Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy

摘要

BACKGROUND:: The mechanism of chemotherapy-induced peripheral neuropathy after paclitaxel treatment is not well understood. Given the poor penetration of paclitaxel into central nervous system, peripheral nervous system is most at risk. METHODS:: Intrinsic membrane properties of dorsal root ganglion neurons were studied by intracellular recordings. Multiple-gene real-time polymerase chain reaction array was used to investigate gene expression of dorsal root ganglion neuronal ion channels. RESULTS:: Paclitaxel increased the incidence of spontaneous activity from 4.8 to 27.1% in large-sized and from 0 to 33.3% in medium-sized neurons. Paclitaxel decreased the rheobase (nA) from 1.6 ± 0.1 to 0.8 ± 0.1 in large-sized, from 1.5 ± 0.2 to 0.6 ± 0.1 in medium-sized, and from 1.6 ± 0.2 to 1.0 ± 0.1 in small-sized neurons. After paclitaxel treatment, other characteristics of membrane properties in each group remained the same except that Aδ neurons showed shorter action potential fall time (ms) (1.0 ± 0.2, n = 10 vs. 1.8 ± 0.3, n = 9, paclitaxel vs. vehicle). Meanwhile, real-time polymerase chain reaction array revealed an alteration in expression of some neuronal ion channel genes including up-regulation of hyperpolarization- activated cyclic nucleotide-gated channel 1 (fold change 1.76 ± 0.06) and Nav1.7 (1.26 ± 0.02) and down-regulation of Kir channels (Kir1.1, 0.73 ± 0.05, Kir3.4, 0.66 ± 0.06) in paclitaxel-treated animals. CONCLUSION:: The increased neuronal excitability and the changes in gene expression of some neuronal ion channels in dorsal root ganglion may provide insight into the molecular and cellular basis of paclitaxel-induced neuropathy, which may lead to novel therapeutic strategies.