Increased Spinal Cord Na+-K+-2Cl− Cotransporter-1 (NKCC1) Activity Contributes to Impairment of Synaptic Inhibition in Paclitaxel-induced Neuropathic Pain

Chen, Shao Rui; Zhu, Lihong; Chen, Hong; Lei, Wen; Laumet, Geoffroy; Pan, Hui Lin

doi:10.1074/jbc.m114.600320

Cited by 51 publications

(46 citation statements)

References 59 publications

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“…Most importantly, as GAD mRNA levels are unchanged in the paclitaxel model, at least when low doses are used, any hypersensitivity resulting from loss of inhibitory function likely arises from alterations in GABAergic inhibitory circuitry. Indeed, in paclitaxel-injected mice, Chen et al [13] recently reported impaired spinal cord GABAergic synaptic inhibition due to a chloride gradient imbalance. On the other hand and consistent with the results of Flatters et al [17], we did not find significant ATF3 induction in DRG cells after paclitaxel.…”

Section: Discussionmentioning

confidence: 99%

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

Bráz¹,

Wang²,

Guan³

et al. 2015

Pain

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Decreased spinal cord GABAergic inhibition is a major contributor to the persistent neuropathic pain that can follow peripheral nerve injury. Recently, we reported that restoring spinal cord GABAergic signaling by intraspinal transplantation of cortical precursors of GABAergic interneurons from the embryonic medial ganglionic eminence (MGE) can reverse the mechanical hypersensitivity (allodynia) that characterizes a neuropathic pain model in the mouse. Here we show that MGE cell transplants are also effective against both the mechanical allodynia and the heat hyperalgesia produced in a paclitaxel-induced, chemotherapy model of neuropathic pain. To test the necessity of GABA release by the transplants, we also studied the utility of transplanting MGE cells from mice with a deletion of VGAT, the vesicular GABA transporter. Transplants from these mice, in which GABA is synthesized but cannot be stored or released, had no effect on mechanical hypersensitivity or heat hyperalgesia in the paclitaxel model. Taken together, these results demonstrate the therapeutic potential of GABAergic precursor cell transplantation in diverse neuropathic pain models and support our contention that restoration of inhibitory controls through release of GABA from the transplants is their mode of action.

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Section: Discussionmentioning

confidence: 99%

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

Bráz¹,

Wang²,

Guan³

et al. 2015

Pain

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“…Presynaptic NMDARs, which have been recorded at many cortical synapses (14,34,35), can regulate neurotransmitter release by causing Ca 2ϩ influx to trigger vesicle exocytosis. The sources of glutamate for the paclitaxelinduced tonic activation of presynaptic NMDARs probably originate from the same primary afferent terminals on which the NMDARs are expressed (autoreceptor) or from excitatory interneurons in the dorsal horn owing to the diminished synaptic inhibition caused by paclitaxel treatment (13), resulting in direct synaptic excitation of presynaptic boutons (axo-axonic). Alternatively, the paclitaxel-induced tonic activation of presyn- aptic NMDARs in the spinal cord may result from glutamate diffusion from an adjacent active terminal (spillover), activitydependent release of glutamate from the dendrites of a postsynaptic cell (retrograde), reduced glutamate reuptake due to reduced glutamate transporter activity, and/or glutamate release from surrounding glial cells (paracrine).…”

Section: Discussionmentioning

confidence: 99%

“…Horn Neurons-In our previous study, we found that paclitaxel treatment has no effect on the activity of postsynaptic NMDARs in the spinal dorsal horn (13). We thus determined whether paclitaxel alters the activity of presynaptic NMDARs by recording glutamatergic mEPSCs, which reflect spontaneous quantal release of glutamate from presynaptic terminals (11,18).…”

Section: Paclitaxel Increases Presynaptic Nmdar Activity Of Dorsalmentioning

confidence: 99%

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

Xie

Chen

et al. 2016

Journal of Biological Chemistry

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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...

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“…Thus, changing the intracellular Cl − concentration can profoundly alter the strength and polarity of GABA- or glycine-mediated responses. Neuropathic pain caused by peripheral nerve damage, spinal cord injury, diabetic neuropathy, and chemotherapy is associated with reduced KCC2 activity or increased NKCC1 activity in spinal dorsal horn neurons (Boulenguez et al, 2010; Chen et al, 2014d; Coull et al, 2003; Jolivalt et al, 2008; Zhou et al, 2012). Nerve injury also increases NKCC1 phosphorylation and activity in dorsal root ganglion (DRG) neurons to reduce presynaptic inhibition (Chen et al, 2014a; Modol et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Chen

et al. 2016

Cell Reports

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SUMMARY Chronic neuropathic pain is a debilitating condition that remains difficult to treat. Diminished synaptic inhibition by GABA and glycine and increased NMDA receptor (NMDAR) activity in the spinal dorsal horn are key mechanisms underlying neuropathic pain. However, the reciprocal relationship between synaptic inhibition and excitation in neuropathic pain is unclear. Here we show that intrathecal delivery of K+-Cl− cotransporter-2 (KCC2) using lentiviral vectors produces a complete and long-lasting reversal of pain hypersensitivity induced by nerve injury. KCC2 gene transfer restores Cl− homeostasis disrupted by nerve injury in both spinal dorsal horn and primary sensory neurons. Remarkably, restoring Cl− homeostasis normalizes both presynaptic and postsynaptic NMDAR activity increased by nerve injury in the spinal dorsal horn. Our findings indicate that nerve injury recruits NMDAR-mediated signaling pathways through disrupting Cl− homeostasis in spinal dorsal horn and primary sensory neurons. Lentiviral vector-mediated KCC2 expression is a promising gene therapy for treating neuropathic pain.

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Increased Spinal Cord Na+-K+-2Cl− Cotransporter-1 (NKCC1) Activity Contributes to Impairment of Synaptic Inhibition in Paclitaxel-induced Neuropathic Pain

Cited by 51 publications

References 59 publications

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity

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

Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

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