cardiotomskСибирский журнал клинической и экспериментальной медициныSiberian Journal of Clinical and Experimental Medicine2713-29272713-265XTSU publishing10.29001/2073-8552-2025-40-2-11-20cardiotomsk-2728Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESСигнальные механизмы кардиопротекторного эффекта пептидных и непептидных агонистов опиоидных рецепторов при реперфузии сердца (обзор литературы)Signaling mechanisms of the cardioprotective effect of peptide and nonpeptide opioid receptor agonists in cardiac reperfusion (literature review)https://orcid.org/0000-0003-1808-556XМухомедзяновА. В.MukhomedzyanovA. V.

Мухомедзянов Александр Валерьевич, канд. мед. наук, научный сотрудник, лаборатория экспериментальной кардиологии

634012, Томск, ул. Киевская, 111а

Alexander V. Mukhomedzyanov, Cand. Sci. (Med.), Research Scientist, Laboratory of Experimental Cardiology

111a, Kievskaya str., Tomsk, 634012

sasha_m91@mail.ruhttps://orcid.org/0000-0002-6020-1598МасловЛ. Н.MaslovL. N.

Маслов Леонид Николаевич, д-р мед. наук, профессор, заведующий лабораторией экспериментальной кардиологии

634012, Томск, ул. Киевская, 111а

Leonid N. Maslov, Dr. Sci. (Med.), Professor, Head of the Laboratory of Experimental Cardiology

111a, Kievskaya str., Tomsk, 634012

maslov@cardio-tomsk.ruhttps://orcid.org/0000-0002-1607-1482ПоповС. B.PopovS. V.

Попов Сергей Валентинович, д-р мед. наук, профессор, академик РАН, директор НИИ кардиологии

634012, Томск, ул. Киевская, 111а

Sergey V. Popov, Dr. Sci. (Med.), Academician of the Russian Academy of Sciences, Director, Cardiology Research Institute

111a, Kievskaya str., Tomsk, 634012

ress@cardio-tomsk.ruКанА.KanA.

Кан Артур, старший лаборант, лаборатория экспериментальной кардиологии, НИИ кардиологии

634012, Томск, ул. Киевская, 111а

Arthur Kan, Senior Laboratory Assistant, Laboratory of Experimental Cardiology

111a, Kievskaya str., Tomsk, 634012

kan989817@gmail.comhttps://orcid.org/0009-0005-7528-3476ГрабА. Е.GrabA. E.

Граб Александр Евгеньевич, аспирант, лаборатория экспериментальной кардиологии

634012, Томск, ул. Киевская, 111а

Alexander E. Grab, Graduate Student, Laboratory of Experimental Cardiology

111a, Kievskaya str., Tomsk, 634012

alieksandr.grab.2000@mail.ruhttps://orcid.org/0000-0003-2264-1928НарыжнаяН. В.NaryzhnayaN. V.

Нарыжная Наталья Владимировна, д-р мед. наук, ведущий научный сотрудник, лаборатория экспериментальной кардиологии

634012, Томск, ул. Киевская, 111а

Natalia V. Naryzhnaya, Dr. Sci. (Med.)., Leading Research Scientist, Laboratory of Experimental Cardiology

111a, Kievskaya str., Tomsk, 634012

natalynar@yandex.ruНаучно-исследовательский институт кардиологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation2025130720254021120Copyright © Мухомедзянов А.В., Маслов Л.Н., Попов С.B., Кан А., Граб А.Е., Нарыжная Н.В., 20252025Мухомедзянов А.В., Маслов Л.Н., Попов С.B., Кан А., Граб А.Е., Нарыжная Н.В.Mukhomedzyanov A.V., Maslov L.N., Popov S.V., Kan A., Grab A.E., Naryzhnaya N.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sibjcem.ru/jour/article/view/2728

Внутригоспитальная смертность у больных острым инфарктом миокарда (ОИМ) составляет 5–8% и в последние годы не снижается. Одной из причин высокой летальности является реперфузионное повреждение сердца. Совершенно очевидно, что существует острая необходимость в разработке препаратов, способных эффективно снизить смертность при ОИМ. Такими препаратами могут стать опиоиды. Активация периферических µ2-, δ2-, κ1-опиоидных рецепторов (ОР) уменьшает размер инфаркта и улучшает сократимость при реперфузии. Периферические µ1-, δ1-, κ2-ОР не участвуют в регуляции толерантности сердца к реперфузионным повреждениям. В кардиопротекторном эффекте опиоидного посткондиционирования принимают участие PI3-киназа (phosphoinositide 3-kinase, PI3K), ERK1/2 (extracellular signal-regulated kinase-1/2), Akt-киназа, рецептор эпидермального фактора роста (epidermal growth factor receptor, EGFR) и растворимая гуанилилциклаза (soluble guanylyl cyclase, sGC). Ингибирование GSK-3β (glycogen synthase kinase-3β) и JNK (c-jun NH2 amino-terminal kinase) вовлечено в опиоидное посткондиционирование, в отличие от Янус-киназы-2 (JAK2) и протеинкиназы A (PKA). Есть доказательства того, что гемоксигеназа-1 (HO-1) и NO-синтаза (NOS) также участвуют в опиоид-индуцированном посткондиционировании. Пептидные и непептидные агонисты µ2-, δ2-, κ1-ОР могут стать препаратами для лечения ОИМ.

