Figure 3. Cation-chloride cotransporters in pain.

There are two major theories concerning the role of cation-chloride cotransporters (CCCs) in chronic pain, and more specifically in touch-evoked pain (allodynia). Under normal conditions (part a), the activation of Aβ fibres, the myelinated fibres responsible for light touch sensation, leads to primary afferent depolarization in C fibres and consequent presynaptic shunting inhibition of pain-conducting C fibres by dorsal horn GABAergic interneurons. This requires the expression of Na⁺–K⁺–2Cl⁻ cotransporter 1 (NKCC1) in dorsal root ganglion (DRG) C fibre neurons. The inhibition blocks the signalling of the C fibres to lamina I projection neurons. Following injury, signalling cascades lead to phosphorylation and thereby kinetic activation of NKCC1 (FIG. 1d) in C fibre terminals. This may be linked to an increase in [Cl⁻]_i, potentially converting Aβ fibre-mediated inhibition into frank excitation of C fibres and leading to activation of pain signalling via lamina I projection neurons. This provides a neurophysiological explanation for allodynia. Very recent evidence suggests that nociceptive-specific (NS) neurons in the deep laminae of the dorsal horn (lamina V) lose KCC2 expression following peripheral nerve injury (PNI), thereby altering the response of these neurons to GABA and unmasking an Aβ fibre-mediated input to NS neurons, effectively converting them to wide dynamic range (WDR) neurons (part b). As in the scenario outlined in part a, this gives the Aβ fibre pathway access to pain signalling through feedforward activation of projection neurons in lamina I/II. Importantly, conversion of NS neurons to WDR neurons following PNI is reversed by positive modulation of KCC2 and this treatment also reduces touch-evoked pain in behavioural assays. GABA_AR, GABA_A receptor.