The chemotherapeutic agent paclitaxel (Taxol) is widely used for the treatment of many different types of carcinomas. At present, the dose of paclitaxel that can be tolerated by patients is limited primarily by the development of a painful peripheral neuropathy characterized by paresthesias, myalgia and arthralgia. Similar dose-limiting painful neuropathies are produced by other microtubule-disrupting chemotherapeutic drugs, dose-limiting painful neuropathies are produced by other microtubule-disrupting chemotherapeutic drugs, including vincristine therapy, but also increase the effectiveness of their treatment by permitting the use of higher doses of the drugs. We propose a series of experiments to elucidate the cellular mechanisms of paclitaxel- and vincristine-induced painful neuropathy. Specifically, we will establish a model of paclitaxel-induced painful peripheral neuropathy in the rat, and then analyze paclitaxel-induced changes in the excitability of nociceptive nerve fibers in this model. Our interpretation of those data will be greatly enhanced by our extensive knowledge of the effects of vincristine on nerve fiber excitability. Because taxol stabilizes microtubules while vincristine stimulates microtubule depolymerization, comparison of similarities and differences in the effects of the two agents may provide valuable insights into the mechanisms by which microtuble disruption causes nociceptor hyperexcitability. Guided by these in vivo electrophysiological analyses, we will employ patch clamp recording of cultured sensory neurons to study the effects of both drugs on specific transduction molecules and ion channels. Finally, we will investigate intracellular second messenger pathways that participate in the production of hyperalgesia and nociceptor hyperexcitability induced by paclitaxel and vincristine. The proposed in vitro studies may identify specific molecules to be targeted by new pharmacological strategies to treat chemotherapy-induced neuropathic pain caused by chemotherapy. By improving our understanding of the cellular mechanisms of neuropathic pain, these studies can potentially provide important insights into the pathophysiology and treatment of orofacial neuropathies.
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