pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2023-11-5-432-442pmedpharm-1396Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯRESEARCH ARTICLEЭлектрофизиологическое исследование каппа-опиоидного анальгетика РУ-1205 с применением методов машинного обученияElectrophysiological effects of kappa-opioid analgesic, RU-1205, using machine learning methodshttps://orcid.org/0000-0002-0079-853XКалитинК. Ю.KalitinK. Yu.

кандидат медицинских наук, доцент кафедры фармакологии и биоинформатики ФГБОУ ВО ВолгГМУ Минздрава России; старший научный сотрудник лаборатории метаботропных лекарственных средств НЦИЛС ФГБОУ ВО ВолгГМУ Минздрава России. 

400131, Россия, г. Волгоград, пл. Павших Борцов, д. 1.

400087, Россия, г. Волгоград, ул. Новороссийская, д. 39.

Candidate of Sciences (Medicine), Assistant Professor, Assistant Professor of Department of Pharmacology and Bioinformatics of Volgograd State Medical University; Senior Researcher at the Laboratory of Metabotropic Drugs of Scientific Center for Innovative Medicines of Volgograd State Medical University. 

1, Pavshih Borcov Sq., Volgograd, Russia, 400131.

39, Novorossiyskaya Str., Volgograd, Russia, 400087.

kkonst8@ya.ruhttps://orcid.org/0000-0002-0429-905XМухаО. Ю.MukhaO. Yu.

соискатель кафедры фармакологии и биоинформатики ФГБОУ ВО ВолгГМУ Минздрава России. 

400131, Россия, г. Волгоград, пл. Павших Борцов, д. 1

external PhD student of the Department of Pharmacology and Bioinformatics of Volgograd State Medical University. 

1, Pavshih Borcov Sq., Volgograd, Russia, 400131

olay.myha14@gmail.comhttps://orcid.org/0000-0002-7185-4826СпасовА. А.SpasovA. A.

доктор медицинских наук, профессор, заведующий кафедрой фармакологии и биоинформатики ФГБОУ ВО ВолгГМУ Минздрава России; руководитель отдела фармакологии и биоинформатики НЦИЛС ФГБОУ ВО ВолгГМУ Минздрава России; академик РАН. 

400131, Россия, г. Волгоград, пл. Павших Борцов, д. 1.

400087, Россия, г. Волгоград, ул. Новороссийская, д. 39.

Doctor of Sciences (Medicine), Professor, Head of the Department of Pharmacology and Bioinformatics of Volgograd State Medical University; Head of the Department of Pharmacology and Bioinformatics of Scientific Center for Innovative Medicines of Volgograd State Medical University; Academician of the RAS. 

1, Pavshih Borcov Sq., Volgograd, Russia, 400131.

39, Novorossiyskaya Str., Volgograd, Russia, 400087.

aaspasov@volgmed.ru1. Федеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской Федерации. 2. Научный центр инновационных лекарственных средств с опытно-промышленным производством федерального государственного бюджетного образовательного учреждения высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссия1. Volgograd State Medical University. 2. Scientific Center for Innovative Medicines with Pilot Production of Volgograd State Medical University.Russian FederationФедеральное государственное бюджетное образовательное учреждение высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияVolgograd State Medical UniversityRussian Federation202329012024115432442Copyright © Калитин К.Ю., Муха О.Ю., Спасов А.А., 20242024Калитин К.Ю., Муха О.Ю., Спасов А.А.Kalitin K.Y., Mukha O.Y., Spasov A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.pharmpharm.ru/jour/article/view/1396

Исследование посвящено изучению нового каппа-опиоидного агониста РУ-1205, который проявляет анальгетическое действие, при этом не вызывает дисфорических или аверсивных эффектов. Предполагается, что это может быть обусловлено функциональной селективностью, либо наличием дополнительного механизма действия, который связан с блокированием p38 митоген-активируемой протеинкиназы (MAPK).

Цель

Цель. Экспериментальное выявление механизмов действия соединения РУ-1205, связанных с ингибированием MAPK p38 и функциональной селективностью в отношении каппа-опиоидных рецепторов.

