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The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives.
Br J Pharmacol. 2015 Jul; 172(13):3397-411.BJ

Abstract

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 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 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 adverse haematological effects of PDs.

Authors+Show Affiliations

Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Pharmacy, University of Pisa, Pisa, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.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.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Corporate Drug Development, Chiesi Farmaceutici SpA, Parma, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25765567

Citation

Nassini, Romina, et al. "The TRPA1 Channel Mediates the Analgesic Action of Dipyrone and Pyrazolone Derivatives." British Journal of Pharmacology, vol. 172, no. 13, 2015, pp. 3397-411.
Nassini R, Fusi C, Materazzi S, et al. The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives. Br J Pharmacol. 2015;172(13):3397-411.
Nassini, R., Fusi, C., Materazzi, S., Coppi, E., Tuccinardi, T., Marone, I. M., De Logu, F., Preti, D., Tonello, R., Chiarugi, A., Patacchini, R., Geppetti, P., & Benemei, S. (2015). The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives. British Journal of Pharmacology, 172(13), 3397-411. https://doi.org/10.1111/bph.13129
Nassini R, et al. The TRPA1 Channel Mediates the Analgesic Action of Dipyrone and Pyrazolone Derivatives. Br J Pharmacol. 2015;172(13):3397-411. PubMed PMID: 25765567.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives. AU - Nassini,Romina, AU - Fusi,Camilla, AU - Materazzi,Serena, AU - Coppi,Elisabetta, AU - Tuccinardi,Tiziano, AU - Marone,Ilaria M, AU - De Logu,Francesco, AU - Preti,Delia, AU - Tonello,Raquel, AU - Chiarugi,Alberto, AU - Patacchini,Riccardo, AU - Geppetti,Pierangelo, AU - Benemei,Silvia, Y1 - 2015/04/24/ PY - 2014/12/18/received PY - 2015/02/23/revised PY - 2015/03/07/accepted PY - 2015/3/14/entrez PY - 2015/3/15/pubmed PY - 2016/4/8/medline SP - 3397 EP - 411 JF - British journal of pharmacology JO - Br J Pharmacol VL - 172 IS - 13 N2 - 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 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 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 adverse haematological effects of PDs. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/25765567/The_TRPA1_channel_mediates_the_analgesic_action_of_dipyrone_and_pyrazolone_derivatives_ L2 - https://doi.org/10.1111/bph.13129 DB - PRIME DP - Unbound Medicine ER -