Paclitaxel Increases High Voltage–Dependent Calcium Channel Current in Dorsal Root Ganglion Neurons of the Rat
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概要
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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 <I>μ</I>M gabapentin. Similar effects in small-diameter DRG neurons were only seen with 100 <I>μ</I>M gabapentin. Western blotting revealed that paclitaxel increased protein levels of the VDCC subunit <I>α</I><SUB>2</SUB><I>δ</I>-1 (Ca<SUB>v</SUB><I>α</I><SUB>2</SUB><I>δ</I>-1) in DRG neurons. Immunohistochemistry showed that paclitaxel treatment increased Ca<SUB>v</SUB><I>α</I><SUB>2</SUB><I>δ</I>-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca<SUB>v</SUB><I>α</I><SUB>2</SUB><I>δ</I>-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons.
著者
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KAWAKAMI Kazuyoshi
Department of Internal Medicine and Infectious Diseases, Graduate School of Medicine, University of
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Taguchi Kyoji
Department Of Neuroscience Showa Pharmaceutical University
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Katagiri Nobuyuki
Department Of Chemical Engineering Nagoya University
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Abe Kenji
Department Of Biochemistry 1 Hamamatsu University School Of Medicine
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Saduka Maya
Department of Medicinal Pharmacology, Showa Pharmaceutical University, Japan
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UTSUNOMIYA Iku
Department of Neuroscience, Showa Pharmaceutical University
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Katagiri Nobuyuki
Department of Pharmacotherapeutics, Showa Pharmaceutical University, Japan
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Chiba Terumasa
Department of Medicinal Pharmacology, Showa Pharmaceutical University, Japan
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Hama Toshihiro
Department of Pharmacy, Cancer Institute Hospital, Japan
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Kawakami Kazuyoshi
Department of Medicinal Pharmacology, Showa Pharmaceutical University, Japan
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Taguchi Kyoji
Department of Medicinal Pharmacology, Showa Pharmaceutical University, Japan
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Abe Kenji
Department of Pharmacology, School of Pharmaceutical Sciences, Ohu University, Japan
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