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.
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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 |
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