Материалы и методы

Материалы и методы. Крысам массой 260–280 г (n=62) имплантировали хронические корковые и глубокие электроды, выполняли регистрацию LFP-активности после интрацеребровентрикулярного введения веществ с хорошо изученными фармакологическими свойствами (селективный каппа-опиоидный агонист U-50488 100 мкг и блокатор MAPK p38 SB203580 1 мкг), а также изучаемого соединения РУ-1205 350 мкг. Рассчитывали взвешенный индекс фазовой задержки (WPLI), после чего применяли методы машинного обучения с целью снижения размерности и получения интегративных характеристик коннективности (метод главных компонент), затем выполняли классификацию сигналов (модели на основе гауссовских процессов).  С помощью метода локальной фиксации потенциала в конфигурации “whole-cell” исследовали спайковую активность пирамидных нейронов базолатеральной миндалины. Нейроны идентифицировали по их свойствам аккомодации. После локальной перфузии исследуемых соединений были получены 3 кривые доза-эффект для: (1) U-50488 в концентрациях от 0,001 до 10 мкМ; (2) комбинации U-50488 (0,001–10 мкМ) и РУ-1205 (10 мкМ); и (3) комбинации U-50488 (0,01–10 мкМ) и РУ-1205 (100 мкМ).

Результаты

Результаты. Разработанные модели позволили с высокой вероятностью классифицировать соединение РУ-1205 как «неингибитор» MAPK p38. Полученные результаты находят подтверждение в экспериментах «Patch Clamp» на живых срезах мозга, где было продемонстрировано, что U-50488 статистически значимо увеличивает спайковую активность пирамидных нейронов базолатеральной миндалины (p <0,05), при этом РУ-1205 взаимодействует с U-50488, конкурентно подавляя его действие на спайковую активность нейронов.

Заключение

Заключение. Таким образом, это позволяет предполагать, что соединение РУ-1205 проявляет функциональную каппа-агонистическую активность и не оказывает значимого влияния на MAPK p38. Исследование демонстрирует возможность интеграции электрофизиологических измерений и передовых методов анализа данных для глубокого понимания нейрональных механизмов фармакологического действия, а также подчеркивает перспективность дальнейших исследований в данном направлении.

The study is focused to the investigation of a new kappa-opioid agonist RU-1205, which exhibits an analgesic effect without causing dysphoric or aversive actions. It is assumed that this effects may be due to its functional selectivity, or the presence of an additional mechanism of action that involves blocking p38 mitogen-activated protein kinase (MAPK).

The aim of the study was an experimental identification of RU-1205 mechanisms of action associated with the inhibition of MAPK p38 and functional selectivity for kappa opioid receptors.

Materials and methods

Materials and methods. The LFP activity was recorded in the male rats weighing 260–280 g (n=62) and implanted with chronic cortical and deep electrodes, after the intracerebroventricular administration of the well-studied reference substances: the selective kappa-opioid agonist U-50488 100 μg; the MAPK p38 blocker SB203580 1 μg; and the investigational compound RU-1205 at 350 μg. The weighted phase lag index (WPLI) was calculated. Subsequently, machine learning methods were employed to reduce the dimensionality and extract connectivity features using the principal component analysis method, then a signal classification was performed (models based on Gaussian processes). Using the local patch-clamp technique in the “whole-cell” configuration, the spike activity of pyramidal neurons in the basolateral amygdala was studied. Neurons were identified by their accommodation properties. After local perfusion of the test compounds, 3 dose-response curves were obtained for: (1) U-50488 at concentrations ranging from 0.001 to 10 μM; (2) combinations of U-50488 (0.001–10 μM) and RU-1205 (10 μM); and (3) the combinations of U-50488 (0.01–10 μM) and RU-1205 (100 μM).

Results

Results. The developed models made it possible to classify the compound RU-1205 as a “non-inhibitor” of MAPK p38 with a high probability. The results obtained were confirmed in patch-clamp experiments on acute brain slices where it was demonstrated that U-50488 statistically significantly increases the spike activity of pyramidal neurons of the basolateral amygdala (p <0.05), and RU-1205 interacts with U-50488, competitively suppressing its effect on the spike activity of neurons.

