title: Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy.
abstract: 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.
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.|Department of Clinical Neurophysiology, Manchester Royal Infirmary, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, U.K.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Marshall
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lee-Kubli
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.
authors.forename: Shazli
authors.initials: S
authors.lastname: Azmi
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, U.K.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ferdousi
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mixcoatl-Zecuatl
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.|Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Petropoulos
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.|Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
authors.forename: Georgios
authors.initials: G
authors.lastname: Ponirakis
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Fineman
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.
authors.forename: Hassan
authors.initials: H
authors.lastname: Fadavi
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Katie
authors.initials: K
authors.lastname: Frizzi
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.|Faculty of Medicine, University of Exeter Medical School, Exeter, U.K.
authors.forename: Mitra
authors.initials: M
authors.lastname: Tavakoli
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.
authors.forename: Maria
authors.identifier: 0000-0002-3492-0177
authors.initials: M
authors.lastname: Jeziorska
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Corinne G
authors.initials: CG
authors.lastname: Jolivalt
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K.
authors.forename: Andrew J M
authors.initials: AJM
authors.lastname: Boulton
authors.affiliation: School of Optometry and Vision Science, Queensland University of Technology, Brisbane, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Efron
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
authors.affiliation: Faculty of Medical and Human Sciences, Centre for Endocrinology and Diabetes, Institute of Human Development, University of Manchester, and National Institute for Health Research/Wellcome Trust Clinical Research Facility, Manchester, U.K. ram2045@qatar-med.cornell.edu rayaz.a.malik@manchester.ac.uk.|Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.
authors.forename: Rayaz A
authors.initials: RA
authors.lastname: Malik
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D003315:Cornea / Q000294:innervation; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003929:Diabetic Neuropathies / Q000209:etiology / Q000503:physiopathology*; D000068736:Duloxetine Hydrochloride / Q000494:pharmacology; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D027981:Symporters / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D000700:Analgesics; D000068736:Duloxetine Hydrochloride; D007004:Hypoglycemic Agents; D007328:Insulin; D044402:Receptor, Serotonin, 5-HT2A; D011963:Receptors, GABA-A; D027981:Symporters; D000096922:K Cl- Cotransporters