Diabetic neuropathy is a widespread clinical problem for which there is no FDA-approved, mechanistically based treatment and is predicted to develop in over half of the approximately 20 million people currently afflicted by diabetes mellitus in the USA. A significant proportion of both insulin-deficient (type 1) and insulin- resistant (type 2) diabetic patients complain of pain or paresthesias that impair quality of life. The etiology of painful diabetic neuropathy is not known and current treatment strategies are limited to drugs with ill-defined mechanisms of action and with side effect profiles that impede normal daily functions and limit effective dosing. Diabetic rats develop hyperalgesia in response to paw formalin injection and allodynia in response to light touch, and they are widely used to model painful diabetic neuropathy in both mechanistic and drug efficacy studies. Recent findings have implicated spinal oligodendrocytes as a site of a pathogenic lesion that initiates spinally mediated hyperalgesia in diabetes. The pathogenic mechanism involves metabolism of excess glucose by aldose reductase, located exclusively in spinal oligodendrocytes, and the subsequent up-regulation of cyclooxygenase 2 (COX-2) in spinal oligodendrocytes and/or neurons. We propose to define the cellular mechanisms by which glucose metabolism by aldose reductase induces COX-2 expression and activity and also the inter-cellular mechanisms that allow oligodendrocytes to initiate spinal hyperalgesa. This will be accomplished by applying a combination of cellular, biochemical and pharmacological techniques to in vitro studies using mature oligodendrocytes derived from the spinal cord of adult normal and diabetic rats. We also intend to investigate pathogenic mechanisms underlying tactile allodynia and formalin-evoked hyperalgesia in diabetic rats that are not related to spinal aldose reductase and COX-2 activity. We will address the hypothesis that decreased expression of the KCC2 cation cotransporter converts spinal GABAergic pathways from inhibitory to excitatory to promote tactile allodynia. The role of altered primary afferent BDNF production in inducing altered spinal KCC2 expression and GABA function and the convergence or divergence of the pathogenic mechanisms during diabetes that induce COX-2 and GABA mediated spinal hyperalgesia will be investigated in diabetic rat models using a combination of behavioral, electrophysiological, pharmacological, biochemical and morphological techniques. The proposed studies are an extension of our recently published and preliminary data and their goal is to define the mechanisms by which diabetes alters spinal sensory processing in favor of amplified and aberrant signals so that new therapeutic targets may be identified and translated into mechanistically directed treatments that will prevent and ameliorate painful diabetic neuropathy.

Public Health Relevance

Our primary aim is to investigate the mechanisms by which diabetes alters the capacity of the spinal cord to transduce sensory information passing from the periphery to the brain. The goal is to understand the role of the spinal cord in the pathogenesis of painful diabetic neuropathy so that new treatments for this debilitating condition can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057629-08
Application #
8118783
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Jones, Teresa L Z
Project Start
2000-04-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2014-07-31
Support Year
8
Fiscal Year
2011
Total Cost
$321,778
Indirect Cost
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Marshall, Andrew G; Lee-Kubli, Corinne; Azmi, Shazli et al. (2017) Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy. Diabetes 66:1380-1390
Calcutt, Nigel A; Smith, Darrell R; Frizzi, Katie et al. (2017) Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. J Clin Invest 127:608-622
Bravo-Hernández, Mariana; Corleto, José A; Barragán-Iglesias, Paulino et al. (2016) The ?5 subunit containing GABAA receptors contribute to chronic pain. Pain 157:613-26
Jolivalt, C G; Rodriguez, M; Wahren, J et al. (2015) Efficacy of a long-acting C-peptide analogue against peripheral neuropathy in streptozotocin-diabetic mice. Diabetes Obes Metab 17:781-8
Hollis 2nd, Edmund R; Ishiko, Nao; Pessian, Maysam et al. (2015) Remodelling of spared proprioceptive circuit involving a small number of neurons supports functional recovery. Nat Commun 6:6079
Hollis 2nd, Edmund R; Ishiko, Nao; Tolentino, Kristine et al. (2015) A novel and robust conditioning lesion induced by ethidium bromide. Exp Neurol 265:30-9
Chowdhury, Subir Roy; Saleh, Ali; Akude, Eli et al. (2014) Ciliary neurotrophic factor reverses aberrant mitochondrial bioenergetics through the JAK/STAT pathway in cultured sensory neurons derived from streptozotocin-induced diabetic rodents. Cell Mol Neurobiol 34:643-9
Lee-Kubli, Corinne A G; Calcutt, Nigel A (2014) Altered rate-dependent depression of the spinal H-reflex as an indicator of spinal disinhibition in models of neuropathic pain. Pain 155:250-60
Hedstrom, Kristian L; Murtie, Joshua C; Albers, Kathryn et al. (2014) Treating small fiber neuropathy by topical application of a small molecule modulator of ligand-induced GFR?/RET receptor signaling. Proc Natl Acad Sci U S A 111:2325-30
Saleh, Ali; Roy Chowdhury, Subir K; Smith, Darrell R et al. (2013) Ciliary neurotrophic factor activates NF-?B to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. Neuropharmacology 65:65-73

Showing the most recent 10 out of 40 publications