Background and purpose Although 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 approach Calcium 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 results Pyrazolone and PDs selectively inhibit calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2O2). In line with recent results obtained with TRPA1 antagonists or TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuate 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 attenuate carrageenan-evoked mechanical allodynia, without affecting prostaglandin E2 levels. PD main metabolites do not target TRPA1 and do not affect TRPA1-dependent nociception and allodynia. Conclusions and Implications Evidence 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 hematologic liability of PDs.
|Autori interni:||TUCCINARDI, TIZIANO|
|Autori:||Nassini R; Fusi C; Materazzi S; Coppi E; Tuccinardi T; Marone IM; De Logu F; Preti D; Tonello R; Chiarugi A; Patacchini R; Geppetti P; Benemei S.|
|Titolo:||The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives|
|Anno del prodotto:||2015|
|Digital Object Identifier (DOI):||10.1111/bph.13129|
|Appare nelle tipologie:||1.1 Articolo in rivista|