title: Nociceptor beta II, delta, and epsilon isoforms of PKC differentially mediate paclitaxel-induced spontaneous and evoked pain.
abstract: As one of the most effective and frequently used chemotherapeutic agents, paclitaxel produces peripheral neuropathy (paclitaxel-induced peripheral neuropathy or PIPN) that negatively affects chemotherapy and persists after cancer therapy. The mechanisms underlying this dose-limiting side effect remain to be fully elucidated. This study aimed to investigate the role of nociceptor protein kinase C (PKC) isoforms in PIPN. Employing multiple complementary approaches, we have identified a subset of PKC isoforms, namely βII, δ, and ϵ, were activated by paclitaxel in the isolated primary afferent sensory neurons. Persistent activation of PKCβII, PKCδ, and PKCϵ was also observed in the dorsal root ganglion neurons after chronic treatment with paclitaxel in a mouse model of PIPN. Isoform-selective inhibitors of PKCβII, PKCδ, and PKCϵ given intrathecally dose-dependently attenuated paclitaxel-induced mechanical allodynia and heat hyperalgesia. Surprisingly, spinal inhibition of PKCβII and PKCδ, but not PKCϵ, blocked the spontaneous pain induced by paclitaxel. These data suggest that a subset of nociceptor PKC isoforms differentially contribute to spontaneous and evoked pain in PIPN, although it is not clear whether PKCϵ in other regions regulates spontaneous pain in PIPN. The findings can potentially offer new selective targets for pharmacological intervention of PIPN.
authors: Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, Illinois 60612.
authors: Ying
authors: Y
authors: He
authors: Department of Biopharmaceutical Sciences and Cancer Center, University of Illinois, Chicago, Illinois 60612 zjwang@uic.edu.
authors: Zaijie Jim
authors: ZJ
authors: Wang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D017239:Paclitaxel / Q000633:toxicity*; D010146:Pain / Q000139:chemically induced / Q000201:enzymology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D017239:Paclitaxel
keywords: cancer; chemotherapy; pain; protein kinase C; taxane