Nociception in Diabetic Neuropathy: Role of Endothelins
Principal Investigator: L N Berti-Mattera
Abstract: 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.
Funding Period: 2003-09-30 - 2006-08-31
more information: NIH RePORT
- NF-κB subunits are differentially distributed in cells of lumbar dorsal root ganglia in naïve and diabetic ratsL N Berti-Mattera
Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
Neurosci Lett 490:41-5. 2011..Our findings raise the possibility that changes in NF-κB activation in a subset of DRG neurons participates in mediating diabetes-induced sensory neuropathy...
- Transient expression of hypoxia-inducible factor-1 alpha and target genes in peripheral nerves from diabetic ratsJuan C Chavez
Department of Anatomy, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Neurosci Lett 374:179-82. 2005....
- Reduced expression of endothelin B receptors and mechanical hyperalgesia in experimental chronic diabetesLiliana N Berti-Mattera
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 7288, USA
Exp Neurol 201:399-406. 2006..These results suggest that changes in the expression of ETBR in peripheral nerve may contribute to the development of mechanical hyperalgesia and tactile allodynia in chronic diabetes...
- Sulfasalazine blocks the development of tactile allodynia in diabetic ratsLiliana N Berti-Mattera
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Diabetes 57:2801-8. 2008..The reported link between nociception and targets of the anti-inflammatory drug sulfasalazine prompted us to investigate its effect on neuropathic pain in diabetes...
- The serum of dysautonomia patients enhances proliferation and signaling in Schwann cellsRein H Lambrecht
Department of Pathology, Case Western Reserve University School of Medicine, 2103 Cornell Road, Cleveland, OH 44016 7288, USA
Neurosci Lett 468:130-5. 2010..Our observations represent a promising first step in the identification of dysautonomia biomarkers...