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Key role for spinal dorsal horn microglial kinin B1receptor in early diabetic pain neuropathy

2010; BioMed Central; Volume: 7; Issue: 1 Linguagem: Inglês

10.1186/1742-2094-7-36

1742-2094

Sébastien Talbot, Emna Chahmi, Jenny Pena Dias, Réjean Couture,

Nerve injury and regeneration

Abstract Background The pro-nociceptive kinin B 1 receptor (B 1 R) 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 B 1 R 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 B 1 R and pro-inflammatory markers. Spinal B 1 R binding sites (( 125 I)-HPP-desArg 10 -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 B 1 R agonist (des-Arg 9 -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 B 1 R 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-Arg 9 -BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B 1 R, IL-1β, TNF-α, TRPV1) and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B 1 R binding sites were reduced by 38%. Conclusion The upregulation of kinin B 1 R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.