Key role for spinal dorsal horn microglial kinin B(1 )receptor in early diabetic pain neuropathy

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.