title: Pre- and post-synaptic switches of GABA actions associated with Cl- homeostatic changes are induced in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain.
abstract: 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 3weeks after CCI. In situ hybridization and immunohistochemical analysis showed that inward-directed Na(+), K(+)-2Cl(-) 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 2weeks, while outward-directed K(+)-Cl(-) 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 Cl(-) homeostatic disruption resulting in perturbation of the inhibitory system possibly increases pain transmission, which may underlie the pathophysiology of trigeminal neuropathic pain.
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: B
authors.initials: B
authors.lastname: Wei
authors.forename: T
authors.initials: T
authors.lastname: Kumada
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: A
authors.initials: A
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D017288:Pain Threshold / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D055366:Synaptic Potentials / Q000502:physiology; D014279:Trigeminal Nucleus, Spinal / Q000378:metabolism* / Q000473:pathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005680:gamma-Aminobutyric Acid