Targeting prostaglandin E2 receptor 2 in Schwann cells inhibits inflammatory pain but not inflammation
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 PGE<sub>2</sub> 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 PGE<sub>2</sub>-mediated persistent inflammatory pain but not PG-dependent protective inflammation.
Authors
- Pierangelo Geppetti (ORCID: https://orcid.org/0000-0003-3797-8371)
- Vincenzo De Giorgi (ORCID: https://orcid.org/0000-0001-6531-7998)
- Matilde Marini (ORCID: https://orcid.org/0000-0002-2199-2905)
- Brian L. Schmidt (ORCID: https://orcid.org/0000-0002-2409-8984)
- Marco Montini (ORCID: https://orcid.org/0009-0002-7880-5987)
- Dane D. Jensen (ORCID: https://orcid.org/0000-0001-6540-2375)
- Chloe J. Peach (ORCID: https://orcid.org/0000-0001-6315-1170)
- Raquel Tonello (ORCID: https://orcid.org/0000-0002-2175-9804)
- Martina Chieca (ORCID: https://orcid.org/0000-0002-0247-9938)
- M. Tesi (ORCID: https://orcid.org/0009-0004-2352-4277)
- Gaetano De Siena (ORCID: https://orcid.org/0000-0003-3600-9130)
- Lorenzo Landini (ORCID: https://orcid.org/0000-0002-3933-2497)
- Antonia Romitelli (ORCID: https://orcid.org/0000-0003-2495-8769)
- Nigel W. Bunnett (ORCID: https://orcid.org/0000-0003-3367-0644)
- Elisa Bellantoni
- Romina Nassini (ORCID: https://orcid.org/0000-0002-9223-8395)
- Jin Zhang (ORCID: https://orcid.org/0000-0002-6835-920X)
- Francesco De Logu (ORCID: https://orcid.org/0000-0001-8360-6929)
- Pasquale Pensieri (ORCID: https://orcid.org/0000-0003-4914-3144)
- Daniel Souza Monteiro de Araújo (ORCID: https://orcid.org/0000-0003-1115-725X)
- Giulia Brancolini (ORCID: https://orcid.org/0009-0008-9269-8253)
- Irene Scuffi (ORCID: https://orcid.org/0009-0008-2312-3325)
- Alessandra Mastricci
- Vittorio Abruzzese
Institutions
- University of California San Diego (US)
- Tumour Institute of Tuscany (IT)
- University of Florence (IT)
- New York University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1038/s41467-025-63782-8
- Citations
- 1
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.16
Funders
- U.S. Department of Defense
- European Commission
- National Institutes of Health