Conclusion

Conclusion. The findings suggest that compound RU-1205 displays properties consistent with a functional kappa agonist activity and does not have a significant effect on MAPK p38. The study demonstrates the possibility of integrating electrophysiological measurements and advanced data analysis methods for a deep understanding of drug action and underscores the potential for further research in this area.

каппа-опиоидные анальгетикиэлектрофизиологияконнективность мозгапатч-зажимметоды машинного обученияp38 MAPKkappa-opioid analgesicselectrophysiologybrain connectivitypatch-clampmachine learning methodsp38 MAPKДанное исследование не имело финансовой поддержки от сторонних организаций.This study did not have financial support from outside organizations.ReferencesZimmer Z., Fraser K., Grol-Prokopczyk H., Zajacova A. A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors // Pain. – 2022. – Vol. 163, No. 9. – P. 1740–1750. DOI: 10.1097/j.pain.0000000000002557Zimmer Z, Fraser K, Grol-Prokopczyk H, Zajacova A. A global study of pain prevalence across 52 countries: examining the role of country-level contextual factors. Pain. 2022;163(9):1740–50. DOI: 10.1097/j.pain.0000000000002557Daveluy A., Micallef J., Sanchez-Pena P., Miremont-Salamé G., Lassalle R., Lacueille C., Grelaud A., Corand V., Victorri-Vigneau C., Batisse A., Le Boisselier R. Ten-year trend of opioid and nonopioid analgesic use in the French adult population // Br J Clin Pharmacol. – 2021. – Vol. 87, No. 2. – P. 555–564. DOI: 10.1111/bcp.14415Daveluy A, Micallef J, Sanchez‐Pena P, Miremont‐Salamé G, Lassalle R, Lacueille C, Grelaud A, Corand V, Victorri‐Vigneau C, Batisse A, Le Boisselier R. Ten‐year trend of opioid and nonopioid analgesic use in the French adult population. Br J Clin Pharmacol. 2021;87(2):555–64. DOI: 10.1111/bcp.14415Pasternak G.W. Mu opioid pharmacology: 40 years to the promised land // Adv Pharmacol. – 2018. – Vol. 82. – P. 261–291. DOI: 10.1016/bs.apha.2017.09.006Pasternak GW. Mu opioid pharmacology: 40 years to the promised land. Adv Pharmacol. 2018;82:261–91. DOI: 10.1016/bs.apha.2017.09.006Dalefield M.L., Scouller B., Bibi R., Kivell B.M. The kappa opioid receptor: A promising therapeutic target for multiple pathologies // Front Pharmacol. – 2022. – Vol. 13. – Art. ID: 837671. DOI: 10.3389/fphar.2022.837671Dalefield ML, Scouller B, Bibi R, Kivell BM. The kappa opioid receptor: A promising therapeutic target for multiple pathologies. Front Pharmacol. 2022;13:837671. DOI: 10.3389/fphar.2022.837671Khan M.I.H., Sawyer B.J., Akins N.S., Le H.V.A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse // Eur J Med Chem. – 2022. – Vol. 243. – Art. ID: 114785. DOI: 10.1016/j.ejmech.2022.114785Khan MIH, Sawyer BJ, Akins NS, Le HV. A systematic review on the kappa opioid receptor and its ligands: New directions for the treatment of pain, anxiety, depression, and drug abuse. Eur J Med Chem. 2022;243:114785. DOI: 10.1016/j.ejmech.2022.114785Vaidya B., Sifat A.E., Karamyan V.T., Abbruscato T.J. The neuroprotective role of the brain opioid system in stroke injury // Drug Discov Today. – 2018. – Vol. 23, No. 7. – P. 1385–1395. DOI: 10.1016/j.drudis.2018.02.011Vaidya B, Sifat AE, Karamyan VT, Abbruscato TJ. The neuroprotective role of the brain opioid system in stroke injury. Drug Discov Today. 