Presynaptic N-Methyl-d-aspartate (NMDA) Receptor Activity Is Increased Through Protein Kinase C in Paclitaxel-induced Neuropathic Pain

Jing-Dun Xie,少瑞 陈,惠麟 潘,维安 曾,红 陈,敬敦 谢,Shao-Rui Chen,Hong Chen,Wei-An Zeng,Hui-Lin Pan

doi:10.1074/jbc.m116.732347

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.

Highlights

The glutamate N-methyl-D-aspartate receptors (NMDARs) are tetramers that contain two essential GluN1 subunits co-assembled with two GluN2 and/or GluN3 subunits, and GluN2 subunits are required for glutamate-dependent NMDAR activation [8]
Our findings indicate that paclitaxel treatment induces tonic activation of presynaptic NMDARs in the spinal cord through protein kinase C (PKC) to potentiate nociceptive input from primary afferent nerves
We found that paclitaxel treatment significantly increased baseline miniature EPSCs (mEPSCs) frequency of dorsal horn neurons, which was readily normalized to the level seen in vehicle-treated rats by bath application of AP5, a selective NMDAR antagonist that competitively inhibits the glutamate binding site on GluN2 subunits [32]

Summary

Introduction

The glutamate N-methyl-D-aspartate receptors (NMDARs) are tetramers that contain two essential GluN1 subunits co-assembled with two GluN2 and/or GluN3 subunits, and GluN2 subunits are required for glutamate-dependent NMDAR activation [8]. In the present study, we investigated the potential effect of paclitaxel treatment on presynaptic NMDAR activity in the spinal dorsal horn using a rat model. Our findings suggest that paclitaxel treatment induces tonic activation of presynaptic NMDAR activity in the spinal cord through protein kinase C (PKC), which contributes to increased nociceptive input from primary afferent nerves and to the development of neuropathic pain.

Results

Conclusion