![conference banner](/images/conference-banner.jpeg)
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 |
Call for Papers in Thematic Issues
Adaptogens—History and Future Perspectives
Adaptogens are pharmacologically active compounds or plant extracts that are associated with the ability to enhance the body’s stability against stress. The intake of adaptogens is associated not only with a better ability to adapt to stress and maintain or normalise metabolic functions but also with better mental and physical ...read more
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
![Wayfinder Image](/images/wayfinder.jpg)
- 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
-
Study of Convolvulus pluricaulis for Antioxidant and Anticonvulsant Activity
Central Nervous System Agents in Medicinal Chemistry Editorial
Current Medicinal Chemistry Structure Activity Relationships of Novel Antiepileptic Drugs
Current Medicinal Chemistry Association Between Seizures and Diabetes Mellitus: A Comprehensive Review of Literature
Current Diabetes Reviews Strategies for Strengthening Patent Protection of Pharmaceutical Inventions in Light of Federal Court Decisions
Current Topics in Medicinal Chemistry Safety and Efficacy of Melatonin in Pediatric Migraine Prophylaxis
Current Drug Safety Aptamers as Tools to Study Dysfunction in the Neuronal System
Current Medicinal Chemistry - Central Nervous System Agents Increased Risk of Falls, Fall-related Injuries and Fractures in People with Type 1 and Type 2 Diabetes - A Nationwide Cohort Study
Current Drug Safety Research Progress of Nanocarriers for the Treatment of Alzheimer's Disease
Current Pharmaceutical Design Analysis of the Residues of Pharmaceuticals in Marine Environment: State-of-the-art, Analytical Problems and Challenges
Current Analytical Chemistry Maternal Exposure to Quetiapine: Effects on Structural Changes in Developing Brain and its Lasting Impact on Neurobehavioral Impairments in Rat Offspring
Current Psychopharmacology The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs)
Current Medicinal Chemistry A Review on Possible Therapeutic Effect of Nigella sativa and Thymoquinone in Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Citrus Peel Extract Attenuates Acute Cyanide Poisoning-Induced Seizures and Oxidative Stress in Rats
CNS & Neurological Disorders - Drug Targets State of the Art on Carbonic Anhydrase Modulators for Biomedical Purposes
Current Medicinal Chemistry Glia: An Important Target for Anti-Inflammatory and Antidepressant Activity
Current Drug Targets Cell Biological Consequences of Mitochondrial NADH: Ubiquinone Oxidoreductase Deficiency
Current Neurovascular Research Established and In-trial GPCR Families in Clinical Trials: A Review for Target Selection
Current Drug Targets Biophysical Modeling and Associated Signal Modeling in Functional Magnetic Resonance Imaging
Neuroscience and Biomedical Engineering (Discontinued) Phytochemicals: Potential in Management of Climacteric Neurobiology
Current Pharmaceutical Design