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

Abstract

Background Opiorphin is a naturally occurring potent analgesic human peptide. It protects enkephalins from degradation and inhibits pain perception in various acute pain models via activation of endogenous opioid pathways. However, the efficacy of opiorphin continuous infusion and its chemically stable form, STR-324, in postoperative pain is unknown. Methods Using the Brennan model of plantar incision–induced hypersensitivity, the authors examined the postsurgical analgesic response to mechanical and thermal stimuli of 7-day continuously intravenously infused drugs (8 to 10 rats per group). Antinociception from opiorphin with reference to morphine and STR-324 was assessed. Spinal c-Fos expression and the involvement of opioid receptor–dependent pathways were investigated. The occurrence of respiratory and hemodynamic adverse effects of opiorphin was also tested. Results Intravenous infusion of opiorphin significantly reduced responses to mechanical stimuli from days 1 to 4 post surgical period at 143 to 175-kPa mean ranges compared with 23 to 30-kPa mean ranges for vehicle (P < 0.05). During the 3-day postoperative period, no respiratory rate, oxygen saturation, arterial pressure, or heart rate adverse effects were induced by opiorphin. STR-324 consistently inhibited mechanical and thermal hyperalgesia with similar potency as that of opiorphin. Mechanistic analyses demonstrated that the STR-324 antinociceptive effect was reversed by the opioid antagonist, naloxone. Also, STR-324 significantly reduced the number of pain-evoked spinal cFos-immunoreactive nuclei. Conclusion Intravenous infusion of opiorphin and STR-324 produced significant antinociceptive effect in a postoperative pain model. This study demonstrates that STR-324 is effective in postoperative pain management due to its strong antihyperalgesic effects mediated via opioid-dependent antinociceptive pathways. Opiorphin analog should represent a new class of potent and safe analgesics.

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

“…Rougeot et al suggested that opiorphin interacts indirectly with opioid receptors (Toth et al, 2012;Benyhe et al, 2014;Sitbon et al, 2016). This was proposed based on two findings (Toth et al, 2012) The finding of the present study that sialorphin did not affect the binding affinity of [ 3 H] DAMGO is in agreement with this earlier observation.…”

“…Administration of either was reported to induce an antinociceptive effect through activation of opioid receptors (Rougeot et al, 2003;Wisner et al, 2006). Rougeot and colleagues suggested that opiorphin protects enkephalins from degradation by two peptidases (NEP and APN), thus improving the affinity of enkephalins without directly interacting with opioid receptors itself (Toth et al, 2012;Benyhe et al, 2014;Sitbon et al, 2016). Increasingly, compounds are being discovered that directly modulate receptors via distinct allosteric rather than orthosteric sites.…”

An Effective and Safe Enkephalin Analog for Antinociception

“…The improved safety of KK-103 might be explained by its high structural similarity to the endogenously produced Leu-ENK. Indeed, various compounds harnessing the endogenous ENK system have been demonstrated to exhibit improved safety without inducing typical side effects caused by MOR agonists, including respiratory depression, tolerance, physical dependence, and constipation [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ].…”

An analgesic to bridge the gap between Narcotics and NSAIDs: opiorphin

“…Intravenous infusion of tritiated STR-324 in monkeys, a selective sequestration of the radioactive peptide was observed in the spinal and cerebral tissues indicating its ability to cross BBB. 4,12 The gene, currently named PROL1 gene, coding the PRL1 is a precursor protein of opiorphin mature peptide product, identified by Dickinson et al, is expressed in human lacrimal and salivary glands. The concentration of opiorphin in human saliva was quantified as 2.8 to 25.9ng/ml.…”

“…17 In spite of the captivating leads of opiorphin peptide, its pharmaceutical development is hindered by its low stability, typical of N-terminal glutamine peptides. 12 The metabolic half-life of opiorphin is 5min owing to it rapid degradation by circulating peptidases. 6…”