TY - JOUR
T1 - Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy
AU - Talbot, Sébastien
AU - Chahmi, Emna
AU - Dias, Jenny P.
AU - Couture, Réjean
N1 - Funding Information:
The present findings support a primary role for spinal microglial kinin B1R in early pain neuropathy in a rat model of type 1 diabetes. Our study provides the first direct evidence that the B1R is involved in allodynia and hyperalgesia in STZ-diabetic rats through a mechanism involving the microglia. This is supported by 1-the similar pattern of inhibition of allodynia by microglia inhibi- tors and B1R antagonists, and 2-the blockade of the transient allodynic and hyperalgesic responses induced by the stimulation of spinal B1R (des-Arg9-BK) by microglia inhibitors. Because spontaneous cold and tactile allo-dynia in STZ-diabetic rats were reversed by intrathecal B1R antagonists and by peripheral administration of R-715, which does not cross the blood brain barrier, it is concluded that both spinal and peripheral B1R are involved in diabetic allodynia. This is consistent with the presence of B1R on spinal dorsal horn microglia in STZ-diabetic rats [22]. An additional argument supporting an interaction between B1R and microglia is the finding that fluorocitrate and minocycline reversed simultaneously the upregulation of B1R and pro-inflammatory cytokines (IL-1β and TNF-α) in the spinal cord. Hence, the results highlight a key role for microglia and pro-inflammatory cytokines in the induction and overexpression of B1R in the spinal cord.
PY - 2010/6/29
Y1 - 2010/6/29
N2 - 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-1β, TNF-α, 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.
AB - 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-1β, TNF-α, 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.
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U2 - 10.1186/1742-2094-7-36
DO - 10.1186/1742-2094-7-36
M3 - Article
C2 - 20587056
AN - SCOPUS:77953951240
SN - 1742-2094
VL - 7
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
M1 - 36
ER -