Цель обзора: анализ сигнальных механизмов кардиопротекторного эффекта пептидных и непептидных агонистов ОР при реперфузии сердца. Поиск литературы по данному вопросу осуществлялся в базе данных PubMed с использованием запросов по следующим ключевым словам: opioid receptors, opioid receptor agonists, cardioprotective effect of opioid receptor agonists.

In-hospital mortality in patients with acute myocardial infarction (AMI) is 5% 8% and has not decreased in recent years. One of the reasons for high mortality is reperfusion cardiac injury. It is quite obvious that there is an urgent need to develop drugs that can effectively reduce mortality in AMI. Opioids could become such drugs. The activation of peripheral µ2-, δ2-, κ1-opioid receptors (ORs) reduces the size of the infarction and improves contractility in reperfusion. Peripheral µ1-, δ1-, κ2ORs is not involved in the regulation of cardiac tolerance to reperfusion injury. PI3-kinase (phosphoinositide 3-kinase), ERK1/2 (extracellular signal-regulated kinase-1/2), Akt-kinase, epidermal growth factor receptor (EGRF) and soluble guanylyl cyclase (sGC) are involved in the cardioprotective effect of opioid postconditioning. Inhibition of GSK-3β (glycogen synthase kinase3β) and JNK (c-jun NH2 amino-terminal kinase) is involved in opioid postconditioning in contrast to Janus kinase-2 (JAK2) and protein kinase A (PKA). There is evidence that hemeoxygenase-1 (HO-1) and NO synthase (NOS) are also involved in opioidinduced postconditioning. Peptide and non-peptide µ2-, δ2-, κ1-OR agonists may become drugs for the treatment of AMI. Aim is to analyze signaling mechanisms of the cardioprotective effect of peptide and non-peptide opioid receptor agonists during cardiac reperfusion. A literature search was carried out in the PubMed database with queries “opioid receptors”, “opioid receptor agonists”, “cardioprotective effect of opioid receptor agonists”.

