Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy.
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%.


CONCLUSIONS
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.
Talbot
Sébastien
S
Department of Physiology, Faculty of Medicine, Université de Montréal, C,P, 6128, Succursale Downtown, Montréal, Québec, H3C 3J7, Canada.
Chahmi
Emna
E
Dias
Jenny Pena
JP
Couture
Réjean
R
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000378:metabolism; D065169:Bradykinin B1 Receptor Antagonists; D002951:Citrates / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D006941:Hyperesthesia / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; D065169:Bradykinin B1 Receptor Antagonists; D002951:Citrates; D053583:Interleukin-1beta; D043783:Receptor, Bradykinin B1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014409:Tumor Necrosis Factor-alpha; C024626:bradykinin, des-Arg(9)-; C007744:fluorocitrate; D001920:Bradykinin