Diabetic neuropathy is one of the major complications of diabetes mellitus. Two distinct clinical manifestations of: the diabetic neuropathy include patients suffering from painful symmetrical polyneuropathy and those with insensitive, painless, feet. Morphometrical analysis shows that small sensory fiber neurons degenerate early and prominently during the course of diabetic neuropathy. Signs and symptoms associated with degeneration of small fibers vary from hyperalgesia to loss of pain and temperature sensation. The endothelins (lETs) constitute a family of vasoactive peptides interacting with different receptor subtypes to regulate blood flow, cell proliferation, muscle contraction or relaxation. Recent observations in normal rats have demonstrated the predominant localization of type A and type B endotbelin receptors (ETAR and ETBR, respectively) in small non-myelinated sensory fibers and their satellite Schwann cells (SC), where they appear to regulate neuropathic and inflammatory pain. The regulation of pain by these receptors seems to be reciprocal, since administration of ETBR agonists counteracts ETAR-mediated excitation of nociceptors. We have recently demonstrated that ETs, acting through the ETBR, modulate the proliferation and phenotype of cultured SC, and have observed a decreased expression of ETBR in diabetic nerves. Based on this information, we hypothesize that in experimental diabetes, the development of mechanical hyperalgesia and tactile allodynia reflects a decreased expression of ETBR in glial cells and/or an increased expression of ETAR in neurons from nociceptive fibers. To test this hypothesis we propose: 1) To compare the expression and localization of ET-1 and ETR in nerves and dorsal root ganglia cells isolated from normal and diabetic rats 2) To study the effect of ETBR agonists and ETAR antagonists on the nociceptive responses in normal and diabetic rats, and to compare the nociceptive responses in control rats with those observed in rats lacking expression of ETBR This short-term exploratory project (R21) is expected to significantly advance our understanding of the role of ETs in diabetic pain, which is currently in early stages of development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK064465-02
Application #
6802783
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Jones, Teresa L Z
Project Start
2003-09-30
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$153,000
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Berti-Mattera, L N; Larkin, B; Hourmouzis, Z et al. (2011) NF-?B subunits are differentially distributed in cells of lumbar dorsal root ganglia in naïve and diabetic rats. Neurosci Lett 490:41-5
Lambrecht, Rein H; Pollard, Katherine A; Alshekhlee, Amer et al. (2010) The serum of dysautonomia patients enhances proliferation and signaling in Schwann cells. Neurosci Lett 468:130-5
Berti-Mattera, Liliana N; Kern, Timothy S; Siegel, Ruth E et al. (2008) Sulfasalazine blocks the development of tactile allodynia in diabetic rats. Diabetes 57:2801-8
Berti-Mattera, Liliana N; Gariepy, Cheryl E; Burke, Rebecca M et al. (2006) Reduced expression of endothelin B receptors and mechanical hyperalgesia in experimental chronic diabetes. Exp Neurol 201:399-406
Chavez, Juan C; Almhanna, Khaldoun; Berti-Mattera, Liliana N (2005) Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic rats. Neurosci Lett 374:179-82