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

Romina Nassini, Lorenzo Landini, Matilde Marini, Martina Chieca, Daniel Souza Monteiro de Araújo, Marco Montini, Pasquale Pensieri, Vittorio Donato Abruzzese, Gaetano De Siena, Jin Zhang, Elisa Bellantoni, Vincenzo De Giorgi, Antonia Romitelli, Giulia Brancolini, Raquel Tonello, Chloe J. Peach, Alessandra Mastricci, Irene Scuffi, Martina Tesi, Dane D. Jensen, Brian L. Schmidt, Nigel W. Bunnett, Francesco De Logu () and Pierangelo Geppetti ()
Additional contact information
Romina Nassini: University of Florence
Lorenzo Landini: University of Florence
Matilde Marini: University of Florence
Martina Chieca: University of Florence
Daniel Souza Monteiro de Araújo: University of Florence
Marco Montini: University of Florence
Pasquale Pensieri: University of Florence
Vittorio Donato Abruzzese: University of Florence
Gaetano De Siena: University of Florence
Jin Zhang: San Diego
Elisa Bellantoni: University of Florence
Vincenzo De Giorgi: University of Florence
Antonia Romitelli: University of Florence
Giulia Brancolini: FloNext srl
Raquel Tonello: New York University
Chloe J. Peach: New York University
Alessandra Mastricci: University of Florence
Irene Scuffi: University of Florence
Martina Tesi: University of Florence
Dane D. Jensen: New York University
Brian L. Schmidt: New York University
Nigel W. Bunnett: New York University
Francesco De Logu: University of Florence
Pierangelo Geppetti: University of Florence

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63782-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63782-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63782-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().