2018;23(7):1385–95. DOI: 10.1016/j.drudis.2018.02.011Paul A.K., Smith C.M., Rahmatullah M., Nissapatorn V., Wilairatana P., Spetea M., Gueven N., Dietis N. Opioid analgesia and opioid-induced adverse effects: A review // Pharmaceuticals. – 2021. – Vol. 14, No. 11. – Art. ID: 1091. DOI: 10.3390/ph14111091Paul AK, Smith CM, Rahmatullah M, Nissapatorn V, Wilairatana P, Spetea M, Gueven N, Dietis N. Opioid analgesia and opioid-induced adverse effects: A review. Pharmaceuticals. 2021;14(11):1091. DOI: 10.3390/ph14111091Gopalakrishnan L., Chatterjee O., Ravishankar N., Suresh S., Raju R., Mahadevan A., Prasad T.K. Opioid receptors signaling network // J Cell Commun Signal. – 2022. – Vol. 16, No. 3. – P. 475–483. DOI: 10.1007/s12079-021-00653-zGopalakrishnan L, Chatterjee O, Ravishankar N, Suresh S, Raju R, Mahadevan A, Prasad TK. Opioid receptors signaling network. J Cell Commun Signal. 2022;16(3):475–83. DOI: 10.1007/s12079-021-00653-zMachelska H., Celik M.Ö. Advances in achieving opioid analgesia without side effects // Front Pharmacol. – 2018. – Vol. 9. – Art. ID: 1388. DOI: 10.3389/fphar.2018.01388Machelska H, Celik MÖ. Advances in achieving opioid analgesia without side effects. Front Pharmacol. 2018;9:1388. DOI: 10.3389/fphar.2018.01388Mores K.L., Cummins B.R., Cassell R.J., van Rijn R.M. A review of the therapeutic potential of recently developed G protein-biased kappa agonists // Front Pharmacol. – 2019. – Vol. 10. – Art. ID: 407. DOI: 10.3389/fphar.2019.00407Mores KL, Cummins BR, Cassell RJ, van Rijn RM. A review of the therapeutic potential of recently developed G protein-biased kappa agonists. Front Pharmacol. 2019;10:407. DOI: 10.3389/fphar.2019.00407Спасов А.А., Калитин К.Ю., Гречко О.Ю., Анисимова В.А. Противоэпилептическая активность нового производного бензимидазола РУ-1205 // Бюллетень экспериментальной биологии и медицины. – 2015. – Т. 160, № 9. – С. 320–323.Spasov AA, Kalitin KY, Grechko OY, Anisimova VA. Antiepileptic activity of a new derivative of benzimidazole RU-1205. Bulletin of Experimental Biology and Medicine. 2015;160(9):320–3. RussianKalitin K.Y., Grechko O.Y., Spasov A.A., Sukhov A.G., Anisimova V.A., Matukhno A.E. GABAergic mechanism of anticonvulsive effect of chemical agent RU-1205 // Bull Exp Biol Med. – 2018. – Vol. 164. – P. 629–635. DOI: 10.1007/s10517-018-4047-4Kalitin KY, Grechko OY, Spasov AA, Sukhov AG, Anisimova VA, Matukhno AE. GABAergic Mechanism of Anticonvulsive Effect of Chemical Agent RU-1205. Bull Exp Biol Med. 2018;164:629–35. DOI: 10.1007/s10517-018-4047-4Калитин К.Ю., Придворов Г.В., Спасов А.А., Муха О.Ю. Влияние каппа-опиоидных агонистов буторфанола и соединения РУ-1205 на биоэлектрическую активность мозга при глобальной ишемии // Вестник Волгоградского государственного медицинского университета. – 2022. – Т. 19, № 3. – С. 128–133. DOI: 10.19163/1994-9480-2022-19-3-128-133Kalitin KY, Pridvorov GV, Spasov AA, Mukha OY. Neuroprotective action of butorphanol and RU-1205 with evaluation of their effect on the bioelectrical activity of the brain in the global ischemia model. Journal of Volgograd State Medical University. 2022;19(3):128–133. DOI: 10.19163/1994-9480-2022-19-3-128-133. RussianLiu-Chen L.Y., Huang P. Signaling underlying kappa opioid receptor-mediated behaviors in rodents // Front Neurosci. – 2022. – Vol. 16. – Art. ID: 964724. DOI: 10.3389/fnins.2022.964724Liu-Chen LY, Huang P. Signaling underlying kappa opioid receptor-mediated behaviors in rodents. Front Neurosci. 