Targeting the Schwann Cell EP2/cAMP Nanodomain to Block Pain but not Inflammation

Nassini, R.; Landini, L.; Marini, M.; Chieca, M.; Souza Monteiro de Araujo, D.; Montini, M.; Pensieri, P.; Abruzzese, V. D.; De Siena, G.; Zhang, J.; De Giorgi, V.; Romitelli, A.; Brancolini, G.; Tonello, R.; Peach, C. J.; Mastricci, A.; Scuffi, I.; Tesi, M.; Jensen, D. D.; Schmidt, B. L.; Bunnett, N. W.; De Logu, F.; Geppetti, P.

doi:10.1101/2024.09.10.612200

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bioRxiv · 10.1101/2024.09.10.612200

Targeting the Schwann Cell EP2/cAMP Nanodomain to Block Pain but not Inflammation

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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 EP2 receptor in Schwann cells via an adeno-associated viral vector 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 PG-mediated persistent inflammatory pain but not protective inflammation.

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Nassini, R., Landini, L., Marini, M., Chieca, M., Souza Monteiro de Araujo, D., Montini, M., Pensieri, P., Abruzzese, V. D., De Siena, G., Zhang, J., De Giorgi, V., Romitelli, A., Brancolini, G., Tonello, R., Peach, C. J., Mastricci, A., Scuffi, I., Tesi, M., Jensen, D. D., Schmidt, B. L., Bunnett, N. W., De Logu, F., Geppetti, P.. 2024-09-14. Targeting the Schwann Cell EP2/cAMP Nanodomain to Block Pain but not Inflammation. https://doi.org/10.1101/2024.09.10.612200

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