опиоидысердцереперфузионное повреждениеразмер инфарктакиназыгемоксигеназа-1NO-синтазаopioidsheartreperfusion injuryinfarct sizekinaseshemeoxygenase-1NO-synthaseИсследование проведено при финансовой поддержке РНФ (грант № 23-65-10017) в рамках выполнения гос. задания № 122020300042-4 Министерства науки и высшего образования Российской Федерации.The study was conducted with the financial support of the Russian Science Foundation (grant No. 23-65-10017) as part of the implementation of state assignment No. 122020300042-4 of the Ministry of Science and Higher Education of the Russian Federation.ReferencesAshraf S., Farooq U., Shahbaz A., Khalique F., Ashraf M., Akmal R. et al. Factors responsible for worse outcomes in STEMI patients with early vs delayed treatment presenting in a tertiary care center in a third world country. Curr. Probl. Cardiol. 2024;49(1Pt B):102049. https://doi.org/10.1016/j.cpcardiol.2023.102049Ashraf S., Farooq U., Shahbaz A., Khalique F., Ashraf M., Akmal R. et al. Factors responsible for worse outcomes in STEMI patients with early vs delayed treatment presenting in a tertiary care center in a third world country. Curr. Probl. Cardiol. 2024;49(1Pt B):102049. https://doi.org/10.1016/j.cpcardiol.2023.102049McCartney P.J., Berry C. Redefining successful primary PCI. Eur. Heart J. Cardiovasc. Imaging. 2019;20(2):133–135. https://doi.org/10.1093/ehjci/jey159McCartney P.J., Berry C. Redefining successful primary PCI. Eur. Heart J. Cardiovasc. Imaging. 2019;20(2):133–135. https://doi.org/10.1093/ehjci/jey159Пантелеев О.О., Рябов В.В. Кардиогенный шок – что нового? Сибирский журнал клинической и экспериментальной медицины. 2021;36(4):45–51. https://doi.org/10.29001/2073-8552-2021-36-4-45-51Panteleev O.O., Ryabov V.V. Cardiogenic shock: What’s new? Siberian Journal of Clinical and Experimental Medicine. 2021;36(4):45–51. (In Russ.). https://doi.org/10.29001/2073-8552-2021-36-4-45-51Maslov L.N., Khaliulin I., Oeltgen P.R., Naryzhnaya N.V., Pei J.M., Brown S.A. et al. Prospects for creation of cardioprotective and antiarrhythmic drugs based on opioid receptor agonists. Med. Res. Rev. 2016;36(5):871–923. https://doi.org/10.1002/med.21395Maslov L.N., Khaliulin I., Oeltgen P.R., Naryzhnaya N.V., Pei J.M., Brown S.A. et al. Prospects for creation of cardioprotective and antiarrhythmic drugs based on opioid receptor agonists. Med. Res. Rev. 2016;36(5):871–923. https://doi.org/10.1002/med.21395Peart J.N., Gross E.R., Reichelt M.E., Hsu A., Headrick J.P., Gross G.J. Activation of kappa-opioid receptors at reperfusion affords cardioprotection in both rat and mouse hearts. Basic Res. Cardiol. 2008;103(5): 454–463. https://doi.org/10.1007/s00395-008-0726-zPeart J.N., Gross E.R., Reichelt M.E., Hsu A., Headrick J.P., Gross G.J. Activation of kappa-opioid receptors at reperfusion affords cardioprotection in both rat and mouse hearts. Basic Res. Cardiol. 2008;103(5): 454–463. https://doi.org/10.1007/s00395-008-0726-zKim J.H., Jang Y.H., Chun K.J., Kim J., Park Y.H., Kim J.S. et al. Kappa-opioid receptor activation during reperfusion limits myocardial infarction via ERK1/2 activation in isolated rat hearts. Korean J. Anesthesiol. 2011;60(5):351–356. https://doi.org/10.4097/kjae.2011.60.5.351Kim J.H., Jang Y.H., Chun K.J., Kim J., Park Y.H., Kim J.S. et al. Kappa-opioid receptor activation during reperfusion limits myocardial infarction via ERK1/2 activation in isolated rat hearts. Korean J. Anesthesiol. 2011;60(5):351–356. https://doi.org/10.4097/kjae.2011.60.5.351Wu X., Zhang B., Fan R., Zhao L., Wang Y., Zhang S. et al. U50,488H inhibits neutrophil accumulation and TNF-alpha induction induced by ischemia-reperfusion in rat heart. Cytokine. 2011;56(2):503–507. https://doi.org/10.1016/j.cyto.2011.07.015Wu X., Zhang B., Fan R., Zhao L., Wang Y., Zhang S. et al. U50,488H inhibits neutrophil accumulation and TNF-alpha induction induced by ischemia-reperfusion in rat heart. Cytokine. 