Abstract
The importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. Here we review recent evidence that two cation-chloride cotransporters, NKCC1 and KCC2 are involved in pain and enhanced nociception. On the one hand, NKCC1 activity is upregulated in primary afferents following an inflammatory insult and this produces excessive GABAergic depolarization in primary afferents leading to cross excitation between low and high threshold afferents. On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
Keywords: pain, hyperalgesia, chloride cotransporters, gaba, glycine
Current Topics in Medicinal Chemistry
Title: Role of Cation-Chloride-Cotransporters (CCC) in Pain and Hyperalgesia
Volume: 5 Issue: 6
Author(s): Theodore J. Price, Fernando Cervero and Yves de Koninck
Affiliation:
Keywords: pain, hyperalgesia, chloride cotransporters, gaba, glycine
Abstract: The importance of the GABAergic system in spinal nociceptive processing has long been appreciated but we have only recently begun to understand how this system is modulated by the regulation of anion gradients. In neuronal tissues, cation-chloride cotransporters regulate Cl- homeostasis and the activity and/or expression of these transporters has important implications for the direction and magnitude of anion flow through GABA-A channels. Here we review recent evidence that two cation-chloride cotransporters, NKCC1 and KCC2 are involved in pain and enhanced nociception. On the one hand, NKCC1 activity is upregulated in primary afferents following an inflammatory insult and this produces excessive GABAergic depolarization in primary afferents leading to cross excitation between low and high threshold afferents. On the other hand, KCC2 expression is reduced in dorsal horn neurons following peripheral nerve injury resulting in a loss of GABA-/glycinergic inhibitory tone and, in some cases, inverting its action into net excitation. Pharmacological targeting of these cation chloride cotransporters to restore normal GABA-/glycinergic transmission in the spinal cord represents an entirely novel approach to the development of analgesics.
Export Options
About this article
Cite this article as:
Theodore J. Price , Fernando Cervero and Yves de Koninck , Role of Cation-Chloride-Cotransporters (CCC) in Pain and Hyperalgesia, Current Topics in Medicinal Chemistry 2005; 5 (6) . https://dx.doi.org/10.2174/1568026054367629
DOI https://dx.doi.org/10.2174/1568026054367629 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Cyclooxygenases in the Central Nervous System: Implications for Treatment of Neurological Disorders
Current Pharmaceutical Design Automated Planar Electrode Electrophysiology in Drug Discovery: Examples of the Use of QPatch in Basic Characterization and High Content Screening on Nav, KCa2.3, and Kv11.1 Channels
Combinatorial Chemistry & High Throughput Screening Pyrrolizidine Alkaloids and their Biological Properties from Indian Heliotropium Species
Current Bioactive Compounds Decreased Expression of Sox-1 in Cerebellum of Rat with Generalized Seizures Induced by Kindling Model
CNS & Neurological Disorders - Drug Targets Unique Medicinal Properties of Withania somnifera: Phytochemical Constituents and Protein Component
Current Pharmaceutical Design New Horizons in the Treatment of Neurological Disorders with Tailorable Gold Nanoparticles
Current Drug Metabolism What have Genetically Engineered Mice Taught Us About Ischemic Injury?
Current Molecular Medicine Investigation of the Roles of New Antiepileptic Drugs and Serum BDNF Levels in Efficacy and Safety Monitoring and Quality of Life: A Clinical Research
Current Clinical Pharmacology Consequences of Iron Accumulation in Microglia and its Implications in Neuropathological Conditions
CNS & Neurological Disorders - Drug Targets Computational Methods Dedicated to Neurological Disorder Detection through Epistasis Analysis: A Review
Current Chinese Engineering Science Role of Cannabinoids and Endocannabinoids in Cerebral Ischemia
Current Pharmaceutical Design Nicotinic Acetylcholine Receptors and Epilepsy
Current Drug Targets - CNS & Neurological Disorders <i>Nigella sativa</i> – A Functional Spice From A Pharaoh’s Tomb to Modern Healthcare
The Natural Products Journal Roles of p75NTR in Maintaining Brain Hemostasis and the Implications for p75NTR-targeted Therapies
Current Alzheimer Research Scorpion Extracts Inhibit Tumor Growth in Esophageal Cancer and Lung Adenocarcinoma
Current Signal Transduction Therapy GABAB Receptors-Associated Proteins: Potential Drug Targets in Neurological Disorders?
Current Drug Targets A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy
Current Diabetes Reviews Mitochondrial Diseases in Childhood
Current Molecular Medicine Stem Cells: In Sickness and in Health
Current Stem Cell Research & Therapy Transglutaminases as Possible Therapeutic Targets in Neurodegenerative Diseases
Recent Patents on CNS Drug Discovery (Discontinued)