2022;16:964724. DOI: 10.3389/fnins.2022.964724Tortella F. C., Robles L., Holaday J. W. U50, 488, a highly selective kappa opioid: anticonvulsant profile in rats // J Pharmacol Exper Ther. – 1986. – Vol. 237, No. 1. – P. 49–53.Tortella FC, Robles L, Holaday JW. U50, 488, a highly selective kappa opioid: anticonvulsant profile in rats. J Pharmacol Exper Ther. 1986;237(1):49–53.Lemos C., Salti A., Amaral I.M., Fontebasso V., Singewald N., Dechant G., Hofer A., El Rawas R. Social interaction reward in rats has anti-stress effects // Addict Biol. – 2021. – Vol. 26, No. 1. – Art. ID: e12878. DOI: 10.1111/adb.12878Lemos C, Salti A, Amaral IM, Fontebasso V, Singewald N, Dechant G, Hofer A, El Rawas R. Social interaction reward in rats has anti‐stress effects. Addict Biol. 2021;26(1):e12878. DOI: 10.1111/adb.12878Ji G., Neugebauer V. Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons // Molecul Brain. – 2020. – Vol. 13, No. 1. – P. 1–10. DOI: 10.1186/s13041-020-00669-3Ji G, Neugebauer V. Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons. Molec Brain. 2020;13(1):1–10. DOI: 10.1186/s13041-020-00669-3Zan G.Y., Wang Q., Wang Y.J., Chen J.C., Wu X., Yang C.H., Chai J.R., Li M., Liu Y., Hu X.W., Shu X.H. p38 mitogen-activated protein kinase activation in amygdala mediates κ opioid receptor agonist U50,488H-induced conditioned place aversion // Neurosci. – 2016. – Vol. 320. – P. 122–128. DOI: 10.1016/j.neuroscience.2016.01.052Zan GY, Wang Q, Wang YJ, Chen JC, Wu X, Yang CH, Chai JR, Li M, Liu Y, Hu XW, Shu XH. p38 mitogen-activated protein kinase activation in amygdala mediates κ opioid receptor agonist U50,488H-induced conditioned place aversion. Neurosci. 2016;320:122–8. DOI: 10.1016/j.neuroscience.2016.01.052Yakhnitsa V., Ji G., Hein M., Presto P., Griffin Z., Ponomareva O., Navratilova E., Porreca F., Neugebauer V. Kappa opioid receptor blockade in the amygdala mitigates pain like-behaviors by inhibiting corticotropin releasing factor neurons in a rat model of functional pain // Front Pharmacol. – 2022. – Vol. 13. – Art. ID: 903978. DOI: 10.3389/fphar.2022.903978Yakhnitsa V, Ji G, Hein M, Presto P, Griffin Z, Ponomareva O, Navratilova E, Porreca F, Neugebauer V. Kappa Opioid Receptor Blockade in the Amygdala Mitigates Pain Like-Behaviors by Inhibiting Corticotropin Releasing Factor Neurons in a Rat Model of Functional Pain. Front Pharmacol. 2022;13:903978. DOI: 10.3389/fphar.2022.903978Dermitzaki E., Tsatsanis C., Gravanis A., Margioris A.N. Corticotropin-releasing hormone induces Fas ligand production and apoptosis in PC12 cells via activation of p38 mitogen-activated protein kinase // J Biologic Chem. – 2002. – Vol. 277, No. 14. – P. 12280–12287. DOI: 10.1074/jbc.M111236200Dermitzaki E, Tsatsanis C, Gravanis A, Margioris AN. Corticotropin-releasing hormone induces Fas ligand production and apoptosis in PC12 cells via activation of p38 mitogen-activated protein kinase. J Biologic Chem. 2002;277(14):12280–7. DOI: 10.1074/jbc.M111236200Ona G. Sampedro F., Romero S., Valle M., Camacho V., Migliorelli C., Mañanas M.Á., Antonijoan R.M., Puntes M., Coimbra J., Ballester M.R. The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A // Int J Neuropsychopharmacol. – 2022. – Vol. 25, No. 1. – P. 54–63. DOI: 10.1093/ijnp/pyab063Ona G, Sampedro F, Romero S, Valle M, Camacho V, Migliorelli C, Mañanas MÁ, Antonijoan RM, Puntes M, Coimbra J, Ballester MR. The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A. Int J Neuropsychopharmacol. 