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.The severe neuropathic pain caused by many effective chemotherapeutic agents, including paclitaxel (Taxol), bortezomib, oxaliplatin, and vincristine, is often the reason for discontinuation of what is otherwise life-saving therapy (1). Paclitaxel, which acts by stabilizing the microtubule cytoskeleton against depolymerization, is widely used to treat patients with breast, lung, ovarian, and other types of solid cancers. The peripheral neuropathy induced by paclitaxel treatment is frequently associated with burning pain, tingling, and numbness in the feet and hands (2-4). Such conditions are chronic and respond poorly to standard analgesics such as opioids, anticonvulsants, and antidepressants (1). Paclitaxel treatment can also damage primary afferent nerves and neurons in the dorsal root ganglion (DRG) 3 (5-7). However, the molecular mechanisms responsible for the increased nociceptive input in paclitaxelinduced neuropathic pain are not fully known.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 gluta...

Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord

“…Paclitaxel, which primarily stabilizes microtubules, disrupts the axonal transport of proteins and subcellular organelles (Dumontet and Jordan, 2010; Jordan and Wilson, 2004). Although paclitaxel and bortezomib have distinct molecular targets, our study reveals that they have similar effects on presynaptic NMDAR activation and PKC activity in the DRG (He and Wang, 2015; Xie et al, 2016). Thus, these two drugs probably have overlapping mechanisms in causing painful neuropathy.…”

“…NMDAR antagonists are effective in treating patients with certain neuropathic pain conditions (Loy et al, 2016; Zhou et al, 2011). Systemic administration of memantine, an orally active NMDAR antagonist used clinically, can reduce chemotherapy (paclitaxel)-induced pain hypersensitivity (Xie et al, 2016). We showed in this study that blocking NMDARs at the spinal cord level with intrathecal injection of AP5 profoundly reversed pain hypersensitivity induced by bortezomib.…”

“…At the spinal cord level, NMDARs are expressed at the central terminals of primary afferent nerves (Liu et al, 1994). Although presynaptic NMDARs in the spinal dorsal horn are latent and not functionally active under physiological conditions, they become activated under various painful conditions (Chen et al, 2011; Chen et al, 2014a; Li et al, 2016; Xie et al, 2016; Zhao et al, 2012). Nevertheless, little is known about whether proteasome inhibition affects presynaptic or postsynaptic NMDAR activity at the spinal cord level.…”

Increased α2δ‐1–NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy‐induced neuropathic pain

“…), confirming that presynaptic NMDARs in the spinal dorsal horn are tonically activated by paclitaxel treatment (Xie et al . ). Treatment with pregabalin (20 μM for 30–60 min) completely normalized the baseline frequency of mEPSCs of lamina II neurons, which had been increased by paclitaxel treatment ( n = 10 neurons, Fig.…”

“…Chemotherapy‐induced neuropathic pain is associated with tonic activation of presynaptic NMDARs, which promotes nociceptive glutamatergic input to spinal dorsal horn neurons (Xie et al . , ). To determine the contribution of α2δ‐1 to the increase in presynaptic NMDAR activity caused by paclitaxel treatment, we examined the effect of pregabalin, a clinically used α2δ‐1 inhibitory ligand (Li et al .…”