Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling.

Abstract

Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile allodynia.

• Authors: Makoto Tsuda, Hikaru Ueno, Ayako Kataoka, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue
• Journal: Glia (Glia) Vol. 56 Issue 4 Pg. 378-86 (Mar 2008) ISSN: 0894-1491 [Print] United States
• PMID: 18186080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (Copyright) 2008 Wiley-Liss, Inc.

Chemical References

• Enzyme Inhibitors
• Nerve Tissue Proteins
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Diabetes Mellitus, Experimental (chemically induced, complications)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation (drug effects)
• Hyperalgesia (etiology, pathology)
• Male
• Microglia (drug effects, enzymology)
• Nerve Tissue Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Spinal Cord (pathology)
• Time Factors