The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

Garbuz, Olga; Gulea, Aurélian; Dyniewicz, Jolanta; Zabłocka, Barbara; Lipkowski, Andrzej W.

doi:10.1016/j.peptides.2014.09.027

Cited by 8 publications

(9 citation statements)

References 6 publications

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“…In 1997, Romanowski et al revealed that biphalin movement across the membrane is controlled by diffusion [82]. In 2015, Garbuz et al demonstrated in a “tube test” assay (without any protein receptor presented) that biphalin has a strong antioxidant capability not related to opioid receptors [83]. Those reports confirmed that the biphalin actions we observed are not always related to opioid receptor signaling.…”

Section: Discussionsupporting

confidence: 76%

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

et al. 2017

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Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.

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Section: Discussionsupporting

confidence: 76%

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

et al. 2017

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“…Biphalin effects on reducing ROS generation were partially reversed by NTX, suggesting that some effects may be through non-OR mechanisms. Recently, the chemical properties of biphalin were assessed for antioxidant capacity and biphalin was found to have an antioxidant capacity 3.6 times higher than that of ascorbic acid (Garbuz et al, 2014). The high antioxidant capacity of biphalin might also contribute to its neuroprotective properties during reperfusion and is probably due to its enhanced tyramine moiety.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

Islam²,

Karamyan³

et al. 2015

Brain Research

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To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

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“…Others reported the anti-264 retroviral activity in vitro [28], anti-proliferative [29] and antioxi-265 dant [30] for Women in Science and Polpharma Foundation Scholarship.…”

mentioning

confidence: 99%

Mixed MOP/DOP agonist biphalin elicits anti-transit effect in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms

Zielińska

Jarmuż

Sałaga

et al. 2016

Pharmacological Reports

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The non-opioid receptor, antioxidant properties of morphine and the opioid peptide analog biphalin

Cited by 8 publications

References 6 publications

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

Mixed MOP/DOP agonist biphalin elicits anti-transit effect in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms

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