The PI3Kγ/AKT signaling pathway mediates peripheral antinociceptive action of dipyrone
| Autor: | Fernando Q. Cunha, Thiago M. Cunha, José C. Alves-Filho, Nerry T. Cecilio, Guilherme R. Souza |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Dipyrone Pain Stimulation Pharmacology 030226 pharmacology & pharmacy Nitric oxide Wortmannin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine ÓXIDO NÍTRICO medicine Animals Class Ib Phosphatidylinositol 3-Kinase Nociception assay Pharmacology (medical) LY294002 Rats Wistar Protein kinase B Analgesics Akt/PKB signaling pathway technology industry and agriculture Nociceptors Rats body regions chemistry Hyperalgesia medicine.symptom Proto-Oncogene Proteins c-akt 030217 neurology & neurosurgery |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1472-8206 0767-3981 |
| DOI: | 10.1111/fcp.12606 |
| Popis: | Dipyrone (DIP), also known as metamizole, is an over-the-counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well-known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre-sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP-treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2-induced hyperalgesia in a dose-dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway. |
| Databáze: | OpenAIRE |
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