Endomorphin-1 analogues (MELs) penetrate the blood–brain barrier and exhibit good analgesic effects with minimal side effects

et al. 2017

ACS Chem. Neurosci.

Self Cite

Opioid peptides are neuromodulators that bind to opioid receptors and reduce pain sensitivity. Endomorphins are among the most active endogenous opioid peptides, and they have good affinity and selectivity toward the μ opioid receptor. However, their clinical usage is hindered by their inability to cross the blood-brain barrier and their poor in vivo activity after peripheral injection. In order to overcome these defects, we have designed and synthesized a series of novel endomorphin analogs with multiple site modifications. Radioligand binding, cAMP accumulation, and β-arrestin-2 recruitment assays were employed to determine the activity of synthesized endomorphin analogs toward opioid receptors. The blood-brain barrier permeability and antinociceptive effect of these analogs were determined in several rodent models of acute and persistent pain. In addition, the side effects of the analogs were examined. The radioligand binding assay and functional activity examination indicated that the MEL-N16 series of compounds were more active agonists against μ opioid receptor than were the parent peptides. Notably, the analogs displayed biased downstream signaling toward G-protein pathways over β-arrestin-2 recruitment. The analogs showed highly potent antinociceptive effects in the tested nociceptive models. In comparison with endomorphins, the synthesized analogs were better able to penetrate the blood-brain barrier and exerted their pain regulatory activity in the central nervous system after peripheral injection. These analogs also have lower tendency to cause side effects than morphine does at similar or equal antinociceptive doses. The MEL-N16 compounds have highly potent and efficacious analgesic effects in various pain models with a favorable side effect profile.

Section: Resultsmentioning

confidence: 98%

Section: ■ Results and Discussionmentioning

confidence: 99%

MEL-N16: A Series of Novel Endomorphin Analogs with Good Analgesic Activity and a Favorable Side Effect Profile

Liu

Zhao

et al. 2017

ACS Chem. Neurosci.

Self Cite

“…In 1997, Zadina et al discovered a class of endogenous peptides named endomorphin‐1 (EM‐1) and endomorphin‐2 (Zadina, Hackler, Ge, & Kastin, 1997). In addition to their analgesic function, endomorphins have an advantage over traditional opioids, such as morphine, with respect to many side effects, such as abuse liability (Codd, Carson, & Colburn, 2009; Nilges et al., 2019), respiratory depression (Zadina et al., 2016), tolerance (Wang et al., 2015), motor impairment (Feehan, Morgenweck, Zhang, Amgott‐Kwan, & Zadina, 2017b), and gastrointestinal function (Czapla & Zadina, 2005; Sobczak, Salaga, Storr, & Fichna, 2014; Wang, Qiu, et al., 2017). However, endomorphins have many problems, such as difficulty passing through the blood–brain barrier, poor enzymatic stability, and short duration of action, which limit their clinical application (Liu et al., 2017).…”

Section: Introductionmentioning

confidence: 99%

Endomorphin analog exhibited superiority in alleviating neuropathic hyperalgesia via weak activation of NMDA receptors

Journal of Neurochemistry

et al. 2020

Self Cite

Morphine is a key drug for the treatment of pain but its side effects limit its clinical application. MEL-0614, an endomorphin-1 analog, has fewer side effects than morphine in addition to its powerful analgesic effect. In this study, we measured the effect of morphine and MEL-0614 on hyperalgesia (7 days) and neuropathic allodynia (14 days) after thermal, mechanical, and cold stimulation. We found that after four and eight consecutive days of intrathecal administration (1, 3, and 10 nmol), morphine induced severe hyperalgesia and neuropathic allodynia, respectively. MEL-0614 did not induce hyperalgesia at low doses (1 and 3 nmol) and had a mitigating effect on morphine-induced neuropathic exacerbations in spared nerve injury mice. Hyperalgesia was blocked by Dynorphin A (1-17) antibody but not by an opioid receptor antagonist. To explore the reasons for the different results of morphine and MEL-0614, we used quantitative PCR and immunofluorescence to explore the effects of both on N-methyl-D-aspartate (NMDA) receptor subtype 2B (NR2B), microglia marker iba-1, and inflammatory mediators. After 8 days of consecutive administration, morphine (10 nmol) promoted an increase in the number of NR2B, iba-1, and inflammatory mediators in the spinal cord of mice. MEL-0614 (10 nmol) had no significant effect on these factors, and after co-administration with morphine, the expression of NR2B, iba-1, and inflammatory mediators was lower than that with morphine injection alone. Our research showed the advantage of MEL-0614 in terms of hyperalgesia and neuropathic allodynia, which may provide clinical relief of hyperalgesia and neuropathic allodynia caused by morphine.

“…In this study, we evaluated the development of tolerance between morphine and MEL-0614 in SMIR-induced chronic postoperative pain model, mice received intrathecal (i.t.) administration of drugs or saline once daily for 7 days after SMIR surgery . Paw withdrawal thresholds to mechanical stimuli were measured at 5, 10, 15, 20, and 30 min after drug or saline administration on days 1 and 7.…”

Section: Methodsmentioning

confidence: 99%

“…administration of drugs or saline once daily for 7 days after SMIR surgery. 66 Paw withdrawal thresholds to mechanical stimuli were measured at 5, 10, 15, 20, and 30 min after drug or saline administration on days 1 and 7. All mice were grouped randomly.…”

Section: Methodsmentioning

confidence: 99%

Repeated Endomorphin Analogue MEL-0614 Reduces Tolerance and Improves Chronic Postoperative Pain without Modulating the P2X7R Signaling Pathway

Wei

Han

et al. 2021

ACS Chem. Neurosci.

Self Cite

The clinical treatment of chronic postoperative pain (CPSP) remains challenging. The side effects of chronic morphine treatment limit its clinical application. MEL-0614, a novel endomorphin analogue that is highly selective and agonistic for μ opioid receptor (MOR), produces a more powerful analgesic effect than that of morphine. In this study, we explored the difference in antinociceptive tolerance and related mechanisms between MEL-0614 and morphine in CPSP induced in a skin/muscle incision and retraction (SMIR) mice model. We found that acute administration of MEL-0614 (1, 3, 5, and 10 nmol, i.t.) produced a dose-dependent analgesic effect that was superior to that of morphine in the SMIR mice model. Long-term MEL-0614 treatment (10 nmol, i.t.) did not induce tolerance compared with morphine. Notably, tolerance induced by morphine could be greatly prevented and/or inhibited via cross-administration or coadministration between MEL-0614 and morphine. In addition, MEL-0614 accelerated the recovery of postoperative pain, whereas morphine aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. In addition, MEL-0614 did not activate microglia and the P2X7R signaling pathway and showed reduced expression iba1 and P2X7R compared with that observed after morphine administration. Release of inflammatory factors was induced by continued administration of morphine during SMIR surgery, but MEL-0614 did not promote the activation of inflammatory factors. Our results showed that MEL-0614 has superior analgesic effects in CPSP and leads to tolerance to a lesser degree than morphine. Further, MEL-0614 may be used as a promising treatment option for the long-term treatment in CPSP.