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Enhancing K–Cl co-transport restores normal spinothalamic sensory coding in a neuropathic pain model

Guillaume Lavertu, Sylvain L. Côté, Yves De Koninck
DOI: http://dx.doi.org/10.1093/brain/awt334 724-738 First published online: 25 December 2013

Summary

Neuropathic pain is a widespread and highly debilitating condition commonly resulting from injury to the nervous system, one main sequela of which is tactile allodynia, a pain induced by innocuous mechanical stimulation of the skin. Yet, the cellular mechanisms and neuronal substrates underlying this pathology have remained elusive. We studied this by quantifying and manipulating behavioural and neuronal nociceptive thresholds in normal and pathological pain conditions. We found that, in both control rats and those with pain hypersensitivity induced by nerve injury, the nociceptive paw withdrawal threshold matches the response threshold of nociceptive-specific deep spinothalamic tract neurons. In contrast, wide dynamic range or multimodal spinothalamic tract neurons showed no such correlation nor any change in properties after nerve injury. Disrupting Cl homeostasis by blocking K+–Cl co-transporter 2 replicated the decrease in threshold of nociceptive-specific spinothalamic tract neurons without affecting wide dynamic range spinothalamic tract cells. Accordingly, only combined blockade of both GABAA- and glycine-gated Cl channels replicated the effects of nerve injury or K+–Cl co-transporter 2 blockade to their full extent. Conversely, rescuing K+–Cl co-transporter 2 function restored the threshold of nociceptive-specific spinothalamic tract neurons to normal values in animals with nerve injury. Thus, we unveil a tight association between tactile allodynia and abnormal sensory coding within the normally nociceptive-specific spinothalamic tract. Thus allodynia appears to result from a switch in modality specificity within normally nociceptive-specific spinal relay neurons rather than a change in gain within a multimodal ascending tract. Our findings identify a neuronal substrate and a novel cellular mechanism as targets for the treatment of pathological pain.

  • Cl homeostasis
  • disinhibition
  • GABA
  • glycine
  • tactile allodynia
  • sensory crosstalk
  • Abbreviations
    KCC2
    K+–Cl co-transporter 2
    NEW
    new class of neuron
    NS
    nociceptive-specific
    STT
    spinothalamic tract
    WDR
    wide dynamic range
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