• Corinne A G Lee-Kubli and Nigel A Calcutt.
• Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA; Graduate School of Biomedical Sciences, Sanford-Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
• Pain. 2014 Feb 1;155(2):250-60.

AbstractThe unpredictable efficacy of current therapies for neuropathic pain may reflect diverse etiological mechanisms operating between, and within, diseases. As descriptions of pain rarely establish specific mechanisms, a tool that can identify underlying causes of neuropathic pain would be useful in developing patient-specific treatments. Rate-dependent depression (RDD), a measure of the change in amplitude of the Hoffman reflex over consecutive stimulations, is attenuated in diabetic rats that also exhibit impaired spinal γ-aminobutyric acid (GABA)A receptor function, reduced spinal potassium chloride co-transporter (KCC2) expression, and indices of painful neuropathy. To investigate whether loss of RDD is a reliable indicator of the contribution of spinal GABAergic dysfunction to neuropathic pain, we assessed RDD, tactile allodynia, and formalin-evoked hyperalgesia in 3 models: rats treated acutely with brain-derived neurotrophic factor (BDNF), diabetic rats treated with the BDNF-sequestering molecule tyrosine receptor kinase B/Fc (TrkB/Fc), and rats with paclitaxel-induced neuropathy. Delivery of BDNF to the spinal cord of normal rats produced RDD deficits and features of painful neuropathy associated with disrupted GABAA receptor-mediated inhibitory function and reduced dorsal spinal KCC2 expression. Treating diabetic rats with TrkB/Fc restored RDD and alleviated indices of painful neuropathy. In paclitaxel-treated rats, RDD was not impaired and behavioral indices of neuropathic pain were not associated with spinal GABAergic dysfunction or reduced dorsal spinal KCC2 expression. Our data reveal BDNF as part of the mechanism underlying spinal cord disinhibition caused by altered GABAA receptor function in diabetic rats and suggest that RDD deficits may be a useful indicator of neuropathic pain states associated with spinal disinhibition, thereby revealing specific therapeutic targets.Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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