2011;56(2):503–507. https://doi.org/10.1016/j.cyto.2011.07.015Wu Y., Wan J., Zhen W.Z., Chen L.F., Zhan J., Ke J.J. et al. The effect of butorphanol postconditioning on myocardial ischaemia reperfusion injury in rats. Interact. Cardiovasc. Thorac. Surg. 2014;18(3):308–312. https://doi.org/10.1093/icvts/ivt516Wu Y., Wan J., Zhen W.Z., Chen L.F., Zhan J., Ke J.J. et al. The effect of butorphanol postconditioning on myocardial ischaemia reperfusion injury in rats. Interact. Cardiovasc. Thorac. Surg. 2014;18(3):308–312. https://doi.org/10.1093/icvts/ivt516Huang L.H., Li J., Gu J.P., Qu M.X., Yu J., Wang Z.Y. Butorphanol attenuates myocardial ischemia reperfusion injury through inhibiting mitochondria-mediated apoptosis in mice. Eur. Rev. Med. Pharmacol. Sci. 2018;22(6):1819–1824. https://doi.org/10.26355/eurrev_201803_14601Huang L.H., Li J., Gu J.P., Qu M.X., Yu J., Wang Z.Y. Butorphanol attenuates myocardial ischemia reperfusion injury through inhibiting mitochondria-mediated apoptosis in mice. Eur. Rev. Med. Pharmacol. Sci. 2018;22(6):1819–1824. https://doi.org/10.26355/eurrev_201803_14601Mukhomedzyanov A.V., Tsibulnikov S.Y., Maslov L.N. Comparative Analysis of infarct size limiting activity of κ-opioid receptor agonists in in vivo reperfused heart. Bull. Exp. Biol. Med. 2021;170(5):594–597. https://doi.org/10.1007/s10517-021-05113-7Mukhomedzyanov A.V., Tsibulnikov S.Y., Maslov L.N. Comparative Analysis of infarct size limiting activity of κ-opioid receptor agonists in in vivo reperfused heart. Bull. Exp. Biol. Med. 2021;170(5):594–597. https://doi. org/10.1007/s10517-021-05113-7Popov S.V., Mukhomedzyanov A.V., Tsibulnikov S.Y., Khaliulin I., Oeltgen P.R., Rajendra Prasad N. et al. Activation of peripheral opioid κ1 receptor prevents cardiac reperfusion injury. Physiol. Res. 2021;523–531. https://doi.org/10.33549/physiolres.934646Popov S.V., Mukhomedzyanov A.V., Tsibulnikov S.Y., Khaliulin I., Oeltgen P.R., Rajendra Prasad N. et al. Activation of peripheral opioid κ1 receptor prevents cardiac reperfusion injury. Physiol. Res. 2021;523–531. https://doi.org/10.33549/physiolres.934646Tian X., Zhou Y., Wang Y., Zhang S., Feng J., Wang X. et al. Mitochondrial dysfunction and apoptosis are attenuated on kappa-opioid receptor activation through AMPK/GSK-3beta pathway after myocardial ischemia and reperfusion. J. Cardiovasc. Pharmacol. 2019;73(2):70–81. https://doi.org/10.1097/FJC.0000000000000635Tian X., Zhou Y., Wang Y., Zhang S., Feng J., Wang X. et al. Mitochondrial dysfunction and apoptosis are attenuated on kappa-opioid receptor activation through AMPK/GSK-3beta pathway after myocardial ischemia and reperfusion. J. Cardiovasc. Pharmacol. 2019;73(2):70–81. https://doi.org/10.1097/FJC.0000000000000635Zhang W.P., Zong Q.F., Gao Q., Yu Y., Gu X.Y., Wang Y. et al. Effects of endomorphin-1 postconditioning on myocardial ischemia/reperfusion injury and myocardial cell apoptosis in a rat model. Mol. Med. Rep. 2016;14(4):3992–3998. https://doi.org/10.3892/mmr.2016.5695Zhang W.P., Zong Q.F., Gao Q., Yu Y., Gu X.Y., Wang Y. et al. Effects of endomorphin-1 postconditioning on myocardial ischemia/reperfusion injury and myocardial cell apoptosis in a rat model. Mol. Med. Rep. 2016;14(4):3992–3998. https://doi.org/10.3892/mmr.2016.5695Wu S., Zhang L., Fan H., Huang Y., Zong Q., Gao Q. et al. PI3K/Akt signaling pathway mediates the protective effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats. Nan Fang Yi Ke Da Xue Xue Bao. 2021;41(6):870–875. https://doi.org/10.12122/j.issn.1673-4254.2021.06.09Wu S., Zhang L., Fan H., Huang Y., Zong Q., Gao Q. et al. PI3K/Akt signaling pathway mediates the protective effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats. Nan Fang Yi Ke Da Xue Xue Bao. 2021;41(6):870–875. https://doi. org/10.12122/j.issn.1673-4254.2021.06.09Huang Y.P., Yang T.H., Jin Z.Y., Wang Y., Ye H.W., Gao Q. et al. Role of mitochondrial permeability transition pore in mediating the effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats. Nan Fang Yi Ke Da Xue Xue Bao. 2018;38(5):547–553. https://doi.org/10.3969/j.issn.1673-4254.2018.05.07Huang Y.P., Yang T.H., Jin Z.Y., Wang Y., Ye H.W., Gao Q. et al. Role of mitochondrial permeability transition pore in mediating the effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats. Nan Fang Yi Ke Da Xue Xue Bao. 