title: Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat.
abstract: Peripheral neuropathic pain is a serious side effect of paclitaxel treatment. However, the mechanism of this paclitaxel-induced neuropathic pain is unknown. In this study, we investigated the effects of paclitaxel on the voltage-dependent calcium channel (VDCC) current in rat dorsal root ganglion (DRG) neurons using the whole-cell patch clamp technique. Behavioral assessment using von Frey filament stimuli showed that 2 and 4 mg/kg paclitaxel treatment induced mechanical allodynia/hyperalgesia. Paclitaxel-induced mechanical hyperalgesia was significantly inhibited by gabapentin (100 mg/kg). Using the patch clamp method, we observed that paclitaxel (4 mg/kg) treatment significantly increased the VDCC current in small- and medium-diameter DRG neurons. Moreover, paclitaxel-induced increase in the VDCC current in medium-diameter DRG neurons was completely inhibited by 10 and 100 μM gabapentin. Similar effects in small-diameter DRG neurons were only seen with 100 μM gabapentin. Western blotting revealed that paclitaxel increased protein levels of the VDCC subunit α₂δ-1 (Ca(v)α₂δ-1) in DRG neurons. Immunohistochemistry showed that paclitaxel treatment increased Ca(v)α₂δ-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca(v)α₂δ-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons.
authors.affiliation: Department of Medicinal Pharmacology, Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawakami
authors.forename: Terumasa
authors.initials: T
authors.lastname: Chiba
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katagiri
authors.forename: Maya
authors.initials: M
authors.lastname: Saduka
authors.forename: Kenji
authors.initials: K
authors.lastname: Abe
authors.forename: Iku
authors.initials: I
authors.lastname: Utsunomiya
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hama
authors.forename: Kyoji
authors.initials: K
authors.lastname: Taguchi
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002120:Calcium Channel Agonists / Q000009:adverse effects / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D020746:Calcium Channels, L-Type; D048429:Cell Size; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C486060:Cacna2d1 protein, rat; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009419:Nerve Tissue Proteins; D017239:Paclitaxel