STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways

Abstract

Opiorphin is a natural human peptide with strong analgesic properties. These analgesic effects thought to result in a reduction in enkephalin hydrolysis secondary to the compound inhibition of enkephalinase. The purpose of this study was to demonstrate that opiorphin and its stable analog STR-324 are promising analgesics that may be the solution to the quest for a new class of effective, yet safe, painkillers. Inhibitors of enkephalin breakdown could potentially be a class of longacting painkillers with a better safety profile than direct opioid receptor agonists. Although their efficacy in postoperative pain models has not been established, both opiorphin and STR-324 reduced mechanical hypersensitivity through opioid receptor–mediated mechanisms without adverse cardiorespiratory effects in a rat incisional pain model. The demonstrationwas done via the Brennanmodel of plantar incision–induced hypersensitivity with examination of the postsurgical analgesic response to mechanical and thermal stimuli in rats with 7 days of continuously intravenously infused drugs There were a total of 8 to 10 rats per group (mechanical and thermal). Antinociception caused by opiorphin was compared with that of morphine and STR-324, and the expression of spinal c-Fos and the role of opioid receptor–dependent pathways were specifically targeted. Tests were also conducted to assess any manifestation of adverse respiratory and hemodynamic effects with opiorphin. It was found that intravenously administered opiorphin infusion significantly decreased responses to mechanical stimuli postsurgery from days 1 to 4 at 143to 175-kPa mean ranges compared with 23to 30-kPa mean ranges for vehicle (P < 0.05). During this period, no adverse effects in respiratory rate, oxygen saturation, arterial pressure, or heart rate were induced by opiorphin. STR-324 repeatedly demonstrated inhibition of mechanical and thermal hyperalgesia with a potency similar to that of opiorphin. STR-324 significantly reduced the number of pain-evoked spinal c-Fos immunoreactive nuclei that could be identified after immunostaining. Through the use of mechanistic analyses, it was also demonstrated that the opioid antagonist naloxone reversed the antinociceptive effect of STR-324. In conclusion, a significant antinociceptive effect of intravenous opiorphin and STR-324 was demonstrated in a postoperative