Chloride regulation in the pain pathway

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 (E anion ), which subsequently impacts fast synaptic inhibition mediated GABA A , and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cationchloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of E anion 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 GABA A receptors

Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice

“…In animals with injured nerves, spinothalamic tract neurons show increased responsiveness to innocuous mechanical stimuli (Palecek et al, 1992). These changes after nerve injury are explained by a reduced Cl Ϫ gradient in the neurons (Coull et al, 2003;Price et al, 2009), because inhibition to nociceptive spinothalamic tract neurons from innocuous afferent inputs is reduced by the change. The reduced Cl Ϫ gradient is attributed to downregulation of the neuron-specific KCl cotransporter (KCC2) in the dorsal horn neurons (Coull et al, 2003).…”

An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

“…In the adult peripheral nervous system, preferential expression of the inwardly directed Na ϩ -K ϩ -Cl Ϫ cotransporter, NKCC1, is responsible for the high intracellular chloride concentration, [Cl Ϫ ] i , compared with central neurons (Price et al, 2009). Under physiological conditions, the high [Cl Ϫ ] i confers depolarizing effects to the ligand-activated chloride channel GABA A , which is involved in the inhibitory control of pain (Price et al, 2009). Following inflammation, occurrence of neurogenic pain is attributed to a further increase [Cl Ϫ ] i , leading to both retrograde and anterograde propagation of electrical activity (Cervero et al, 2003).…”

Allosteric modulation of metabotropic glutamate receptors by chloride ions

“…neuropathic pain (1). Indeed, Cl 2 is involved in many cellular functions, including volume control, intracellular membrane trafficking, and excitability.…”

“…The mGluR family is composed of 8 members [metabotropic glutamate (mGlu) [1][2][3][4][5][6][7][8] and is divided into 3 groups. Group I mGluRs (mGlu1 and 5) are postsynaptic receptors that positively modulate neuronal excitability.…”