Key Role for Spinal Dorsal Horn Microglial Kinin B1 Receptor in Early Diabetic Pain Neuropathy

J Neuroinflammation. 2010 Jun 29;7(1):36. doi: 10.1186/1742-2094-7-36.

Abstract

Background: The pro-nociceptive kinin B1 receptor (B1R) is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ)-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy.

Methods: Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p.), and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p.) were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR) of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I)-HPP-desArg10-Hoe 140) were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK) and antagonists (SSR240612 and R-715) were measured on neuropathic pain manifestations.

Results: STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1beta, TNF-alpha, TRPV1) and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%.

Conclusion: The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bradykinin / analogs & derivatives
  • Bradykinin / metabolism
  • Bradykinin B1 Receptor Antagonists
  • Citrates / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetic Neuropathies / metabolism*
  • Diabetic Neuropathies / physiopathology
  • Humans
  • Hyperesthesia / metabolism
  • Hyperesthesia / physiopathology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Male
  • Microglia / cytology
  • Microglia / metabolism
  • Pain / physiopathology*
  • Pain Measurement
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Bradykinin B1 / genetics
  • Receptor, Bradykinin B1 / metabolism*
  • Spinal Cord / cytology
  • Spinal Cord / metabolism*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Biomarkers
  • Bradykinin B1 Receptor Antagonists
  • Citrates
  • Interleukin-1beta
  • Receptor, Bradykinin B1
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Tumor Necrosis Factor-alpha
  • bradykinin, des-Arg(9)-
  • fluorocitrate
  • Bradykinin