Effect of Peptidase Inhibitors on Dynorphin A (1-17) or (1-13)-Induced Antinociception and Toxicity at Spinal Level

• 作者: Hiroyuki Kobayashi Junko Ajimi Kenji Ito Mariko Watanabe Masaaki Miura Masanobu Yoshikawa Mitsumasa Matsuda Shigeru Takahashi Takugi Kan Toshiyasu Suzuki
• 来源期刊: 药理与制药(英文)
• 学科: 医学
• 关键词: DYNORPHIN A PEPTIDASE Dynorphin-Converting Enzyme ANTINOCICEPTION ALLODYNIA
• 年，卷（期）: 2017,（2）
• 页码范围: 33-51
• 页数: 19页
• 分类号: R73

摘要

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.