title: Antinociceptive effect of paeoniflorin via spinal α₂-adrenoceptor activation in diabetic mice.
abstract: BACKGROUND
  Shakuyakukanzoto (SKT) has been shown to modulate nociception in streptozotocin-induced diabetic mice via selective activation of the descending noradrenergic systems. However, the active components of SKT that exert the analgesic effect remain unknown. Here, we administered Glycyrrhizae radix (G. radix), Paeoniae radix (P. radix), and the two active constituents of P. radix, paeoniflorin and albiflorin, to determine the components that stimulate spinal α₂-adrenoceptors by promoting noradrenaline release.
  
  
  METHODS
  The two SKT components were separately administered to diabetic and non-diabetic mice. A tail-pressure test was used to determine the nociceptive threshold between 0 and 3h after oral dosing. The time-course profiles of the nociceptive threshold (g) and the area under the time response curve (AUC) were evaluated. Yohimbine, an α₂-adrenoceptor antagonist, was intrathecally injected 15 min after paeoniflorin administration.
  
  
  RESULTS
  P. radix and G. radix did not induce significant antinociception in non-diabetic mice. However, P. radix (250, 500 mg/kg) dose-dependently and significantly increased the nociceptive threshold in diabetic mice between 0.5 and 2 h after administration, whereas all the tested doses of G. radix did not increase the nociceptive threshold. Both paeoniflorin (30 mg/kg) and albiflorin (10 mg/kg) significantly elevated the nociceptive threshold between 0.5 and 3h and between 0.5 and 1h after administration, respectively. The antinociceptive effect of paeoniflorin (30 mg/kg) was completely abolished by yohimbine.
  
  
  CONCLUSIONS
  Our findings suggest that paeoniflorin is the key antinociceptive component in SKT that increases noradrenaline release and activates α₂-adrenoceptors to modulate spinal nociceptive transmission in diabetic neuropathy.
authors: Department of Hospital Administration, Center for Advanced Kampo Medicine and Clinical Research, Graduate School of Medicine, Juntendo University, Japan. lee_keiko@mail.tsumura.co.jp
authors: Keiko K
authors: KK
authors: Lee
authors: Yuji
authors: Y
authors: Omiya
authors: Mitsutoshi
authors: M
authors: Yuzurihara
authors: Yoshio
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authors: Kase
authors: Hiroyuki
authors: H
authors: Kobayashi