Опиоидные антагонисты как потенциальный новый психофармакологический класс для коррекции ангедонии

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.

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