Endomorphins are endogenous high-affinity selective agonists of the μ-receptor, which is expressed on the cells of the immune system, due to which endomorphins can have an immunomodulatory effect. The aim of this study was to estimate the effect of endomorphin-1 and endomorphin-2 on the functional activity of monocytes and neutrophils in peripheral blood in vitro. It was found that endomorphin-1 reduces spontaneous production of reactive oxygen species by leukocytes and the intensity of respiratory burst in stimulated neutrophil cultures. Endomorphin-2 inhibited spontaneous production of oxygen radicals by the leukocyte fraction of peripheral blood, stimulated spontaneous production of reactive oxygen species by the neutrophil fraction, but suppressed their induced production. Endomorphin-1 increased the rate of monocyte phagocytosis, enhanced spontaneous IL-1β production, and inhibited stimulated IL-10 production by mononuclear cells. Endomorphine-2 also enhanced spontaneous IL-1β production and reduced stimulated IL-10 production by mononuclear cells, stimulated the absorption activity of both neutrophils and monocytes. Thus, endomorphins are important modulators of the functional activity of innate immunity effector cells.

Background. A high percentage of people in the world suffer from acute or chronic pain, the treatment of which is based on the introduction of morphine and its derivatives, agonists of the µ-opioid receptors, leading to the development of addiction in patients. An urgent task is to study the properties of endogenous opioid peptides, which are capable of showing not only pronounced analgesic activity, but also have a number of other effects on the periphery, while having a much smaller spectrum of side effects. Of particular interest are the immunomodulatory effects of peptide agonists of µ-receptors – endomorphins, tetrapeptides, the effects of which are not described in detail in the literature. Due to their structure and properties, endorphins can be considered as potential substitutes for low-molecular-weight opiates.   The aim. To investigate the effect of endorphins-1,2 on the synthesis of oxygen radicals and the absorption activity of innate immunity cells in vitro, in vivo.   Materials and methods. The object of the in vitro study is peripheral venous blood leukocytes from donors aged 22–40 years; the object of the in vivo study is peritoneal flush cells of Swiss white male mice. Oxygen-dependent microbicidal activity was evaluated using a luminol-dependent chemiluminescence reaction. Phagocytic activity was evaluated by flow cytometry.   Results. It has been found that endomorphins inhibited spontaneous production of reactive oxygen species in vitro, in vivo. Endomorphin-2 reduced the intensity of respiratory explosion in stimulated cultures of peritoneal macrophages. Blockade of opiate receptors with naloxone in vitro, in vivo did not cancel the effects of endomorphins. Both peptides and naloxone had no effect on the phagocytic activity of macrophages of the peritoneal cavity of mice in vivo, but in vitro endomorphins led to an increase in the percentage of phagocytosis of peripheral blood leukocytes.   Conclusions. The effects of endomorphins in vitro, in vivo are predominantly depressive.

Endogenous opioid peptides are a large group of physiologically active compounds with a pronounced affinity for opioid-type receptors, capable of showing pronounced analgesic activity, as well as having additional effects on the periphery, due to their wide distribution on the cells of many organs and tissues. Little studied representatives of this group are endomorphins, which due to their structure and properties, are capable of producing a strong antinociceptive effect after central administration, which means that, in the future, they can be considered as potential substitutes for low molecular weight opiates. The aim of this study is to evaluate the effect of endomorphins on the humoral immune response, the production of Th1/Th2/Th17 cytokines and apoptosis of CD4+, CD8+ lymphocytes in vivo. The splenocytes of Swiss white mice were used as the object of the study. The number of antibody-forming cells in the spleen was assessed using the method of local hemolysis in agarose gel according to Jerne. Quantitative determination of cytokines was carried out by enzyme-linked immunosorbent assay using kits (R&D, USA) according to the method proposed by the manufacturer. Apoptosis was assessed using Annexin V-FITC/7-AAD kit reagents (Beckman Coulter, USA) according to the manufacturer’s instructions by flow cytometry on a CytoFLEX S flow cytometer (Beckman Coulter, USA). In the course of the study, it was found that endomorphins enhance the antibody genesis of the spleen, and the preliminary blockade of opiate receptors with naloxone led to the cancellation of the stimulating effect of peptides. Endomorphins didn’t affect splenocyte production of IL-2, IL-4, and IFNg, however, the introduction of endomorphin-2 naloxone-independent enhanced the induced production of IL-17. Evaluation of the effect of endomorphins on apoptosis of splenocytes in 24-h cultures showed that endomorphin-2 in unstimulated cultures of naloxone-dependently increased the percentage of late apoptosis of CD8+ lymphocytes, however, in stimulated cultures, both endomorphins increased the apoptotic activity of CD8+ lymphocytes, regardless of the preliminary blockade of opioid receptors. In summary, we can say that in the in vivo system, endomorphins have a wide range of multidirectional immunomodulatory effects, which may be of interest for practical use in the future.

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