2018;38(5):547–553. https://doi.org/10.3969/j.issn.1673-4254.2018.05.07Mukhomedzyanov A.V., Maslov L.N., Tsibulnikov S.Y., Pei J.M. Endomorphins and β-endorphin do not affect heart tolerance to the pathogenic effect of reperfusion. Bull. Exp. Biol. Med. 2016;162(1):23–26. https://doi.org/10.1007/s10517-016-3535-7Mukhomedzyanov A.V., Maslov L.N., Tsibulnikov S.Y., Pei J.M. Endomorphins and β-endorphin do not affect heart tolerance to the pathogenic effect of reperfusion. Bull. Exp. Biol. Med. 2016;162(1):23–26. https://doi.org/10.1007/s10517-016-3535-7He S.F., Jin S.Y., Yang W., Pan Y.L., Huang J., Zhang S.J. et al. Cardiac μ-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure. Br. J. Anaesth. 2018;121(1):26–37. https://doi.org/10.1016/j.bja.2017.11.110He S.F., Jin S.Y., Yang W., Pan Y.L., Huang J., Zhang S.J. et al. Cardiac μ-opioid receptor contributes to opioid-induced cardioprotection in chronic heart failure. Br. J. Anaesth. 2018;121(1):26–37. https://doi.org/10.1016/j.bja.2017.11.110Goldberg I.E., Rossi G.C., Letchworth S.R., Mathis J.P., Ryan-Moro J., Leventhal L. et al. Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J. Pharmacol. Exp. Ther. 1998;286(2):1007–1013. PMID: 9694962.Goldberg I.E., Rossi G.C., Letchworth S.R., Mathis J.P., Ryan-Moro J., Leventhal L. et al. Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J. Pharmacol. Exp. Ther. 1998;286(2):1007–1013. PMID: 9694962.Wu Y., Gu E.W., Zhu Y., Zhang L., Liu X.Q., Fang W.P. Sufentanil limits the myocardial infarct size by preservation of the phosphorylated connexin 43. Int. Immunopharmacol. 2012;13(3):341–346. https://doi.org/10.1016/j.intimp.2012.04.009Wu Y., Gu E.W., Zhu Y., Zhang L., Liu X.Q., Fang W.P. Sufentanil limits the myocardial infarct size by preservation of the phosphorylated connexin 43. Int. Immunopharmacol. 2012;13(3):341–346. https://doi. org/10.1016/j.intimp.2012.04.009Lei Y., Li X.X., Guo Z. Impact of timing of morphine treatment on infarct size in experimental animal model of acute myocardial ischemia and reperfusion. Eur. J. Pharmacol. 2022;928:175094. https://doi.org/10.1016/j.ejphar.2022.175094Lei Y., Li X.X., Guo Z. Impact of timing of morphine treatment on infarct size in experimental animal model of acute myocardial ischemia and reperfusion. Eur. J. Pharmacol. 2022;928:175094. https://doi.org/10.1016/j.ejphar.2022.175094Aitchison K.A., Baxter G.F., Moneeb Awan M., Smith R.M., Yellon D.M. et al. Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: implications for ischemic preconditioning. Basic Res. Cardiol. 2000;95(1):1–10. https://doi.org/10.1007/s003950050001Aitchison K.A., Baxter G.F., Moneeb Awan M., Smith R.M., Yellon D.M. et al. Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: implications for ischemic preconditioning. Basic Res. Cardiol. 2000;95(1):1–10. https://doi.org/10.1007/s003950050001Zhu Y., Chi J., Cai S., Liu S., Yuan J., Xu H. et al. High-dose remifentanil exacerbates myocardial ischemia-reperfusion injury through activation of calcium-sensing receptor-mediated pyroptosis. Int. J. Med. Sci. 2023;20(12):1570–1583. https://doi.org/10.7150/ijms.83207Zhu Y., Chi J., Cai S., Liu S., Yuan J., Xu H. et al. High-dose remifentanil exacerbates myocardial ischemia-reperfusion injury through activation of calcium-sensing receptor-mediated pyroptosis. Int. J. Med. Sci. 2023;20(12):1570–1583. https://doi.org/10.7150/ijms.83207Kim J.H., Chun K.J., Park Y.H., Kim J., Kim J.S., Jang Y.H. et al. Morphine-induced postconditioning modulates mitochondrial permeability transition pore opening via delta-1 opioid receptors activation in isolated rat hearts. Korean J. Anesthesiol. 2011;61(1):69. https://doi.org/10.4097/kjae.2011.61.1.69Kim J.H., Chun K.J., Park Y.H., Kim J., Kim J.S., Jang Y.H. et al. Morphine-induced postconditioning modulates mitochondrial permeability transition pore opening via delta-1 opioid receptors activation in isolated rat hearts. Korean J. Anesthesiol. 2011;61(1):69. https://doi.org/10.4097/kjae.2011.61.1.69Schultz J.E.J., Hsu A.K., Nagase H., Gross G.J. TAN-67, a δ 1 -opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am. J. Physiol. Circ. Physiol. 