Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy

Marshall, Andrew G ORCID: 0000-0001-8273-7089, Lee-Kubli, Corinne, Azmi, Shazli, Zhang, Michael, Ferdousi, Maryam, Mixcoatl-Zecuatl, Teresa, Petropoulos, Ioannis N, Ponirakis, Georgios, Fineman, Mark S, Fadavi, Hassan
et al (show 8 more authors) (2017) Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy. Diabetes, 66 (5). pp. 1380-1390.

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Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Item Type: Article
Uncontrolled Keywords: Spinal Cord, Cornea, Animals, Humans, Rats, Rats, Zucker, Rats, Sprague-Dawley, Hyperalgesia, Diabetic Neuropathies, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Insulin, Symporters, Receptor, Serotonin, 5-HT2A, Receptors, GABA-A, Analgesics, Hypoglycemic Agents, Blotting, Western, Case-Control Studies, Neural Inhibition, Adult, Aged, Middle Aged, Female, Male, Duloxetine Hydrochloride, K Cl- Cotransporters
Depositing User: Symplectic Admin
Date Deposited: 11 Jul 2019 13:59
Last Modified: 27 Dec 2023 17:55
DOI: 10.2337/db16-1181
Open Access URL: https://www.research.manchester.ac.uk/portal/en/pu...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3049396