ArticleThe Journal of biological chemistry2014
Increased spinal cord Na⁺-K⁺-2Cl⁻ cotransporter-1 (NKCC1) activity contributes to impairment of synaptic inhibition in paclitaxel-induced neuropathic pain.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 53 citations in OpenAlex.
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- Evaluation and application analysis of animal models of PIPNP based on data mining.Open life sciences · 2025Review
- TRPV1-dependent NKCC1 activation in mouse lens involves integrin and the tubulin cytoskeleton.Journal of cellular physiology · 2024Article
- Calcineurin and CK2 Reciprocally Regulate Synaptic AMPA Receptor Phenotypes via α2δ-1 in Spinal Excitatory Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Mitotic Functions and Characters of KIF11 in Cancers.Biomolecules · 2024Review
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- Constitutive KCC2 Cell- and Synapse-Specifically Regulates NMDA Receptor Activity in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Bidirectional Regulation of GABALife (Basel, Switzerland) · 2024Review
- Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy.Frontiers in molecular neuroscience · 2024Review
- The role ofJournal of pharmaceutical analysis · 2023Review
- mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Targeting Anti-Inflammatory Pathways to Treat Diabetes-Induced Neuropathy by 6-Hydroxyflavanone.Nutrients · 2023Article
- NMDA Receptors at Primary Afferent-Excitatory Neuron Synapses Differentially Sustain Chemotherapy- and Nerve Trauma-Induced Chronic Pain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow.Circulation research · 2022Article
- Dual PI3Kδ/γ Inhibitor Duvelisib Prevents Development of Neuropathic Pain in Model of Paclitaxel-Induced Peripheral Neuropathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- GABAergic Mechanisms Can Redress the Tilted Balance between Excitation and Inhibition in Damaged Spinal Networks.Molecular neurobiology · 2021Review
- Neuropathic Injury-Induced Plasticity of GABAergic System in Peripheral Sensory Ganglia.Frontiers in pharmacology · 2021Article
- Calcineurin Inhibition Causes α2δ-1-Mediated Tonic Activation of Synaptic NMDA Receptors and Pain Hypersensitivity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Microtubule-stabilizing agents, such as paclitaxel (Taxol), are effective chemotherapy drugs for treating many cancers, and painful neuropathy is a major dose-limiting adverse effect. Cation-chloride cotransporters, such as Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) and K(+)-Cl(-) cotransporter-2 (KCC2), critically influence spinal synaptic inhibition by regulating intracellular chloride concentrations. Here we show that paclitaxel treatment in rats significantly reduced GABA-induced membrane hyperpolarization and caused a depolarizing shift in GABA reversal potential of dorsal horn neurons. However, paclitaxel had no significant effect on AMPA or NMDA receptor-mediated glutamatergic input from primary afferents to dorsal horn neurons. Paclitaxel treatment significantly increased protein levels, but not mRNA levels, of NKCC1 in spinal cords. Inhibition of NKCC1 with bumetanide reversed the paclitaxel effect on GABA-mediated hyperpolarization and GABA reversal potentials. Also, intrathecal bumetanide significantly attenuated hyperalgesia and allodynia induced by paclitaxel. Co-immunoprecipitation revealed that NKCC1 interacted with β-tubulin and β-actin in spinal cords. Remarkably, paclitaxel increased NKCC1 protein levels at the plasma membrane and reduced NKCC1 levels in the cytosol of spinal cords. In contrast, treatment with an actin-stabilizing agent had no significant effect on NKCC1 protein levels in the plasma membrane or cytosolic fractions of spinal cords. In addition, inhibition of the motor protein dynein blocked paclitaxel-induced subcellular redistribution of NKCC1, whereas inhibition of kinesin-5 mimicked the paclitaxel effect. Our findings suggest that increased NKCC1 activity contributes to diminished spinal synaptic inhibition and neuropathic pain caused by paclitaxel. Paclitaxel disrupts intracellular NKCC1 trafficking by interfering with microtubule dynamics and associated motor proteins.
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