold proteins, notably AKAP79/150, organize that signal.

Together, these methods allowed the team to move from receptor and cell identification to the precise subcellular cAMP signaling mechanisms that translate receptor activation into persistent pain-like behavior.

The breakthrough discovery

EP2 on Schwann cells encodes sustained inflammatory pain, but not inflammation

Contrary to the common expectation that prostaglandin-driven pain springs purely from direct neuronal effects, the team found that the EP2 receptor, when expressed on Schwann cells, is necessary for the sustained mechanical hypersensitivity produced by PGE2 and by inflammatory stimuli such as carrageenan and CFA. Silencing EP2 selectively in Schwann cells abolished PGE2-dependent mechanical allodynia and attenuated carrageenan- and CFA-evoked allodynia and grimace behavior. Importantly, the same Schwann cell EP2 silencing did not change paw edema, myeloperoxidase activity, or local increases in inflammatory cytokines, indicating that the inflammatory response itself remained intact. In contrast, systemic indomethacin lowered both pain and inflammation. In short, Schwann cell EP2 is necessary for the pain component that NSAIDs suppress, but it does not mediate the protective inflammatory responses that NSAIDs also block.

EP4 and neurons mediate transient spontaneous pain

The experiments also clarified the cellular division of labor among PGE2 receptors. EP4, acting in sensory neurons, accounted for the short-lived spontaneous nociceptive behaviors evoked by injected PGE2, whereas EP2 in Schwann cells principally mediated the longer lasting mechanical allodynia. Selective EP2 antagonists reduced inflammatory allodynia in vivo, while selective EP4 antagonists primarily reduced the transient spontaneous nociception. These complementary results explain previous conflicting data produced by systemic and non-selective manipulations.

The pain signal lives in plasma membrane cAMP nanodomains, organized by AKAP-PKA

Perhaps the most mechanistic and surprising finding is that EP2 signaling in Schwann cells produces a plasma membrane-restricted increase in cyclic adenosine monophosphate (cAMP) that activates a membrane-associated pool of protein kinase A (PKA), organized by the scaffold AKAP79/150. Using membrane-targeted biosensors and optogenetic generation of membrane cAMP, the scientists showed that stimulating membrane cAMP in Schwann cells is sufficient to produce mechanical allodynia in mice. Conversely, activating a membrane-localized light-sensitive phosphodiesterase to degrade membrane cAMP prevented pain-like behaviors produced by PGE2 and by inflammatory stimuli. Disrupting AKAP/PKA interactions with a peptide inhibitor likewise reduced inflammatory allodynia. Together, these data indicate that a precise, subcellular cAMP/PKA nanodomain at the Schwann cell plasma membrane encodes persistent inflammatory pain.

EP2 couples to TRPA1 and oxidative signaling in Schwann cells

The study also provides evidence that EP2 activation in Schwann cells is linked to downstream effectors, including TRPA1 and locally generated hydrogen peroxide, which can contribute to sensory neuron sensitization. While the paper focuses on the EP2–cAMP–AKAP–PKA axis as the central mechanism, these additional links suggest a multi-step pathway by which glial receptor activation promotes neuronal hypersensitivity.

Why these results matter

1. Decoupling pain from protective inflammation. The discovery that Schwann cell EP2 mediates pain but not inflammation raises the possibility of analgesics that relieve inflammatory pain while allowing the immune response to proceed, reducing the risk that treatment delays healing. This is conceptually important, because it challenges the standard idea that prostaglandin blockade must suppress both phenomena together.
2. A new therapeutic target in glia. Most analgesic strategies focus on neurons. Demonstrating a glial receptor with a dominant role in inflammatory pain highlights Schwann cells as an actionable cell type for analgesic development. Targeting EP2 in Schwann cells, or the membrane cAMP/AKAP/PKA nanodomain it engages, could generate drugs with fewer systemic side effects than NSAIDs.
3. Precision pharmacology at the subcellular level. The finding that signaling is confined to plasma membrane cAMP nanodomains organized by AKAP suggests alternative intervention points beyond the receptor itself, such as disrupting AKAP/PKA scaffolding or selectively modulating membrane cAMP pools. These strategies could avoid the systemic consequences of global COX inhibition.
4. Clinical relevance. Because NSAIDs are widely used but carry significant risks, a drug that reduces inflammatory pain without interfering with inflammation would be attractive clinically, especially for patients at high risk of NSAID toxicity, and for conditions where inflammation is needed for healing. The translational path will require more work, but the mechanism is druggable, given available EP2 antagonists and AKAP-targeting peptides used experimentally.

Caveats and open questions

The scientists acknowledge several important limitations that temper immediate clinical translation.

• Which Schwann cell subtype matters? Schwann cells are heterogeneous, including myelinating and non-myelinating (Remak) subtypes. Current tools do not clearly identify which subtype is responsible for EP2-mediated pain, and future studies with more selective genetic tools will be needed.
• Incomplete silencing. The AAV-shRNA approach, while cell-selective, is not equivalent to a full genetic knockout, and incomplete knockdown could complicate interpretation in some experiments. A conditional floxed mouse model for Ptger2 would help validate the findings.
• Species and model differences. Mouse models and cultured human Schwann cells provide strong mechanistic insight, but human inflammatory diseases can differ in tissue architecture and drug access. Translation to human therapy will require careful pharmacology, safety testing, and disease-specific studies.
• Delivery and specificity. Achieving Schwann cell-selective delivery of drugs in humans presents practical challenges. Systemic EP2 antagonists might affect EP2 receptors in other tissues, so methods that favor local delivery or that exploit unique Schwann cell features will be needed.

Despite these caveats, the convergence of genetic, pharmacological, imaging, and optogenetic lines of evidence strengthens the central conclusion and points clearly to next steps for preclinical and translational work.

What should come next

A sensible set of priorities would include generating conditional Ptger2 knockout mice to confirm and extend the AAV-shRNA results, testing EP2-targeted therapies in larger animal models and in disease-specific contexts, and exploring drug delivery strategies that restrict action to peripheral glia. Parallel work should probe how EP2–AKAP–PKA signaling interfaces with TRPA1 and oxidative mediators, to map downstream nodes that might be targeted when receptor-level inhibition is not feasible. Finally, safety and off-target profiling of candidate EP2 modulators will be essential before human trials begin.

Bottom line

This study identifies a surprising cellular locus for prostaglandin-driven inflammatory pain: EP2 receptors on Schwann cells, which signal through a plasma membrane cAMP/AKAP/PKA nanodomain to produce persistent mechanical hypersensitivity, while leaving measurable inflammation intact. The result is a clear proof of principle that pain and protective inflammation can be separated molecularly, opening the door to new analgesic strategies that avoid the systemic hazards of current NSAIDs. The path to the clinic will require further validation and careful drug development, but the mechanism is precise, reproducible in multiple assays, and amenable to pharmacological targeting.

The research was published in Nature Communications on September 25, 2025.