Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level
Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level
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DOI：
10.4236/pp.2017.82003
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
M. Matsuda;M. Yoshikawa;Takugi Kan;Mariko Watanabe;J. Ajimi;Shigeru Takahashi;M. Miura;Kenji Ito;Hiroyuki Kobayashi;Toshiyasu Suzuki
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文献类型：
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作者：
M. Matsuda;M. Yoshikawa;Takugi Kan;Mariko Watanabe;J. Ajimi;Shigeru Takahashi;M. Miura;Kenji Ito;Hiroyuki Kobayashi;Toshiyasu Suzuki
我们的研究小组早些时候已经证明，三种对肽酶抑制剂（pi）敏感的酶，阿马伐他汀(A)-，卡托普利(C)-和磷酰胺(P)，在脊髓水平的脑啡肽失活中起重要作用。dynorphin -converting enzyme （DCE）主要在Arg6-Arg7键处水解dynorphin (Dyn) A（1-17）或Dyn A（1-13）。Dynorphin A及其衍生肽分别在N端和c端与阿片受体和谷氨酸受体相互作用。本研究的目的是评估在ACP和/或DCE抑制剂对羟基汞苯甲酸酯（PHMB）预处理下鞘内给药Dyn A（1-17）、Dyn A（1-13）或Dyn A（1-6）的抗痛感效力和毒性。我们还研究了这些PIs对Dyn A（1-17）诱导的小鼠输精管电诱发收缩抑制的影响。在ACP预处理下，Dyn A（1-17）对小鼠输精管电诱发收缩的抑制效力高于AC、AP或CP。ACP预处理使Dyn A（1-17）或（1-13）诱导的抗痛感增强了约50或30倍，在低剂量鞘内给药时没有异常痛的迹象。ACP和PHMB预处理诱导的神经病变。这些结果表明，在ACP预处理下，鞘内给药低剂量DynA（1-17）或DynA（1-13）增加了大鼠的抗痛觉性，但没有异常性疼痛的迹象。
Our group has earlier demonstrated that three enzymes sensitive to peptidase inhibitors (PIs), amastatin (A)-, captopril (C)-, and phosphoramidon (P), played an important role in inactivation of enkephalins at the spinal level. Dynorphin-converting enzyme (DCE) hydrolyzes dynorphin (Dyn) A (1-17) or Dyn A (1-13) mainly at the Arg6-Arg7 bond. Dynorphin A and its derived peptides interact with opioid and glutamate receptors at their N- and C-terminals, respectively. The purpose of the present study was to evaluate the antinociceptive potency and toxicity of intrathecal administered Dyn A (1-17), Dyn A (1-13), or Dyn A (1-6) under pretreatment with ACP and/or the DCE inhibitor p-hydroxymercuribenzoate (PHMB). The effect of these PIs on Dyn A (1-17)-induced inhibition of electrically-evoked contractions in mouse vas deferens was also investigated. The inhibitory potency of Dyn A (1-17) on electrically-evoked contractions in mouse vas deferens under pretreatment with ACP was higher than that with AC, AP, or CP. Pretreatment with ACP augmented Dyn A (1-17) or (1-13)-induced antinociception by approximately 50- or 30-fold with no sign of allodynia when administered intrathecally at low doses. Pretreatment with ACP and PHMB induced neuropathy. These findings showed that intrathecal administration of low-dose Dyn A (1-17) or DynA (1-13) increased antinociception under pretreatment with ACP, but without signs of allodynia in rat.