pmedpharmФармация и фармакологияPharmacy & Pharmacology2307-92662413-2241Pyatigorsk Medical and Pharmaceutical Institute - branch of Volgograd State Medical Univer10.19163/2307-9266-2025-13-2-98-110pmedpharm-1683Research ArticleОРИГИНАЛЬНАЯ СТАТЬЯRESEARCH ARTICLEВлияние каппа-опиоидного агониста РУ-1205 на локальный полевой потенциал и поведение в модели дискриминации стимулаThe effects of kappa opioid agonist RU-1205 on local field potentials and behavior in the discriminative stimulus paradigmhttps://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.

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

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

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

1. 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131.

2. 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; младший научный сотрудник лаборатории метаботропных лекарственных средств НЦИЛС ФГБОУ ВО ВолгГМУ Минздрава России.

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

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

PhD candidate of the Department of Pharmacology and Bioinformatics, junior researcher at the Laboratory of Metabotropic Drugs, Scientific Center for Innovative Drugs, Volgograd State Medical University.

1. 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131.

2. 39, Novorossiyskaya Str., Volgograd, Russia, 400087.

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

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

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

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

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

1. 1, Pavshikh Bortsov Sq., Volgograd, Russia, 400131.

2. 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 федерального государственного бюджетного образовательного учреждения высшего образования «Волгоградский государственный медицинский университет» Министерства здравоохранения Российской Федерации.Россия1. Volgograd State Medical University. 2. Scientific Center for Innovative Drugs.Russian Federation20252307202513298110Copyright © Калитин К.Ю., Муха О.Ю., Спасов А.А., 20252025Калитин 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/1683

Каппа-опиоидные рецепторы играют ключевую роль в регуляции физиологических и психических процессов. Было показано, что производное бензимидазола РУ-1205, специфический агонист каппа-опиоидных рецепторов, модулирует активность нейронов. Однако комплексное воздействие соединения РУ-1205 на нейрональную активность остается недостаточно изученным.

Цель

Цель. Поиск и интерпретация изменений локального полевого потенциала, а также оценка поведения в модели дискриминации стимула под влиянием каппа-опиоидного агониста РУ-1205.

Материалы и методы

Материалы и методы. Крысам (260–280 г) имплантировали корковые (F — фронтальные, O — окципитальные, P — париетальные), а также глубокие электроды в зону медиальной префронтальной коры (mPFC), гиппокампа (Hipp), прилежащего ядра (NAc), вентральной области покрышки (VTA) и миндалины (Amy). Проводился спектральный и когерентный анализ LFP-сигналов, полученных после введения соединения РУ-1205 (350 мкг/5 мкл интрацеребровентрикулярно). Использовалась модель дискриминации стимула, чтобы оценить сходство соединения РУ-1205 с селективным агонистом каппа-опиоидных рецепторов U-50488 и ингибитором MAPK p38 SB203580 (в том числе в комбинации с блокатором опиоидных рецепторов налоксоном).

Результаты

Результаты. Зафиксированы изменения: повышение мощности в диапазоне тета-частот (4–8 Гц) на отведениях F, P и mPFC, снижение мощности в диапазоне дельта-частот (0,5–4 Гц) сигналов с O и Hipp отведений, а также подавление гамма-активности (30–50 Гц) на отведениях F и mPFC (p <0,05). После введения РУ-1205 наблюдалось снижение когерентности между парами электродов: P–O, P–F, F–O и mPFC–Hipp (p <0,05). Отсутствие p38-ингибирующей активности РУ-1205 и его сходство с U-50488 подтверждено в модели дискриминации стимула.

Заключение

Заключение. Установлено, что по сравнению с селективным каппа-опиоидным агонистом U-50488 соединение РУ-1205 вызывает менее выраженные изменения LFP-активности без электрофизиологических и поведенческих признаков активации бета-аррестинового пути. Совокупность данных свидетельствует о принадлежности соединения РУ-1205 к функционально селективным агонистам каппа-опиоидных рецепторов.

Kappa opioid receptors play a pivotal role in regulating both physiological and cognitive processes. RU-1205, a benzimidazole derivative acting as a specific kappa opioid receptor agonist, has demonstrated the capacity to modulate neuronal activity. However, the nuanced effects of RU-1205 on neuronal activity remain incompletely understood.

The aim of the study was to identify and elucidate the effects of the kappa opioid agonist RU-1205 on local field potentials and behavior in the discriminative stimulus paradigm.

Materials and methods

Materials and methods. The experiments were conducted in male rats weighing 260–280 g. The animals were surgically implanted with cortical electrodes (F — frontal, O — occipital, P — parietal) as well as deep electrodes in specific brain regions, including the medial prefrontal cortex (mPFC), hippocampus (Hipp), nucleus accumbens (NAc), ventral tegmental area (VTA) and amygdala (Amy). LFP signals were obtained and analyzed after the administration of the compound RU-1205 (350 μg/5 μl intracerebroventricular injections) using spectral and coherence analysis methods. Drug discrimination paradigm was employed to evaluate the similarity of the compound RU-1205 to the selective kappa opioid receptor agonist U-50488 and the p38 MAPK inhibitor SB203580 (including in combination with the opioid receptor blocker naloxone).

Results

Results. Electrophysiological changes observed include an increase in power of theta frequencies (4–8 Hz) in F, P and mPFC leads, along with a reduced power of delta frequencies (0.5–4 Hz) in O and Hipp leads, and a suppression of gamma activity (30–50 Hz) in F and mPFC leads, all with statistical significance (p <0.05). Post-administration of RU-1205 resulted in a decreased coherence between pairs of electrodes: P–O, P–F, F–O, and mPFC–Hipp (all p <0.05). It was found that the compound RU-1205 is similar to U-50488 and does not exhibit p38 inhibitory activity in the discriminative stimulus paradigm.

Conclusion

Conclusion. Compared to the selective kappa-opioid agonist U-50488, the compound RU-1205 induces less significant changes in LFP activity without electrophysiological and behavioral signs of beta-arrestin pathway activation. The overall data suggest that RU-1205 is a functionally selective agonist of kappa-opioid receptors.

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