2022;25(1):54–63. DOI: 10.1093/ijnp/pyab063Tejeda H.A., Hanks A.N., Scott L., Mejias-Aponte C., Hughes Z.A., O’donnell P. Prefrontal cortical kappa opioid receptors attenuate responses to amygdala inputs //Neuropsychopharmacol. – 2015. – Vol. 40, No. 13. – P. 2856–2864. DOI: 10.1038/npp.2015.138Tejeda HA, Hanks AN, Scott L, Mejias-Aponte C, Hughes ZA, O'donnell P. Prefrontal cortical kappa opioid receptors attenuate responses to amygdala inputs. Neuropsychopharmacol. 2015;40(13):2856–64. DOI: 10.1038/npp.2015.138Jamali S., Dezfouli M.P., Kalbasi A., Daliri M.R., Haghparast A. Selective modulation of hippocampal theta oscillations in response to morphine versus natural reward // Brain Sci. – 2023. – Vol. 13, No. 2. – Art. ID: 322. DOI: 10.3390/brainsci13020322Jamali S, Dezfouli MP, Kalbasi A, Daliri MR, Haghparast A. Selective Modulation of Hippocampal Theta Oscillations in Response to Morphine versus Natural Reward. Brain Sci. 2023;13(2):322. DOI: 10.3390/brainsci13020322Ahmadi Soleimani S.M., Mohamadi M. A. H. M.H., Raoufy M.R., Azizi H., Nasehi M., Zarrindast M.R. Acute morphine administration alters the power of local field potentials in mesolimbic pathway of freely moving rats: Involvement of dopamine receptors // Neurosci Lett. – 2018. – Vol. 686. – P. 168–174. DOI: 10.1016/j.neulet.2018.09.016Soleimani SM, MAH MH, Raoufy MR, Azizi H, Nasehi M, Zarrindast MR. Acute morphine administration alters the power of local field potentials in mesolimbic pathway of freely moving rats: Involvement of dopamine receptors. Neurosci Lett. 2018;686:168–174. DOI: 10.1016/j.neulet.2018.09.016Reakkamnuan C., Cheaha D., Kumarnsit E. Nucleus accumbens local field potential power spectrums, phase-amplitude couplings and coherences following morphine treatment // Acta Neurobiol Exp (Wars). – 2017. – Vol. 77, No. 3. – P. 214–224. DOI: 10.21307/ane-2017-055Reakkamnuan C, Cheaha D, Kumarnsit E. Nucleus accumbens local field potential power spectrums, phase-amplitude couplings and coherences following morphine treatment. Acta Neurobiol Exp (Wars). 2017;77(3):214–24. DOI: 10.21307/ane-2017-055Hein M., Ji G., Tidwell D., D’Souza P., Kiritoshi T., Yakhnitsa V., Navratilova E., Porreca F., Neugebauer V. Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors // Neuropharmacolog. – 2021. – Vol. 185. – Art. ID: 108456. DOI: 10.1016/j.neuropharm.2021.108456Hein M, Ji G, Tidwell D, D'Souza P, Kiritoshi T, Yakhnitsa V, Navratilova E, Porreca F, Neugebauer V. Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors. Neuropharmacol. 2021;185:108456. DOI: 10.1016/j.neuropharm.2021.108456Ittner A.A., Gladbach A., Bertz J., Suh L.S., Ittner L.M. p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease // Acta Neuropathol Commun. – 2014. – Vol. 2. – P. 1–17. DOI: 10.1186/s40478-014-0149-zIttner AA, Gladbach A, Bertz J, Suh LS, Ittner LM. p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease. Acta Neuropathol Commun. 2014;2:1–17. DOI: 10.1186/s40478-014-0149-zZhang F., Wang F., Yue L., Zhang H., Peng W., Hu L. Cross-species investigation on resting state electroencephalogram // Brain Topogr. – 2019. – Vol. 32. – P. 808–824. DOI: 10.1007/s10548-019-00723-xZhang F, Wang F, Yue L, Zhang H, Peng W, Hu L. Cross-species investigation on resting state electroencephalogram. Brain Topogr. 