bekhterevОбозрение психиатрии и медицинской психологии имени В.М.БехтереваV.M. BEKHTEREV REVIEW OF PSYCHIATRY AND MEDICAL PSYCHOLOGY2313-70532713-055XV. M. BEKHTEREV NATIONAL RESEARCH MEDICAL CENTER FOR PSYCHIATRY AND NEUROLOGY OF THE RUSSIAN FEDERATION MINISTRY OF HEALTH10.31363/2313-7053-2026-1-1179bekhterev-1319Research ArticleНАУЧНЫЕ ОБЗОРЫSCIENTIFIC REVIEWОпиоидные антагонисты как потенциальный новый психофармакологический класс для коррекции ангедонииOpioid Antagonists as a Potential Novel Class of Psychopharmacological Agents for Management of Anhedoniahttps://orcid.org/0000-0002-3130-3149ШагиахметовФ. Ш.ShagiakhmetovF. Sh.

Шагиахметов Фарид Шамилевич — к.м.н., старший научный сотрудник отдела клинической наркологии, Национальный научный центр наркологии, филиал 

119034, г. Москва, Кропоткинский переулок, д. 23

St. Petersburg

f.shagiakhmetov@gmail.comhttps://orcid.org/0000-0002-0529-4525КрупицкийЕ. М.KrupitskyE. M.

Крупицкий Евгений Михайлович — д.м.н., профессор, заместитель директора по научной работе и руководитель Института Аддиктологии; директор Института Фармакологии им. А.В. Вальдмана 

192019, Санкт-Петербург, ул.Бехтерева, 3

197022, г. Санкт-Петербург, ул. Льва Толстого, д. 6-8

St. Petersburg

kruenator@gmail.comhttps://orcid.org/0000-0001-9037-3932ШамакинаИ. Ю.ShamakinaI. Yu.

Шамакина Инна Юрьевна — к.б.н., руководитель лаборатории психофармакологии Отдела фундаментальной и прикладной нейробиологии

119034, г. Москва, Кропоткинский переулок, д. 23

St. Petersburg

shamakina@yahoo.comhttps://orcid.org/0000-0002-7974-5077АнохинП. К.AnokhinP. K.

Анохин Петр Константинович — к.б.н., старший научный сотрудник лаборатории психофармакологии отдела фундаментальной и прикладной нейробиологии

119034, г. Москва, Кропоткинский переулок, д. 23

St. Petersburg

petranokhin@mail.ruhttps://orcid.org/0009-0001-4506-0694АркусМ. Л.ArkusM. L.

Аркус Максим Леонидович — к.м.н., старший научный сотрудник отдела клинической наркологии

119034, г. Москва, Кропоткинский переулок, д. 23

St. Petersburg

arkus.m@serbsky.ruhttps://orcid.org/0000-0002-8460-4121ШайдеггерЮ. М.ScheideggerYu. M.

Шайдеггер Юлия Михайловна — научный сотрудник отдела психотерапии и медицинской реабилитации в амбулаторных и стационарных условиях

119034, г. Москва, Кропоткинский переулок, д. 23

St. Petersburg

scheidegger.y@serbsky.ruНациональный медицинский исследовательский центр психиатрии и наркологии им. В.П. СербскогоРоссияV.P. Serbsky National Medical Research Center of Psychiatry and NarcologyRussian FederationНациональный медицинский исследовательский центр психиатрии и неврологии имени В.М. Бехтерева; Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. ПавловаРоссияV.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology; I.P. Pavlov First St. Petersburg State Medical UniversityRussian Federation2026020320266015180Copyright © Шагиахметов Ф.Ш., Крупицкий Е.М., Шамакина И.Ю., Анохин П.К., Аркус М.Л., Шайдеггер Ю.М., 20262026Шагиахметов Ф.Ш., Крупицкий Е.М., Шамакина И.Ю., Анохин П.К., Аркус М.Л., Шайдеггер Ю.М.Shagiakhmetov F.S., Krupitsky E.M., Shamakina I.Y., Anokhin P.K., Arkus M.L., Scheidegger Y.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.bekhterevreview.com/jour/article/view/1319

