Phosphorylation and Membrane Recruitment of the NKCC1 Cotransporter and Referred Visceral Hyperalgesia

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The Na+-K+-2Cl~ cotransporter isoform 1 (NKCC1) is a member of the cation-dependent Cl_ transporter family whose main function is to move chloride ions into the cell using the energy of the sodium gradient created by the Na-K-ATPase pump (88). The function of the NKCC1 cotransporter is tightly regulated by phosphorylation of Thr184 and Thr189 in the intracellular N-terminal domain and this has been demonstrated to be a mechanism for the enhancement of the cotransporter's activity (89). The activity of the NKCC1 cotransporter is a key contributor to the postsynaptic actions of gamma-aminobutyric acid (GABA) (90).

Recently, several studies have suggested a role for the NKCC1 cotransporter in nocicep-tive processing and in the generation and maintenance of hyperalgesic states. Disruption of the gene encoding NKCC1 causes an impaired behavioral response to the hot plate test (91) and a reduction in stroking hyperalgesia (touch-evoked pain or allodynia) evoked by capsaicin injections (92). NKCC1 is expressed in primary afferent neurons and in sensory neurons in the spinal cord and the induction of an experimental arthritis alters the expression of NKCC1 in these neurons (93). The process by which NKCC1 may be involved in pain processing involves the role of the cotransporter in the generation of presynaptic inhibition in the spinal cord (94), a mechanism proposed in the gate control theory of pain (95) to explain interactions between low- and high-threshold afferents in spinal nociceptive processing.

The upregulation of NKCC1 during the generation of a visceral hyperalgesic state has been studied recently (96). Using a murine model of visceral hyperalgesia (54), it was found that the noxious visceral stimulus induces a delivery of the NKCC1 cotransporter to the plasma membrane of neurons in the spinal cord. Additionally, the noxious visceral stimulation evokes a rapid and transient phosphorylation of the NKCC1 cotransporter in the membrane fraction of the lumbosacral spinal cord (Fig. 5) (96).

Figure 5 Intracolonic capsaicin induces Na+-K+-2Cr cotransporter isoform 1 cotransporter phosphorylation. (A) Western blot from membrane protein extracts showing the time course of NKCC1 phosphorylation. Lane marked "B" in the immunoblot contains control (basal) tissue. (B) Quantification of phospho-NKCCI normalized to ^-tubulin values after intracolonic capsaicin. Asterisks indicate a significant difference from control levels (p < 0.01). Source: From Ref. 96.

If the membrane mobilization of NKCC1 occurred in the spinal cord terminals of primary afferents, this would produce an increase in the intracellular concentration of chloride and an enhanced GABA-mediated primary afferent depolarization (PAD). It has been proposed that such an enhancement of PAD can lead to touch-evoked pain (97,98); it has been demonstrated that PAD can be increased by inflammatory stimuli to levels that will evoke spike activity (99).

Manipulation of anion gradients in primary afferent neurons, particularly those involved in nociceptive signalling, represents an entirely novel approach to the development of new therapeutic strategies for the treatment and prevention of persistent pain. Traditional pharmacological approaches are usually based on targeting neurotransmitters and their receptors or the enzymes responsible for their metabolism. The results described above offer a new avenue in pain control by approaching the ionic basis of the actions of some neurotransmitters particularly those, such as GABA, that can change from inhibitory under normal conditions to excitatory in certain pain states.

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