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

Mitsumasa Matsuda,Kenji Ito,Shigeru Takahashi,Takugi Kan,Masaaki Miura,Mariko Watanabe,Masanobu Yoshikawa,Hiroyuki Kobayashi,Toshiyasu Suzuki,Junko Ajimi

doi:10.4236/pp.2017.82003

Abstract

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.

Highlights

Dynorphin (Dyn) A (1-17) and (1-13) interacts with both opioid and N-methylD-aspartate (NMDA) receptors: their N-terminals activate the former with high affinity, while its C-terminals activate the latter with low affinity [1] [2] [3] [4]
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
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

Summary

Introduction

Dynorphin (Dyn) A (1-17) and (1-13) interacts with both opioid and N-methylD-aspartate (NMDA) receptors: their N-terminals activate the former with high affinity, while its C-terminals activate the latter with low affinity [1] [2] [3] [4]. Earlier research on the inhibitory potency of LE or Dyn A (1-8) against electrically-evoked contractions in mouse vas deferens (MVD) demonstrated that it was enhanced by exposure to various combinations of amastatin (A), captopril (C), and phosphoramidon (P) [14] [15]. These results correspond with the results of the previous in vivo studies showing that intracerebroventricular (i.c.v.) administration of ACP increased LE-, Dyn A (1-8)-, and Dyn A (1-17)-induced antinociception by more than 500- [14], 100- [16], and 30-fold [17], respectively

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