title: Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.
abstract: Peripheral neuropathy (PN) is a debilitating and dose-limiting side effect of treatment with the chemotherapeutic agent, paclitaxel. Understanding the effects of paclitaxel on sensory neuronal function and the signaling pathways which mediate these paclitaxel-induced changes in function are critical for the development of therapies to prevent or alleviate the PN. The effects of long-term administration of paclitaxel on the function of sensory neurons grown in culture, using the release of the neuropeptide calcitonin gene-related peptide (CGRP) as an endpoint of sensory neuronal function, were examined. Dorsal root ganglion cultures were treated with low (10 nM) and high (300 nM) concentrations of paclitaxel for 1, 3, or 5 days. Following paclitaxel treatment, the release of CGRP was determined using capsaicin, a TRPV1 agonist; allyl isothiocyanate (AITC), a TRPA1 agonist; or high extracellular potassium. The effects of paclitaxel on the release of CGRP were stimulant-, concentration-, and time-dependent. When neurons were stimulated with capsaicin or AITC, a low concentration of paclitaxel (10nM) augmented transmitter release, whereas a high concentration (300 nM) reduced transmitter release in a time-dependent manner; however, when high extracellular potassium was used as the evoking stimulus, all concentrations of paclitaxel augmented CGRP release from sensory neurons. These results suggest that paclitaxel alters the function of sensory neurons in vitro, and suggest that the mechanisms by which paclitaxel alters neuronal function may include functional changes in TRP channel activity. The described in vitro model will facilitate future studies to identify the signaling pathways by which paclitaxel alters neuronal sensitivity.
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, USA. Electronic address: skpittma@iupui.edu.
authors.forename: Sherry K
authors.initials: SK
authors.lastname: Pittman
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, USA; Indiana University School of Medicine, Stark Neuroscience Research Institute, USA; Columbia University, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, USA. Electronic address: ng2373@columbia.edu.
authors.forename: Neilia G
authors.initials: NG
authors.lastname: Gracias
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, USA; Indiana University School of Medicine, Stark Neuroscience Research Institute, USA; Indiana University School of Medicine, Department of Anesthesiology, USA. Electronic address: vaskom@iu.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
authors.affiliation: Indiana University School of Medicine, Department of Pharmacology and Toxicology, USA; Indiana University School of Medicine, Stark Neuroscience Research Institute, USA; Indiana University School of Medicine, Department of Anesthesiology, USA. Electronic address: jfehrenb@iu.edu.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Fehrenbacher
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D016877:Oxidants / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects*; D050916:TRPV Cation Channels / Q000819:agonists; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017879:Isothiocyanates; D016877:Oxidants; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C037152:isothiocyanic acid; D006861:Hydrogen Peroxide; D015740:Calcitonin Gene-Related Peptide; D017239:Paclitaxel; D011188:Potassium
keywords: CGRP; Chemotherapy-induced peripheral neuropathy; Dorsal root ganglion culture; Neuropeptide release; Neurotoxicity; Paclitaxel; Peripheral sensory neuron; TRPA1; TRPV1