Methodological approaches for studying the mechanisms of action and interpreting the effects of kappa-opioid receptor agonists (literature review)

The search for new highly analgesic agents devoid of the side effects characteristic of the µ-opioid receptors agonists (drug dependence, respiratory depression, gastrointestinal disorders) is one of the priorities in the development of modern medicine. In this regard, selective k-opioid receptor agonists are of considerable interest, as they exhibit a pronounced analgesic effect comparable to that of µ-opioid receptor agonists. However, their widespread introduction into medical practice is limited by a high risk of affective disorders. In addition, the lack of a unified methodological approach to the assessing of side effects of k-opioid receptor agonists at the preclinical study stage leads to fragmented data and makes it difficult to form a reliable system for predicting their therapeutic potential and safety profile.

The material for the analysis was the literature sources presented in the bibliographic databases PubMed, Scopus, Web of Science, MedLine, RSCI and eLIBRARY.RU.

The article discusses the results of domestic and foreign studies on methods for evaluating and interpreting the effects of compounds with k-opioid activity. The necessity of applying a comprehensive approach is demonstrated, including molecular and cellular modeling methods, studies on isolated tissues, preclinical investigations, and strictly regulated clinical trials. A flowchart reflecting the structure of the experimental study of the mechanism of action and pharmacological effects of k-opioid receptor agonists has been developed.

The systematization of study strategies will improve the accuracy of assessing the therapeutic activity, tolerability and safety of compounds of this class, which will help to increase the prognostic significance of the data obtained, as well as reduce the complexity and duration of research.

Author contribution:
Subbotina S.N. – the concept and design of the study, collection of material and data processing, text writing and editing;
Shcherbinina K.E. – collection of material and data processing, text writing and editing;
Nikiforov A.S. – editing, critical revision of the manuscript;
Yudin M.A. – editing, approval of the final version of the article.
All co-authors – responsibility for the integrity of all parts of the article.

Conflict of interest. The authors declare that there are no obvious and potential conflicts of interest in connection with the publication of this article.

Funding. The study had no sponsorship.

Received: November 25, 2025 / Revised: February 25, 2026 / Accepted: June 1, 2026 / Published: June 30, 2026

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