2019;32:808–24. DOI: 10.1007/s10548-019-00723-xImperatori L.S., Cataldi J., Betta M., Ricciardi E., Ince R.A., Siclari F., Bernardi G. Cross-participant prediction of vigilance stages through the combined use of wPLI and wSMI EEG functional connectivity metrics // Sleep. – 2021. – Vol. 44, No. 5. – Art. ID: zsaa247. DOI: 10.1093/sleep/zsaa247Imperatori LS, Cataldi J, Betta M, Ricciardi E, Ince RA, Siclari F, Bernardi G. Cross-participant prediction of vigilance stages through the combined use of wPLI and wSMI EEG functional connectivity metrics. Sleep. 2021;44(5):zsaa247. DOI: 10.1093/sleep/zsaa247Banks M.I., Krause B.M., Endemann C.M., Campbell D.I., Kovach C.K., Dyken M.E., Kawasaki H., Nourski K.V. Cortical functional connectivity indexes arousal state during sleep and anesthesia // Neuroimage. – 2020. – Vol. 211. – Art. ID: 116627. DOI: 10.1016/j.neuroimage.2020.116627Banks MI, Krause BM, Endemann CM, Campbell DI, Kovach CK, Dyken ME, Kawasaki H, Nourski KV. Cortical functional connectivity indexes arousal state during sleep and anesthesia. Neuroimage. 2020;211:116627. DOI: 10.1016/j.neuroimage.2020.116627Delgado-Sallent C., Nebot P., Gener T., Fath A.B., Timplalexi M., Puig M.V. Atypical, but not typical, antipsychotic drugs reduce hypersynchronized prefrontal-hippocampal circuits during psychosis-like states in mice: Contribution of 5-HT2A and 5-HT1A receptors // Cereb Cortex. – 2022. – Vol. 32, No. 16. – P. 3472–3487. DOI: 10.1093/cercor/bhab427Delgado-Sallent C, Nebot P, Gener T, Fath AB, Timplalexi M, Puig MV. Atypical, but not typical, antipsychotic drugs reduce hypersynchronized prefrontal-hippocampal circuits during psychosis-like states in mice: Contribution of 5-HT2A and 5-HT1A receptors. Cerebr Cortex. 2022;32(16):3472–87. DOI: 10.1093/cercor/bhab427Huang Y., Yi Y., Chen Q., Li H., Feng S., Zhou S., Zhang Z., Liu C., Li J., Lu Q., Zhang L. Analysis of EEG features and study of automatic classification in first-episode and drug-naïve patients with major depressive disorder // BMC Psychiatry. – 2023. – Vol. 23, No. 1. – Art. ID: 832. DOI: 10.1186/s12888-023-05349-9Huang Y, Yi Y, Chen Q, Li H, Feng S, Zhou S, Zhang Z, Liu C, Li J, Lu Q, Zhang L. Analysis of EEG features and study of automatic classification in first-episode and drug-naïve patients with major depressive disorder. BMC Psychiatry. 2023;23(1):832. DOI: 10.1186/s12888-023-05349-9Desai R., Porob P., Rebelo P., Edla D.R., Bablani A. EEG data classification for mental state analysis using wavelet packet transform and gaussian process classifier // Wireless Personal Communications. – 2020. – Vol. 115, No. 3. – P. 2149–2169. DOI: 10.1007/s11277-020-07675-7Desai R, Porob P, Rebelo P, Edla DR, Bablani A. EEG data classification for mental state analysis using wavelet packet transform and gaussian process classifier. Wireless Personal Communications. 2020;115(3):2149–69. DOI: 10.1007/s11277-020-07675-7Chinara S. Automatic classification methods for detecting drowsiness using wavelet packet transform extracted time-domain features from single-channel EEG signal // J Neurosci Methods. – 2021. – Vol. 347. – Art. ID: 108927. DOI: 10.1016/j.jneumeth.2020.108927Chinara S. Automatic classification methods for detecting drowsiness using wavelet packet transform extracted time-domain features from single-channel EEG signal. J Neurosci Methods. 