Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6275286 | Neuroscience | 2013 | 15 Pages |
Although trigeminal neuropathic pain is one of the most common chronic pain syndromes, the etiology is still unknown. Here, a rat model was generated using chronic constrictive injury (CCI) with ligation of the infraorbital nerve to test the hypothesis that collapse of chloride homeostasis in trigeminal neurons causes impairment of γ-aminobutyric acid-ergic (GABAergic) inhibition and induces trigeminal allodynia. Rats showed a reduction and increase in pain threshold and pain response scores, respectively, to mechanical stimulation, 1 and 3 weeks after CCI. In situ hybridization and immunohistochemical analysis showed that inward-directed Na+, K+-2Clâ cotransporter (NKCC1) mRNA and protein were upregulated in the small-sized and large-sized primary neurons in the injured side of the trigeminal ganglion and in the peripherin-positive terminal, respectively, for the first 2 weeks, while outward-directed K+-Clâ cotransporter (KCC2) mRNA and protein were downregulated in secondary relay neurons on the injured side of the spinal trigeminal nucleus caudalis (Sp5C). Optical imaging of evoked synaptic responses using a voltage-sensitive dye revealed that pre- and post-synaptic GABA actions were disinhibited and excitatory in the injured side, respectively, but inhibited in the sham-operated side of the Sp5C. This downregulation of KCC2 in the Sp5C may result in an excitatory switch by impairing postsynaptic GABA inhibition. GABA-mediated presynaptic disinhibition was attenuated by bumetanide, suggesting that NKCC1 upregulation in primary neurons may facilitate pain transmission by presynaptic GABAergic depolarization. Such Clâ homeostatic disruption resulting in perturbation of the inhibitory system possibly increases pain transmission, which may underlie the pathophysiology of trigeminal neuropathic pain.
Graphical abstractDownload high-res image (147KB)Download full-size imageHighlights⺠We made neuropathic pain model by chronic constrictive infraorbital nerve injury. ⺠KCC2 downregulated in relay neurons in spinal trigeminal nucleus caudalis (Sp5C). ⺠NKCC1 immunoreactivity increased in primary afferent terminals in the Sp5C. ⺠Pre- and post-synaptic GABAergic inhibition was lost and reversed, respectively. ⺠Clâ homeostatic collapses in trigeminal relay/primary neurons underlie allodynia.