MEL endomorphins act as potent inflammatory analgesics with the inhibition of activated non-neuronal cells and modulation of pro-inflammatory cytokines

Cui, Jiaming; Zhao, Long; Wang, Zhao-Juan; Ma, Miling; Wang, Yuan; Luo, Keyao; Wang, Linqing; Wei, Shuang; Zhang, Xianghui; Han, Chao-Zhen-Yi; Liu, Xin; Wang, Rui

doi:10.1016/j.neuropharm.2020.107992

Cited by 5 publications

(5 citation statements)

References 65 publications

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“…Previous findings have shown that chronic morphine treatment remarkably prolonged persistent sensitization and increased pain sensitivity, , which greatly limited the long-term treatment of chronic pain with opioids. It has been reported that continuous administration of morphine after inflammatory and neuropathic pain prolonged the recovery time by months. , Our previous work confirmed that MEL-0614 could relieve CFA-induced inflammatory pain and reverse the pro-inflammatory effects induced by chronic morphine administration . Notably, our results showed that MEL-0614 accelerated the recovery of postoperative pain, whereas morphine still aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment.…”

Section: Discussionsupporting

confidence: 50%

“…59,60 Our previous work confirmed that MEL-0614 could relieve CFA-induced inflammatory pain and reverse the pro-inflammatory effects induced by chronic morphine administration. 61 Notably, our results showed that MEL-0614 accelerated the recovery of postoperative pain, whereas morphine still aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. This suggested that MEL-0614 showed better effects than morphine in the treatment of CPSP.…”

Section: Discussionmentioning

confidence: 50%

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

Wei

Han

Wang

et al. 2021

ACS Chem. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 50%

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

Wei

Han

Wang

et al. 2021

ACS Chem. Neurosci.

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“…NSAIDs and morphine are the most common analgesic in acute pain [ 5 ], but their use is limited due to many side effects [ 7 ]. Concerning this issue, the design or discovery of a new molecule with lesser complication is necessary [ 8 , 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Among analgesic drugs, NSAIDs are routinely used for acute pain, but in the case of contraindication and severe pain, opioids are used [ 5 ]. Among opioids, morphine is the gold standard for pain relief, but their use is limited due to a number of side effects, including respiratory depression, constipation, intolerance, dependence, and addiction [ 7 ]. Thus, the design or discovery of a new molecule with a lesser complication is necessary.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a New Analgesic Peptide, Leptucin, from the Iranian Scorpion, Hemiscorpius lepturus

et al. 2021

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Hemiscorpius lepturus scorpion stings do not induce considerable pain based on epidemiological surveys conducted in the southwest part of Iran. Accordingly, this study was aimed to identify the analgesic molecule in H. lepturus venom by analyzing a cDNA library of the scorpion venom gland looking for sequences having homology with known animal venom analgesic peptides. The analgesic molecule is a cysteine rich peptide of 55 amino acids. the synthetic peptide was deprotected and refolded. RP-HPLC, Ellman’s, and DLS assays confirmed the refolding accuracy. Circular dichroism (CD) showed helix and beta sheet contents. This peptide, called leptucin, demonstrated 95% analgesic activity at the dose of 0.48 mg/kg in hot plate assay. Leptucin at the doses of 0.32, 0.48, and 0.64 mg/kg showed 100% activity in thermal tail flick test. No hemolysis or cytotoxicity was observed at 8 and 16 µg. Histopathology evaluations indicated no hepatotoxicity, nephrotoxicity, and cardiotoxicity. We thus report that leptucin is the analgesic agent of H. lepturus venom. Regarding the high in vivo efficacy of leptucin and the fact it shows no observable toxicity, it could be suggested as a drug lead in a preclinical study of acute pain as well as the study of its mechanism of action.

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“…Although it is effective, its prominent disadvantages are severe side effects and drug resistance after repeated use [22,23]. However, the emerging peptide drugs have the advantages of small molecular weight, strong tissue permeability, low immunity, high affinity with the target and few side effects [24,25]. The designing strategy of JP3 was based on the anti-cancer functions and mechanisms identified in previous studies.…”

Section: Discussionmentioning

confidence: 99%

JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis

Chen

Ren

Shu

et al. 2020

J Exp Clin Cancer Res

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Background: Gastric cancer (GC) is the most prevalent gastrointestinal tumor with an unfavorable clinical prognosis. GC patients are largely threatened owing to metastasis and drug resistance. Tumor angiogenesis plays an important role in the development of gastric cancer and is a challenge in the treatment of gastric cancer. Methods: Mouse xenograft models were used for screening of therapeutic peptides on GC growth and metastasis. Routine laboratory experimental methods including conditional cell culture, tube formation assay, qRT-PCR, Western blotting, immunohistochemistry (IHC), ubiquitination assay, and immunofluorescence (IF) were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3/SP1 and TRIM25/MEK1/2. Results: We identified an MMP2-targeted peptide JP3 that plays inhibiting roles in modulating growth and metastasis of GC in vivo and has no observable toxic side effects. JP3 reduced tumor microvessel density (MVD) in vivo and human umbilical vein endothelial cells (HUVECs) tube formation in vitro. Mechanistic studies revealed that JP3 reduces polyubiquitination-mediated degradation of TRIM25 by increasing the stability of TRIM25 through phosphorylating it at Ser12. TRIM25, as an E3 ubiquitin ligase, promoted the ubiquitin of SP1 at K610, further suppressed expression of MMP2 and inhibited angiogenesis in GC. Importantly, the inversely association between TRIM25 and SP1 protein level was further verified in human GC tissues. Decreased TRIM25 expression and increased SP1 expression in tumor tissues were positively correlated with poor prognosis of GC patients. Conclusions: MMP2-targeted peptide JP3 plays a therapeutic role in GC through anti-angiogenesis by modulating TRIM25/SP1/MMP2.

show abstract

MEL endomorphins act as potent inflammatory analgesics with the inhibition of activated non-neuronal cells and modulation of pro-inflammatory cytokines

Cited by 5 publications

References 65 publications

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

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

Discovery of a New Analgesic Peptide, Leptucin, from the Iranian Scorpion, Hemiscorpius lepturus

JP3, an antiangiogenic peptide, inhibits growth and metastasis of gastric cancer through TRIM25/SP1/MMP2 axis

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