1998;274(3):H909–Н914. https://doi.org/10.1152/ajpheart.1998.274.3.H909Schultz J.E.J., Hsu A.K., Nagase H., Gross G.J. TAN-67, a δ 1 -opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am. J. Physiol. Circ. Physiol. 1998;274(3):H909–Н914. https://doi.org/10.1152/ajpheart.1998.274.3.H909Huh J., Gross G.J., Nagase H., Liang B.T. Protection of cardiac myocytes via δ 1 -opioid receptors, protein kinase C, and mitochondrial K ATP channels. Am. J. Physiol. Circ. Physiol. 2001;280(1):H377–Н383. https://doi.org/10.1152/ajpheart.2001.280.1.H377Huh J., Gross G.J., Nagase H., Liang B.T. Protection of cardiac myocytes via δ 1 -opioid receptors, protein kinase C, and mitochondrial K ATP channels. Am. J. Physiol. Circ. Physiol. 2001;280(1):H377–Н383. https://doi.org/10.1152/ajpheart.2001.280.1.H377Gross G. Role of opioids in acute and delayed preconditioning. J. Mol. Cell. Cardiol. 2003;35(7):709–718. https://doi.org/10.1016/S00222828(03)00135-4Gross G. Role of opioids in acute and delayed preconditioning. J. Mol. Cell. Cardiol. 2003;35(7):709–718. https://doi.org/10.1016/S00222828(03)00135-4Roques B., Gacel G., Daugé V., Baamonde A., Calenco G., Turcaud S. et al. Novel approaches in the development of new analgesics. Neurophysiol. Clin. Neurophysiol. 1990;20(5):369–387. https://doi.org/10.1016/S0987-7053(05)80205-9Roques B., Gacel G., Daugé V., Baamonde A., Calenco G., Turcaud S. et al. Novel approaches in the development of new analgesics. Neurophysiol. Clin. Neurophysiol. 1990;20(5):369–387. https://doi.org/10.1016/S0987-7053(05)80205-9Naryzhnaya N.V., Mukhomedzyanov A.V., Sirotina M., Maslov L.N., Kurbatov B.K., Gorbunov A.S. et al. δ-opioid receptor as a molecular target for increasing cardiac resistance to reperfusion in drug development. Biomedicines. 2023;11(7):1887. https://doi.org/10.3390/biomedicines11071887Naryzhnaya N.V., Mukhomedzyanov A.V., Sirotina M., Maslov L.N., Kurbatov B.K., Gorbunov A.S. et al. δ-opioid receptor as a molecular target for increasing cardiac resistance to reperfusion in drug development. Biomedicines. 2023;11(7):1887. https://doi.org/10.3390/biomedicines11071887Chen Z., Li T., Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J. Surg. Res. 2008;145(2):287– 294. https://doi.org/10.1016/j.jss.2007.07.020Chen Z., Li T., Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J. Surg. Res. 2008;145(2):287– 294. https://doi.org/10.1016/j.jss.2007.07.020Ha J.Y., Lee Y.C., Park S.J., Jang Y.H., Kim J.H. Remifentanil postconditioning has cross talk with adenosine receptors in the ischemic-reperfused rat heart. J. Surg. Res. 2015;195(1):37–43. https://doi.org/10.1016/j.jss.2015.01.010Ha J.Y., Lee Y.C., Park S.J., Jang Y.H., Kim J.H. Remifentanil postconditioning has cross talk with adenosine receptors in the ischemic-reperfused rat heart. J. Surg. Res. 2015;195(1):37–43. https://doi. org/10.1016/j.jss.2015.01.010Zhao S., Zhang C., Pi Z., Li R., Han P., Guo L. Oxycodone protects cardiomyocytes from ischemia-reperfusion-induced apoptosis via PI3K/ Akt pathway. Pharmazie. 2020;75(9):430–435. https://doi.org/10.1691/ph.2020.0497Zhao S., Zhang C., Pi Z., Li R., Han P., Guo L. Oxycodone protects cardiomyocytes from ischemia-reperfusion-induced apoptosis via PI3K/ Akt pathway. Pharmazie. 2020;75(9):430–435. https://doi.org/10.1691/ph.2020.0497Mourouzis I., Saranteas T., Perimenis P., Tesseromatis C., Kostopanagiotou G., Pantos C. et al. Morphine administration at reperfusion fails to improve postischaemic cardiac function but limits myocardial injury probably via heat-shock protein 27 phosphorylation. Eur. J. Anaesthesiol. 2009;26(7):572–581. https://doi.org/10.1097/EJA.0b013e32832a225aMourouzis I., Saranteas T., Perimenis P., Tesseromatis C., Kostopanagiotou G., Pantos C. et al. Morphine administration at reperfusion fails to improve postischaemic cardiac function but limits myocardial injury probably via heat-shock protein 27 phosphorylation. Eur. J. Anaesthesiol. 2009;26(7):572–581. https://doi.org/10.1097/EJA.0b013e32832a225aWong G.T.C., Li R., Jiang L.L., Irwin M.G. Remifentanil post-conditioning attenuates cardiac ischemia–reperfusion injury via κ or δ opioid receptor activation. Acta Anaesthesiol. Scand. 