Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Andrew G Marshall
  • Corinne Lee-Kubli
  • Shazli Azmi
  • Michael Zhang
  • Teresa Mixcoatl-Zecuatl
  • Ioannis N Petropoulos
  • Georgios Ponirakis
  • Mark S Fineman
  • Hassan Fadavi
  • Katie Frizzi
  • Mitra Tavakoli
  • Corinne G Jolivalt
  • Nathan Efron
  • Nigel A Calcutt
  • Rayaz A Malik


Impaired rate dependent depression (RDD) of the Hoffman-reflex is associated with reduced dorsal spinal cord potassium chloride co-transporter expression and impaired spinal GABAA 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 5HT2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy when compared to healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fibre pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help to identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Bibliographical metadata

Original languageEnglish
Pages (from-to)1380-1390
Issue number5
Early online date15 Feb 2017
Publication statusPublished - 1 May 2017

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