Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture

Sherry K. Pittman, Neilia G. Gracias, Michael R. Vasko, Jill C. Fehrenbacher

Research output: Contribution to journalArticle

15 Scopus citations

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 (10. nM) 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.

Original languageEnglish (US)
Pages (from-to)146-153
Number of pages8
JournalExperimental Neurology
Volume253
DOIs
StatePublished - Mar 1 2014

Keywords

  • CGRP
  • Chemotherapy-induced peripheral neuropathy
  • Dorsal root ganglion culture
  • Neuropeptide release
  • Neurotoxicity
  • Paclitaxel
  • Peripheral sensory neuron
  • TRPA1
  • TRPV1

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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