Spinal disinhibition in experimental and clinical painful diabetic neuropathy

Andrew G. Marshall, Corinne Lee-Kubli, Shazli Azmi, Michael Zhang, Maryam Ferdousi, Teresa Mixcoatl-Zecuatl, Ioannis N. Petropoulos, Georgios Ponirakis, Mark S. Fineman, Hassan Fadavi, Katie Frizzi, Mitra Tavakoli, Maria Jeziorska, Corinne G. Jolivalt, Andrew J.M. Boulton, Nathan Efron, Nigel A. Calcutt, Rayaz Malik

Research output: Contribution to journalArticle

18 Citations (Scopus)


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 ratswith 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 spinallymediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Original languageEnglish
Pages (from-to)1380-1390
Number of pages11
Issue number5
Publication statusPublished - 1 May 2017


ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Marshall, A. G., Lee-Kubli, C., Azmi, S., Zhang, M., Ferdousi, M., Mixcoatl-Zecuatl, T., Petropoulos, I. N., Ponirakis, G., Fineman, M. S., Fadavi, H., Frizzi, K., Tavakoli, M., Jeziorska, M., Jolivalt, C. G., Boulton, A. J. M., Efron, N., Calcutt, N. A., & Malik, R. (2017). Spinal disinhibition in experimental and clinical painful diabetic neuropathy. Diabetes, 66(5), 1380-1390. https://doi.org/10.2337/db16-1181