title: The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Pyrazolone 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
  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 adverse haematological effects of PDs.
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Fusi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Coppi
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Marone
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Logu
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.|Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
authors.forename: Raquel
authors.initials: R
authors.lastname: Tonello
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
authors.affiliation: Department of Corporate Drug Development, Chiesi Farmaceutici SpA, Parma, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Benemei
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004177:Dipyrone / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D047069:Pyrazolones / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D000700:Analgesics; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D047069:Pyrazolones; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; C038362:pyrazolone; D004177:Dipyrone