title: Role of protein kinase Cepsilon and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat.
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.
authors.affiliation: Department of Medicine, Division of Neuroscience and Biomedical Sciences Program, NIH Pain Center (UCSF), University of California at San Francisco, San Francisco, CA 94143-0440, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Dina
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Reichling
authors.forename: J D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000502:physiology; D017239:Paclitaxel; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D010812:Physical Stimulation; D011493:Protein Kinase C / Q000502:physiology*; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007527:Isoenzymes; C497257:Prkce protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D017239:Paclitaxel