• Romina Nassini, Camilla Fusi, Serena Materazzi, Elisabetta Coppi, Tiziano Tuccinardi, Ilaria M Marone, Francesco De Logu, Delia Preti, Raquel Tonello, Alberto Chiarugi, Riccardo Patacchini, Pierangelo Geppetti, and Silvia Benemei.
• Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
• Br. J. Pharmacol. 2015 Jul 1; 172 (13): 3397-411.

Background And PurposeAlthough still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect.Experimental ApproachCalcium responses and currents were studied in cultured TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice.Key ResultsPyrazolone and PDs selectively inhibited calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists and TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuated TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuated carrageenan-evoked mechanical allodynia, without affecting PGE2 levels. The main metabolites of PDs did not target TRPA1 and did not affect TRPA1-dependent nociception and allodynia.Conclusions And ImplicationsEvidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans and that TRPA1 antagonists could be novel analgesics, devoid of the adverse haematological effects of PDs.© 2015 The British Pharmacological Society.

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