Role of protein kinase Cepsilon and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat.
Neuroscience
; 108(3): 507-15, 2001.
Article
em En
| MEDLINE
| ID: mdl-11738263
ABSTRACT
The clinical use of the antineoplastic agent paclitaxel (Taxol) is significantly limited in its effectiveness by a dose-related painful peripheral neuropathy. To evaluate underlying mechanisms, we developed a model of Taxol-induced painful peripheral neuropathy in the rat and determined the involvement of two second messengers that contribute to enhanced nociception in other models of inflammatory and neuropathic pain, protein kinase Cepsilon and protein kinase A. Taxol administered acutely, or chronically over 12 days, produced a decrease in mechanical nociceptive threshold. Acutely, Taxol induced hyperalgesia that was significant within 1 h, maximal after 6 h and resolved completely by 24 h after a single treatment. Chronically, Taxol treatment resulted in a dose (0.1-1 mg/kg/day)-dependent decrease in nociceptive threshold, measured 24 h after administration, maximal within 5 days from the commencement of Taxol administration and resolving by 2 weeks after the last dose of Taxol. Chronic Taxol treatment also increased the number of action potentials evoked by sustained (60-s) threshold and suprathreshold (10-g) stimulation of a sub-population of C-fibers in rats with Taxol-induced hyperalgesia. Mechanical allodynia and thermal hyperalgesia were also present in Taxol-treated rats. Hyperalgesia, produced by both acute and chronic Taxol, was attenuated by intradermal injection of selective second messenger antagonists for protein kinase Cepsilon and protein kinase A. These findings provide insight into the mechanism of Taxol-induced painful peripheral neuropathy that may help control side effects of chemotherapy and improve its clinical efficacy.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteína Quinase C
/
Paclitaxel
/
Proteínas Quinases Dependentes de AMP Cíclico
/
Doenças do Sistema Nervoso Periférico
/
Hiperalgesia
/
Isoenzimas
/
Antineoplásicos Fitogênicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Neuroscience
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Estados Unidos