Elsevier

Brain Research Reviews

Volume 60, Issue 1, April 2009, Pages 149-170
Brain Research Reviews

Review
Chloride regulation in the pain pathway

https://doi.org/10.1016/j.brainresrev.2008.12.015Get rights and content

Abstract

Melzack and Wall's Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential (Eanion), which subsequently impacts fast synaptic inhibition mediated by GABAA, and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cation-chloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of Eanion which in turn appears to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury. This review summarizes the current state of knowledge in this area with particular attention to how such findings relate to endogenous mechanisms of hyperalgesia and allodynia and potential applications for therapeutics based on modulation of intracellular Cl gradients or pharmacological interventions targeting GABAA receptors.

Introduction

Pain is a highly dynamic sensation. The enhanced sensitivity to pain that follows an injury or inflammation, generally known as hyperalgesia, is the archetypical expression of such plasticity. For over a century, hyperalgesic states have been interpreted as the consequence of the increased excitability of the peripheral and central nervous system induced by injury or inflammation. These enhancements of excitability are referred to as peripheral or central sensitization and can be produced by increased synaptic excitation, decreased synaptic inhibition (i.e. disinhibition), increased neuronal responsiveness, or any combination thereof.

This review focuses on disinhibition, and more specifically, on disinhibition caused by changes in Cl regulation. Several studies have shown that hyperalgesia and allodynia are produced by pharmacologically blocking inhibition in the spinal cord (Loomis et al., 2001b, Malan et al., 2002, Schoffnegger et al., 2008, Sherman and Loomis, 1994, Sherman and Loomis, 1995, Sherman and Loomis, 1996, Sivilotti and Woolf, 1994, Sorkin and Puig, 1996, Sorkin et al., 1998, Yaksh, 1989b) or through genetic changes that reduce inhibition (Ugarte et al., 2000). Conversely, increasing inhibition can reduce hyperalgesia and allodynia (Eaton et al., 1999, Hwang and Yaksh, 1997, Rode et al., 2005, Stubley et al., 2001). Indeed, such results are predicted by the Gate Control Theory of Pain (Melzack and Wall, 1965). This influential theory proposed that in the superficial dorsal horn, afferent activity arriving along “large” (Aβ) fibers could reduce transmission of impulses in “small” (Aδ and C) afferents and thus reduce pain sensation. The original theory focused on presynaptic mechanisms of inhibition (see Section 3), but subsequent work has revealed that postsynaptic mechanisms are also involved (see Section 5).

Synaptic inhibition can be reduced through several mechanisms including reduction of transmitter release or number of receptors. However, the potency of synaptic inhibition can also be modulated through changes that are independent of the transmitter or the receptor. This is because GABAA and glycine receptors depend on the transmembrane Cl gradient for their mechanism of action. The transmembrane Cl gradient is maintained by co-transporters (see Section 2.1). Changes in the expression and/or function of those co-transporters is an important pathophysiological mechanism responsible, at least in part, for disinhibition implicated in chronic pain and in other neurological disorders such as epilepsy. With respect to the processing of nociceptive information at the first synapse in the central nervous system, such changes affect both pre- and postsynaptic inhibition, although there are important distinctions based on differences in normal Cl regulation between the two loci. Furthermore, derangement of Cl regulation can lead to paradoxical excitation (rather than simply a reduction in inhibition) and requires special consideration for its therapeutic correction.

This article reviews the current state of knowledge on Cl regulation and its impact on nociceptive processing in the spinal cord dorsal horn, together with the implications of recent observations for the development of new pain therapies. A particularly exciting aspect of these novel approaches is that they are not based on the classic interactions between transmitters and receptors but, rather, they consider changes in the ionic composition of cells that in turn lead to major alterations in synaptic function. This opens up new therapeutic possibilities that are as yet unexplored.

Section snippets

Chloride regulation by co-transporters

In order for ion channels to pass current, an electrochemical gradient must exist across the cell membrane. The direction and magnitude of current depends on the direction and steepness of that gradient. The transmembrane Cl gradient is maintained primarily by cation-chloride co-transporters (for review see Payne et al. 2003). Among neurons, the two most important co-transporters for regulating intracellular Cl concentration ([Cl]in) are NKCC1 (sodium–potassium-chloride co-transporter, that

GABA actions on primary afferent neurons and the role of NKCC1

The Gate Control Theory of Pain, proposed in 1965 by Melzack and Wall, recognized that afferent inputs interact in the spinal dorsal horn and that this interaction can play a key role in the processing of pain-related information (see Section 1). The most innovative aspects of the Gate theory were the idea of the gating of sensory inputs at the first synaptic relay and the proposal that the underlying mechanism was presynaptic interaction between primary sensory afferents in the superficial

Pharmacological considerations

Investigations that seek to establish the causality of NKCC1 in sensory function face a number of challenges and limitations. One of the most significant limitations concerns the selectivity of the pharmacological antagonists or inhibitors that are currently available. Benzmetanide, bumetanide, piretanide and furosemide are all inhibitors of NKCC1. Of these, bumetanide is the most specific for NKCC1 and is considered the prototypic agent for pharmacologic investigations of the role of NKCC1 (

Postsynaptic inhibition of spinal dorsal horn neurons

The original Gate Control Theory emphasized the role of presynaptic inhibition (Melzack and Wall, 1965) (see Section 3), but inhibition acting postsynaptically on dorsal horn neurons is also critical for controlling the flow of sensory information from the periphery through the spinal cord to the brain (Brown et al., 1987, De Koninck and Henry, 1994, Kato et al., 2006, Lin et al., 1996a, Todd and Spike, 1993, Yoshimura and Nishi, 1995). Unlike primary afferent cells, which lack KCC2 (Coull et

Role of GABAA receptors in allodynia and hyperalgesia

As detailed in the preceding sections of this review, there is compelling evidence to suggest that tissue injury results in a depolarizing shift in the anion equilibrium potential (Eanion) which, depending on the magnitude of the shift, may be associated with either a simple loss of inhibition or the emergence of excitation associated with the activation of Cl channels such as the GABAA receptor. Indeed, direct electrophysiological evidence indicates that, following nerve injury, there is a

Closing remarks

While Melzack and Wall's Gate Control Theory first laid the foundations for a major role for GABAergic neurotransmission in pain control, recent advances have made it clear that pain control via manipulation of GABAergic and glycinergic transmission in the dorsal horn is subject to nuances in receptor localization, subunit composition and Cl gradients that are only now beginning to be fully appreciated. A better understanding of Cl (and HCO3) regulation and its impact on synaptic

Acknowledgments

TJP is supported by startup funds from the University of Arizona and by the University of Arizona Foundation. FC is the holder of a CIHR Research Chair. Work in his lab is supported by CIHR, FRSQ and CFI. MSG is supported by 7R01NS044992-05 from NIH. DLH is supported by R01DA016430 from NIH. SAP is supported by startup funds from the University of Pittsburgh.

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