title: Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain.
abstract: Painful peripheral neuropathy is a severe adverse effect of chemotherapeutic drugs such as paclitaxel (Taxol). The glutamate N-methyl-d-aspartate receptors (NMDARs) are critically involved in the synaptic plasticity associated with neuropathic pain. However, paclitaxel treatment does not alter the postsynaptic NMDAR activity of spinal dorsal horn neurons. In this study, we determined whether paclitaxel affects presynaptic NMDAR activity by recording excitatory postsynaptic currents (EPSCs) of dorsal horn neurons in spinal cord slices. In paclitaxel-treated rats, the baseline frequency of miniature EPSCs (mEPSCs) was significantly increased; the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP5) completely normalized this frequency. Also, AP5 significantly reduced the amplitude of monosynaptic EPSCs evoked by dorsal root stimulation and reversed the reduction in the paired-pulse ratio of evoked EPSCs in paclitaxel-treated rats. Blocking GluN2A-containing, but not GluN2B-containing, NMDARs largely decreased the frequency of mEPSCs and the amplitude of evoked EPSCs of dorsal horn neurons in paclitaxel-treated rats. Furthermore, inhibition of protein kinase C fully reversed the increased frequency of mEPSCs and the amplitude of evoked EPSCs in paclitaxel-treated rats. Paclitaxel treatment significantly increased the protein level of GluN2A and phosphorylated GluN1 in the dorsal root ganglion. In addition, intrathecal injection of AP5 or systemic administration of memantine profoundly attenuated pain hypersensitivity induced by paclitaxel. Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C to potentiate nociceptive input from primary afferent nerves. Targeting presynaptic NMDARs at the spinal cord level may be an effective strategy for treating chemotherapy-induced neuropathic pain.
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Jing-Dun
authors.initials: JD
authors.lastname: Xie
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and schen@mdanderson.org.
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
authors.forename: Wei-An
authors.initials: WA
authors.lastname: Zeng
authors.affiliation: From the Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and huilinpan@mdanderson.org.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects* / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D015763:2-Amino-5-phosphonovalerate; D017239:Paclitaxel; D011493:Protein Kinase C; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor
keywords: electrophysiology; ion channel; neuron; pain; synaptic plasticity; toxicity