Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.
Modern pain-control theory predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes. However, the nature of the mechanisms that underlie such disinhibition has remained controversial. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium-chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.
Coull
Jeffrey A M
JA
Neurobiologie Cellulaire, Centre de recherche Université Laval Robert-Giffard, Québec, Québec G1J 2G3, Canada.
Boudreau
Dominic
D
Bachand
Karine
K
Prescott
Steven A
SA
Nault
Francine
F
Sík
Attila
A
De Koninck
Paul
P
De Koninck
Yves
Y
D000818:Animals; D000838:Anions / Q000378:metabolism; D002908:Chronic Disease; D006706:Homeostasis; D066298:In Vitro Techniques; D008297:Male; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism*; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000503:physiopathology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology* / Q000503:physiopathology*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D000096922:K Cl- Cotransporters
D000838:Anions; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D027981:Symporters; D000096922:K Cl- Cotransporters