2010;54(4):510–518. https://doi.org/10.1111/j.1399-6576.2009.02145.xWong G.T.C., Li R., Jiang L.L., Irwin M.G. Remifentanil post-conditioning attenuates cardiac ischemia–reperfusion injury via κ or δ opioid receptor activation. Acta Anaesthesiol. Scand. 2010;54(4):510–518. https://doi.org/10.1111/j.1399-6576.2009.02145.xSeewald M., Coles J.A., Sigg D.C., Iaizzo P.A. Featured article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts. Exp. Biol. Med. 2017;242(9): 986–995. https://doi.org/10.1177/1535370216684041Seewald M., Coles J.A., Sigg D.C., Iaizzo P.A. Featured article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts. Exp. Biol. Med. 2017;242(9): 986–995. https://doi.org/10.1177/1535370216684041Wang J., Gareri C., Rockman H.A. G-protein-coupled receptors in heart disease. Circ. Res. 2018; 123(6):716–735. https://doi.org/10.1161/CIRCRESAHA.118.311403Wang J., Gareri C., Rockman H.A. G-protein-coupled receptors in heart disease. Circ. Res. 2018; 123(6):716–735. https://doi.org/10.1161/CIRCRESAHA.118.311403Gross G.J., Auchampach J.A. Reperfusion injury: does it exist? J. Mol. Cell. Cardiol. 2007;42(1):12–18. https://doi.org/10.1016/j.yjmcc.2006.09.009Gross G.J., Auchampach J.A. Reperfusion injury: does it exist? J. Mol. Cell. Cardiol. 2007;42(1):12–18. https://doi.org/10.1016/j. yjmcc.2006.09.009Popov S.V., Mukhomedzyanov A.V., Maslov L.N., Naryzhnaya N.V., Kurbatov B.K., Prasad N.R. et al. The infarct-reducing effect of the delta2 opioid receptor agonist deltorphin II: The molecular mechanism. Membranes (Basel). 2023;13(1):63. https://doi.org/10.3390/membranes13010063Popov S.V., Mukhomedzyanov A.V., Maslov L.N., Naryzhnaya N.V., Kurbatov B.K., Prasad N.R. et al. The infarct-reducing effect of the delta2 opioid receptor agonist deltorphin II: The molecular mechanism. Membranes (Basel). 2023;13(1):63. https://doi.org/10.3390/membranes13010063Mukhomedzyanov A.V., Popov S.V., Maslov L.N., Diez E.R., Azev V.N. Role of PI3K, ERK1/2, and JAK2 kinases in the cardioprotective effect of deltorphin II during cardiac reperfusion. Bull. Exp. Biol. Med. 2023;175(1):17–19. https://doi.org/10.1007/s10517-023-05801-6Mukhomedzyanov A.V., Popov S.V., Maslov L.N., Diez E.R., Azev V.N. Role of PI3K, ERK1/2, and JAK2 kinases in the cardioprotective effect of deltorphin II during cardiac reperfusion. Bull. Exp. Biol. Med. 2023;175(1):17–19. https://doi.org/10.1007/s10517-023-05801-6Förster K., Kuno A., Solenkova N., Felix S.B., Krieg T. The delta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation. Am. J. Physiol. Heart Circ. Physiol. 2007;293(3):H1604–H16048. https://doi.org/10.1152/ajpheart.00418.2007Förster K., Kuno A., Solenkova N., Felix S.B., Krieg T. The delta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation. Am. J. Physiol. Heart Circ. Physiol. 2007;293(3):H1604–H16048. https://doi.org/10.1152/ajpheart.00418.2007Chen Z., Spahn D.R., Zhang X., Liu Y., Chu H., Liu Z. Morphine postconditioning protects against reperfusion injury: the role of protein kinase C-epsilon, extracellular signal-regulated kinase 1/2 and mitochondrial permeability transition pores. Cell. Physiol. Biochem. 2016;39(5):1930– 1940. https://doi.org/10.1159/000447890Chen Z., Spahn D.R., Zhang X., Liu Y., Chu H., Liu Z. Morphine postconditioning protects against reperfusion injury: the role of protein kinase C-epsilon, extracellular signal-regulated kinase 1/2 and mitochondrial permeability transition pores. Cell. Physiol. Biochem. 2016;39(5):1930– 1940. https://doi.org/10.1159/000447890Tao H., Nuo M., Min S. Sufentanil protects the rat myocardium against ischemia-reperfusion injury via activation of the ERK1/2 pathway. Cytotechnology. 2018;70(1):169–176. https://doi.org/10.1007/s10616017-0127-yTao H., Nuo M., Min S. Sufentanil protects the rat myocardium against ischemia-reperfusion injury via activation of the ERK1/2 pathway. Cytotechnology. 