2021;347:108927. DOI: 10.1016/j.jneumeth.2020.108927Ieracitano C., Mammone N., Hussain A., Morabito F.C. A novel multi-modal machine learning based approach for automatic classification of EEG recordings in dementia // Neural Networks. – 2020. – Vol. 123. – P. 176–190. DOI: 10.1016/j.neunet.2019.12.006Ieracitano C, Mammone N, Hussain A, Morabito FC. A novel multi-modal machine learning based approach for automatic classification of EEG recordings in dementia. Neural Networks. 2020;123:176–90. DOI: 10.1016/j.neunet.2019.12.006Zanettini C., Scaglione A., Keighron J.D., Giancola J.B., Lin S.C., Newman A.H., Tanda G. Pharmacological classification of centrally acting drugs using EEG in freely moving rats: an old tool to identify new atypical dopamine uptake inhibitors // Neuropharmacol. – 2019. – Vol. 161. – Art. ID: 107446. DOI: 10.1016/j.neuropharm.2018.11.034Zanettini C, Scaglione A, Keighron JD, Giancola JB, Lin SC, Newman AH, Tanda G. Pharmacological classification of centrally acting drugs using EEG in freely moving rats: an old tool to identify new atypical dopamine uptake inhibitors. Neuropharmacol. 2019;161:107446. DOI: 10.1016/j.neuropharm.2018.11.034Shahabi M.S., Shalbaf A., Maghsoudi A. Prediction of drug response in major depressive disorder using ensemble of transfer learning with convolutional neural network based on EEG // Biocybernet Biomed Engineer. – 2021. – Vol. 41, No. 3. – P. 946–959. DOI: 10.1016/j.bbe.2021.06.006Shahabi MS, Shalbaf A, Maghsoudi A. Prediction of drug response in major depressive disorder using ensemble of transfer learning with convolutional neural network based on EEG. Biocybernet Biomed Engineer. 2021;41(3):946–59. DOI: 10.1016/j.bbe.2021.06.006Rives M.L., Rossillo M., Liu-Chen L.Y., Javitch J.A. 6′-Guanidinonaltrindole (6′-GNTI) is a G protein-biased κ-opioid receptor agonist that inhibits arrestin recruitment // J Biologic Chem. – 2012. – Vol. 287, No. 32. – P. 27050–27054. DOI: 10.1074/jbc.C112.387332Rives ML, Rossillo M, Liu-Chen LY, Javitch JA. 6′-Guanidinonaltrindole (6′-GNTI) is a G protein-biased κ-opioid receptor agonist that inhibits arrestin recruitment. J Biologic Chem. 2012;287(32):27050–4. DOI: 10.1074/jbc.C112.387332Kalitin K.Y., Spasov A.A., Mukha O.Y. Effects of kappa-opioid agonist U-50488 and p38 MAPK inhibitor SB203580 on the spike activity of pyramidal neurons in the basolateral amygdala // Research Ress Pharmacol. – 2024. – Vol. 10, No. 1. – P. 1–6. DOI: 10.18413/rrpharmacology.10.400Kalitin KY, Spasov AA, Mukha OY. Effects of kappa-opioid agonist U-50488 and p38 MAPK inhibitor SB203580 on the spike activity of pyramidal neurons in the basolateral amygdala. Research Res Pharmacol. 2024;10(1):1–6. DOI: 10.18413/rrpharmacology.10.400Courtin J., Karalis N., Gonzalez-Campo C., Wurtz H., Herry C. Persistence of amygdala gamma oscillations during extinction learning predicts spontaneous fear recovery // Neurobiol Learn Memory. – 2014. – Vol. 113. – P. 82–89. DOI: 10.1016/j.nlm.2013.09.015Courtin J, Karalis N, Gonzalez-Campo C, Wurtz H, Herry C. Persistence of amygdala gamma oscillations during extinction learning predicts spontaneous fear recovery. Neurobiol Learn Memory. 2014;113:82–9. DOI: 10.1016/j.nlm.2013.09.015

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