Our group has earlier demonstrated that three enzymes sensitive to peptidase\ninhibitors (PIs), amastatin (A)-, captopril (C)-, and phosphoramidon (P),\nplayed an important role in inactivation of enkephalins at the spinal level.\nDynorphin-converting enzyme (DCE) hydrolyzes dynorphin (Dyn) A (1-17)\nor Dyn A (1-13) mainly at the Arg6-Arg7 bond. Dynorphin A and its derived\npeptides interact with opioid and glutamate receptors at their N- and C-terminals,\nrespectively. The purpose of the present study was to evaluate the antinociceptive\npotency and toxicity of intrathecal administered Dyn A (1-17),\nDyn A (1-13), or Dyn A (1-6) under pretreatment with ACP and/or the DCE\ninhibitor p-hydroxymercuribenzoate (PHMB). The effect of these PIs on Dyn\nA (1-17)-induced inhibition of electrically-evoked contractions in mouse vas\ndeferens was also investigated. The inhibitory potency of Dyn A (1-17) on\nelectrically-evoked contractions in mouse vas deferens under pretreatment\nwith ACP was higher than that with AC, AP, or CP. Pretreatment with ACP\naugmented Dyn A (1-17) or (1-13)-induced antinociception by approximately\n50- or 30-fold with no sign of allodynia when administered intrathecally at\nlow doses. Pretreatment with ACP and PHMB induced neuropathy. These\nfindings showed that intrathecal administration of low-dose Dyn A (1-17) or\nDynA (1-13) increased antinociception under pretreatment with ACP, but\nwithout signs of allodynia in rat.
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