Система «антинаграды» тесно связана с функциями каппа-опиоидных (KOP) и ноцицептиновых опиоидных (NOP) рецепторов. Их гиперактивация подавляет дофаминергическую нейротрансмиссию и сопровождается развитием ангедонии и отрицательных эмоциональных состояний. Опиоидные антагонисты, направленные на блокирование компонентов системы антинаграды, представляют собой потенциальный новый класс психофармакологических средств. Их действие направлено не на прямую стимуляцию механизмов награды, как у традиционных антидепрессантов, а на ослабление гиперактивных процессов антинаграды. Однако препараты, находящиеся в настоящее время в клинической разработке, блокируют только один тип рецепторов — KOP. Возможно, с этим связаны разочаровывающие результаты фазы 3 клинических исследований трех каппа-опиоидных антагонистов (атикапрант, навакапрант, ALKS-5461). Возможной причиной неудачи этих KOP-антагонистов может быть отсутствие у них способности предотвращать самопроизвольную (конститутивную) активацию рецепторов.

Если терапевтическая резистентность депрессии связана с повышением конститутивной активности KOP рецепторов, то нейтральные антагонисты KOP рецепторов не являются идеальными кандидатами для ее преодоления. Кроме того, KOP и NOP рецепторы — эволюционные паралоги, возникшие в результате дупликации одного гена, разошедшиеся в процессе эволюции, но сохранившие при этом значительную степень функциональной гомологии и способность компенсировать утрату функции друг друга. Можно предположить, что одновременная блокада KOP и NOP рецепторов повысит клиническую эффективность фармакотерапии. По-видимому, наиболее перспективной может оказаться разработка двойных инверсных (обратных) агонистов KOP и NOP рецепторов. Данный обзор посвящен теоретическому обоснованию возможности рождения нового психофармакологического класса — блокаторов гиперактивной опиоидергической отрицательной обратной связи в системе награды мозга. Мы предлагаем для него название «гедолиберанты», как отражающее механизм освобождения от патологической супрессии эндогенной системы награды.

The «anti-reward» system is closely linked to the functions of kappa-opioid (KOP) and nociceptin opioid (NOP) receptors. Their hyperactivation suppresses dopaminergic neurotransmission and leads to the development of anhedonia and negative affective states. Opioid antagonists aimed at supression of the antireward system represent a potentially novel class of psychopharmacological agents. Their action is directed not at stimulation of reward mechanisms, unlike traditional antidepressants, but at weakening hyperactive antireward processes. However, drugs currently undergoing clinical trials block only one type of receptor — KOP. This selective targeting may explain the disappointing results of phase 3 clinical trials of three kappa-opioid antagonists (aticaprant, navacaprant, ALKS-5461). A possible reason for the failure of KOP antagonists may be their lack of ability to prevent spontaneous (constitutive) receptor activation. Critically, if treatment-resistant depression results from increased constitutive activity of KOP receptors, then neutral KOP receptor antagonists are not ideal pharmacotherapeutic tools.

KOP and NOP receptors are evolutionary paralogs formed by duplication of a single ancestor gene. They diverged during evolution but retained some degree of functional homology thus being able to compensate for each other’s loss of function. It can be assumed that simultaneous blockade of both KOP and NOP receptors would increase the clinical efficacy. Apparently, development of dual inverse agonists of both KOP and NOP receptors may prove the most promising. This review represents a theoretical basis for the emergence of a new psychopharmacological class — antagonists (blockers) of hyperactive opioidergic negative feedback loop within the endogenous reward system. We propose the name «hedoliberants» for this class (from Greek ‘hedone’ meaning pleasure and Latin ‘liberare’ meaning to free), reflecting the mechanism of liberation from pathological suppression of the endogenous reward system.

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