2018;70(1):169–176. https://doi.org/10.1007/s10616017-0127-yXu J., Bian X., Zhao H., Sun Y., Tian Y., Li X. et al. Morphine prevents ischemia/reperfusion-induced myocardial mitochondrial damage by activating delta-opioid receptor/EGFR/ROS pathway. Cardiovasc. Drugs Ther. 2022;36(5):841–857. https://doi.org/10.1007/s10557-02107215-wXu J., Bian X., Zhao H., Sun Y., Tian Y., Li X. et al. Morphine prevents ischemia/reperfusion-induced myocardial mitochondrial damage by activating delta-opioid receptor/EGFR/ROS pathway. Cardiovasc. Drugs Ther. 2022;36(5):841–857. https://doi.org/10.1007/s10557-02107215-wChen Q.L., Gu E.W., Zhang L., Cao Y.Y., Zhu Y., Fang W.P. Diabetes mellitus abrogates the cardioprotection of sufentanil against ischaemia/ reperfusion injury by altering glycogen synthase kinase-3beta. Acta Anaesthesiol. Scand. 2013;57(2):236–242. https://doi.org/10.1111/j.13996576.2012.02748.xChen Q.L., Gu E.W., Zhang L., Cao Y.Y., Zhu Y., Fang W.P. Diabetes mellitus abrogates the cardioprotection of sufentanil against ischaemia/ reperfusion injury by altering glycogen synthase kinase-3beta. Acta Anaesthesiol. Scand. 2013;57(2):236–242. https://doi.org/10.1111/j.13996576.2012.02748.xChen M., Liu Q., Chen L., Zhang L., Cheng X., Gu E. HDAC3 mediates cardioprotection of remifentanil postconditioning by targeting GSK3β in H9c2 cardiomyocytes in hypoxia/reoxygenation injury. Shock. 2018;50(2):240–247. https://doi.org/10.1097/SHK.0000000000001008Chen M., Liu Q., Chen L., Zhang L., Cheng X., Gu E. HDAC3 mediates cardioprotection of remifentanil postconditioning by targeting GSK3β in H9c2 cardiomyocytes in hypoxia/reoxygenation injury. Shock. 2018;50(2):240–247. https://doi.org/10.1097/SHK.0000000000001008Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 2015;116(4): 674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ. Res. 2015;116(4): 674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348Chen Z., Zhang X., Liu Y., Liu Z. Morphine postconditioning protects against reperfusion injury via inhibiting JNK/p38 MAPK and mitochondrial permeability transition pores signaling pathways. Cell. Physiol. Biochem. 2016;39(1):61–70. https://doi.org/10.1159/000445605Chen Z., Zhang X., Liu Y., Liu Z. Morphine postconditioning protects against reperfusion injury via inhibiting JNK/p38 MAPK and mitochondrial permeability transition pores signaling pathways. Cell. Physiol. Biochem. 2016;39(1):61–70. https://doi.org/10.1159/000445605Tsutsumi Y.M., Yokoyama T., Horikawa Y., Roth D.M., Patel H.H. Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci. 2007;81(15): 1223–1227. https://doi.org/10.1016/j.lfs.2007.08.031Tsutsumi Y.M., Yokoyama T., Horikawa Y., Roth D.M., Patel H.H. Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci. 2007;81(15): 1223–1227. https://doi.org/10.1016/j.lfs.2007.08.031Patel H.H., Hsu A., Gross G.J. Delayed cardioprotection is mediated via a non-peptide δ opioid agonist, SNC-121, independent of opioid receptor stimulation. Basic Res. Cardiol. 2004;99(1):38–45. https://doi.org/10.1007/s00395-003-0438-3Patel H.H., Hsu A., Gross G.J. Delayed cardioprotection is mediated via a non-peptide δ opioid agonist, SNC-121, independent of opioid receptor stimulation. Basic Res. Cardiol. 2004;99(1):38–45. https://doi.org/10.1007/s00395-003-0438-3Kunecki M., Roleder T., Biernat J., Kukla P., Tomkiewicz-Pająk L., Deja M.A. et al. Opioidergic conditioning of the human heart muscle in nitric oxide-dependent mechanism. Adv. Clin. Exp. Med. 2018;27(8): 1069–1073. https://doi.org/10.17219/acem/70192Kunecki M., Roleder T., Biernat J., Kukla P., Tomkiewicz-Pająk L., Deja M.A. et al. Opioidergic conditioning of the human heart muscle in nitric oxide-dependent mechanism. Adv. Clin. Exp. Med. 2018;27(8): 1069–1073. https://doi.org/10.17219/acem/70192Tong G., Zhang B., Zhou X., Zhao J., Sun Z., Tao Y. et al. Kappa-opioid agonist U50,488H-mediated protection against heart failure following myocardial ischemia/reperfusion: Dual roles of heme oxygenase-1. Cell. Physiol. Biochem. 2016;39(6):2158–2172. https://doi.org/10.1159/000447911Tong G., Zhang B., Zhou X., Zhao J., Sun Z., Tao Y. et al. Kappa-opioid agonist U50,488H-mediated protection against heart failure following myocardial ischemia/reperfusion: Dual roles of heme oxygenase-1. Cell. Physiol. Biochem. 2016;39(6):2158–2172. https://doi.org/10.1159/000447911

The authors declare that there are no conflicts of interest present.