Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.

TitleTrans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.
Publication TypeJournal Article
Year of Publication2003
AuthorsCoull JAM, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y
JournalNature
Volume424
Issue6951
Pagination938-42
Date Published2003 Aug 21
ISSN1476-4687
KeywordsAnimals, Anions, Chronic Disease, Homeostasis, In Vitro Techniques, Male, Models, Neurological, Neurons, Pain, Pain Threshold, Peripheral Nerve Injuries, Peripheral Nerves, Rats, Receptors, GABA-A, Receptors, Glycine, Spinal Cord, Symporters, Synapses
Abstract

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.

DOI10.1038/nature01868
Alternate JournalNature
PubMed ID12931188

Funding

Our research endeavors are made possible by the following agencies:

Canadian Institutes of Health Research - Instituts de recherche en santé du Canada Fonds de recherche du Québec – Nature et technologies (FRQNT)Fonds de la recherche en santé du Québec NARSAD Natural Sciences and Engineering Research Council of Canada (NSERC) - Conseil de recherche en sciences naturelles et en génie du Canada (CRSNG)innovation.caHuman Frontier Science Program