Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Li, Lingyong; Chen, Shao Rui; Chen, Hong; Lei, Wen; Hittelman, Walter N.; Xie, Jing; Pan, Hui Lin

doi:10.1016/j.celrep.2016.04.039

Cited by 79 publications

(88 citation statements)

References 31 publications

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“…1). As reported previously (Chen et al, 2014b; Li et al, 2016), the amplitude of currents of spinal dorsal horn neurons elicited by puff NMDA was much larger in SNL than in sham control rats. L-arginine produced a similar inhibitory effect on NMDAR currents of 12 dorsal horn neurons recorded from SNL rats (Fig.…”

Section: Resultssupporting

confidence: 87%

“…In the central nervous system, nNOS is located at the postsynaptic density and is closely linked to NMDARs (Christopherson et al, 1999; Valtschanoff and Weinberg, 2001). Peripheral nerve injury causes a large increase in synaptic NMDAR activity of spinal dorsal horn neurons (Chen et al, 2014b; Li et al, 2016). Because increased NO synthesis and release often occur in the same neurons after NMDAR activation, endogenous NO may be involved in negative feedback inhibition of NMDARs and NMDAR-mediated nociceptive transmission in the spinal dorsal horn under physiological and neuropathic pain conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Glutamate is the most predominant excitatory neurotransmitter involved in synaptic transmission from primary sensory nerves to spinal dorsal horn neurons (Pan and Pan, 2004; Yoshimura and Jessell, 1990). The glutamate N-methyl-D-aspartate receptor (NMDAR) activity in the spinal dorsal horn is markedly increased after peripheral nerve injury and is essential for synaptic plasticity associated with development of chronic neuropathic pain (Chen et al, 2014b; Isaev et al, 2000; Li et al, 2016; Zhou et al, 2012). However, it remains unclear how the NMDAR activity of dorsal horn neurons is regulated under physiological and neuropathic pain conditions.…”

Section: Introductionmentioning

confidence: 99%

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Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury

2017

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The role of nitric oxide (NO) in nociceptive transmission at the spinal cord level remains uncertain. Increased activity of spinal N-methyl-D-aspartate (NMDA) receptors contributes to development of chronic pain induced by peripheral nerve injury. In this study, we determined how endogenous NO affects NMDA receptor activity of spinal cord dorsal horn neurons in control and spinal nerve-ligated rats. Bath application of the NO precursor L-arginine or the NO donor S-nitroso-N-acetylpenicillamine (SNAP) significantly inhibited NMDA receptor currents of spinal dorsal horn neurons in both sham control and nerve-injured rats. Inhibition of neuronal nitric oxide synthase (nNOS) or blocking the S-nitrosylation reaction with N-ethylmaleimide abolished the inhibitory effects of L-arginine on NMDA receptor currents recorded from spinal dorsal horn neurons in sham control and nerve-injured rats. However, bath application of the cGMP analog 8-bromo-cGMP had no significant effects on spinal NMDA receptor currents. Inhibition of soluble guanylyl cyclase also did not alter the inhibitory effect of L-arginine on spinal NMDA receptor activity. Furthermore, knockdown of nNOS with siRNA abolished the inhibitory effects of L-arginine, but not SNAP, on spinal NMDA receptor activity in both groups of rats. Additionally, intrathecal injection of L-arginine significantly attenuated mechanical or thermal hyperalgesia induced by nerve injury, and the L-arginine effect was diminished in rats treated with a nNOS inhibitor or nNOS-specific siRNA. These findings suggest that endogenous NO inhibits spinal NMDA receptor activity through S-nitrosylation. NO derived from nNOS attenuates spinal nociceptive transmission and neuropathic pain induced by nerve injury.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury

2017

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“…Similarly, in a nerve injury model, intrathecal delivery of KCC2 using lentiviral vector results in a complete and long-lasting reversal of pain hypersensitivity by restoring Cl − homeostasis both at spinal and peripheral levels [14]. Unlike KCC2, the role of VGAT in pathophysiology of GABA disinhibition is not clearly defined.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

Zhang

Kannampalli

et al. 2017

Pain

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Loss of GABAergic inhibition in pain pathways has been considered to be a key component in the development of chronic pain. In the present study, we intended to examine whether miR-92b–mediated posttranscriptional dysregulation of spinal potassium chloride cotransporter (KCC2) and vesicular γ-aminobutyric acid transporter (VGAT) plays a major role in the development and maintenance of long-term visceral hyperalgesia in neonatal zymosan–treated rats. Neonatal cystitis was induced by transurethral zymosan administration from postnatal (P) days 14 to 16 (protocol 1). Two other zymosan protocols were also used: adult rechallenge on P57 to 59 following neonatal P14 to 16 exposures (protocol 2), and adult zymosan exposures on P57 to 59 (protocol 3). Both neonatal and adult bladder inflammation protocols demonstrated an increase in spinal miR-92b-3p expression and subsequent decrease in KCC2 and VGAT expression in spinal dorsal horn neurons. In situ hybridization demonstrated a significant upregulation of miR-92b-3p in the spinal dorsal horn neurons of neonatal cystitis rats compared with saline-treated controls. In dual in situ hybridization and immunohistochemistry studies, we further demonstrated coexpression of miR-92b-3p with targets KCC2 and VGAT in spinal dorsal horn neurons, emphasizing a possible regulatory role both at pre- and post-synaptic levels. Intrathecal administration of lentiviral pLSyn-miR-92b-3p sponge (miR-92b-3p inhibitor) upregulated KCC2 and VGAT expression in spinal dorsal horn neurons. In behavioral studies, intrathecal administration of lentiviral miR-92b-3p sponge attenuated an increase in visceromotor responses and referred viscerosomatic hypersensitivity following the induction of cystitis. These findings indicate that miR-92b-3p–mediated posttranscriptional regulation of spinal GABAergic system plays an important role in sensory pathophysiology of zymosan-induced cystitis.

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“…At the spinal cord level, NMDARs are expressed at the central terminals of primary afferent nerves and at second-order dorsal horn neurons (9,17,18). Under physiological conditions, presynaptic NMDARs in the spinal dorsal horn are latent and not functionally active in regulating glutamate release (9,19). However, in opioid-induced hyperalgesia and traumatic nerve injury-induced chronic pain conditions, presynaptic NMDARs in the spinal cord become active and are tonically stimulated by endogenous glutamate (9, 18 -20).…”

mentioning

confidence: 99%

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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Chloride Homeostasis Critically Regulates Synaptic NMDA Receptor Activity in Neuropathic Pain

Cited by 79 publications

References 31 publications

Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury

Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury

MicroRNA–mediated downregulation of potassium-chloride-cotransporter and vesicular γ-aminobutyric acid transporter expression in spinal cord contributes to neonatal cystitis–induced visceral pain in rats

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

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