Diabetes attenuates the response of the lumbospinal noradrenergic system to idazoxan

Milad Sami Bitar, Charles W.T. Pilcher

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Allodynia is a common feature of painful diabetic neuropathy. This phenomenon appears to be under endogenous noradrenergic control and can be ameliorated effectively by α2-adrenoceptor agonists. Accordingly, diabetic lumbospinal noradrenergic dynamics was evaluated using high performance liquid chromatography with electrochemical detector (HPLC-ECD), in vitro ligand binding and RT-PCR-based techniques. Streptozotocin (STZ)-treated and Goto-Kakizaki (GK) diabetic rats were included, respectively, as models for type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus. The data from these studies revealed that lumbospinal norepinephrine (NE) release, as indicated by the 3-methoxy-4-hydroxyphenyl glycol (MHPG)/NE ratio, was decreased as a function of diabetes. Similarly, the binding density of [3H] p-aminoclonidine and the level of expression of mRNA transcripts encoding for the α(2A)-adrenoceptor subtype and noradrenergic transporter were also reduced in this disease state. Analogous findings were obtained in non-diabetic Wistar rats rendered hypercortisolemic by the subcutaneous implantation of slow releasing pellets containing a supraphysiological dose of glucocorticoid (GC). Tactile allodynia was consistently observed in STZ- and GC-treated animals. The responsiveness of α2-adrenoceptors to idazoxan (α2-adrenoceptor antagonist) indicated a dose-dependent enhancement of noradrenergic transmission in lumbar segments of normal spinal cord. In stark contrast, this neurochemical action of idazoxan was attenuated in diabetic and hypercortisolemic animals. The institution of insulin therapy ameliorated diabetes-related abnormalities in lumbospinal noradrenergic dynamics. Overall, the current finding suggests that diabetic and hypercortisolemic allodynic symptoms may stem from, at least in part, down-regulation of α2-adrenoceptors in these disease states. Copyright (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)247-255
Number of pages9
JournalPharmacology Biochemistry and Behavior
Volume67
Issue number2
DOIs
Publication statusPublished - 1 Dec 2000

Keywords

  • α-Adrenoceptor
  • Allodynia
  • Diabetes mellitus
  • Hypercortisolemia
  • Idazoxan
  • Spinal cord

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