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

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 Arg 6 -Arg 7 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.

Sialorphin Potentiates Effects of [Met5]Enkephalin without Toxicity by Action other than Peptidase Inhibition

“…High-dose administration of opioids can lead to lethal toxicity in multiple organ systems (Boyer, 2012). Earlier studies by the present group revealed that administration of a mixture of PIs enhanced antinociception induced by low-dose administration of dynorphin without toxicity (Ajimi et al, 2015;Matsuda et al, 2017). These results demonstrated that the use of PIs synergizes and potentiates intrinsic signaling pathways, which would allow a reduction in the doses required and subsequent avoidance of toxicity.…”

“…accordance with the method in earlier studies by the present group (Kitamura et al, 2000;Takahashi et al, 2007;Akahori et al, 2008;Murata et al, 2014;Ajimi et al, 2015;Matsuda et al, 2017), nociceptive stimulation was achieved by immersing the tail of each rat in hot water (55ºC) for a maximum of 5 sec. This time limit was set to prevent injury to the animal in accordance with the result from earlier studies by the present group showing that persistent pain occurs when the tail is placed in hot water for more than 5 seconds (data not shown).…”