Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy

• Published in: Diabetes (New York, N.Y.) Vol. 66; no. 5; pp. 1380 - 1390
• Main Authors: Marshall, Andrew G, Lee-Kubli, Corinne, Azmi, Shazli, Zhang, Michael, Ferdousi, Maryam, Mixcoatl-Zecuatl, Teresa, Petropoulos, Ioannis N, Ponirakis, Georgios, Fineman, Mark S, Fadavi, Hassan, Frizzi, Katie, Tavakoli, Mitra, Jeziorska, Maria, Jolivalt, Corinne G, Boulton, Andrew J M, Efron, Nathan, Calcutt, Nigel A, Malik, Rayaz A
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.05.2017
• Subjects: Adult; Aged; Analgesics - pharmacology; Animals; Blotting, Western; Case-Control Studies; Complications; Cornea; Cornea - innervation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 2 - complications; Diabetic Neuropathies - etiology; Diabetic Neuropathies - physiopathology; Diabetic neuropathy; Duloxetine; Duloxetine Hydrochloride - pharmacology; Experiments; Female; Humans; Hyperalgesia - etiology; Hyperalgesia - physiopathology; Hypoglycemic Agents - pharmacology; Insulin; Insulin - pharmacology; K Cl- Cotransporters; Male; Mental depression; Middle Aged; Neural Inhibition - drug effects; Neural Inhibition - physiology; Pain perception; Pathogenesis; Potassium chloride; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptor, Serotonin, 5-HT2A; Receptors, GABA-A - metabolism; Rodents; Serotonin; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; Supplements; Symporters - metabolism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db16-1181

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.