The TRPA1 channel mediates the analgesic action of dipyrone and pyrazolone derivatives

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 H2O2). 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.

Management of Acute Postoperative Pain in Hand Surgery: A Systematic Review

“…The mechanism of action for metamizole is not fully understood, but there is evidence that ampyrone sulfonates block the transient receptor potential family of calcium channels. 29 This medication has been withdrawn from the US market because of an association with agranulocytosis, but it is still available in many formulations worldwide. There was no significant difference in pain regimen satisfaction for acetaminophen compared with metamizole.…”

Blocking TRPA1 and TNF-α Signal Improves Bortezomib-Induced Neuropathic Pain

“…TRPA1 appears in DRG neurons [7] and is engaged in development of mechanical hypersensitivity and painfully cold temperatures [9,10]. Additional studies further indicate that TRPA1 mediates mechanical and cold hypersensitivity induced by chemotherapeutic agents [11,29]. Our current study suggests that TRPA1 plays a role in regulating BTZ-evoked neuropathic pain.…”

Pain transduction: a pharmacologic perspective

“…TRPA1 channels are activated by a host of endogenous mediators and substances including allyl isothiocyanate (the spicy substance in wasabi and horseradish), acrolein, cinnamaldehyde, formalin, iodoacetamide, methanethiosulphonate, mustard oil, and pentenal [14, 15, 37, 38]. In addition, activation of TRPA1 channels by chemotherapeutic agents such as bortezomib (a proteasome inhibitor) and oxaliplatin (a platinum-containing alkylating agent) has been shown to contribute to pain induction and allodynia in cancer patients [38, 39].…”

“…In addition, activation of TRPA1 channels by chemotherapeutic agents such as bortezomib (a proteasome inhibitor) and oxaliplatin (a platinum-containing alkylating agent) has been shown to contribute to pain induction and allodynia in cancer patients [38, 39]. …”

“…These drugs were widely used, despite an unknown mechanism of action, until their hematologic side effects (e.g., agranulocytosis) became apparent. Recently, however, the mechanism of pyrazolones was elucidated [38]. Using rat and mouse dorsal root ganglia neurons stimulated by allyl isothiocyanate (a known TRPA1 agonist), it was shown that treatment with pyrazolones selectively reduced calcium influx via TRPA1 channels [38].…”