Aversion-related effects of kappa-opioid agonist U-50488 on neural activity and functional connectivity between amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens





Introduction: Among the various receptor systems in the brain, the opioid receptors have been the subject of extensive research due to their integral role in pain modulation, reward processing, and emotional regulation. The kappa-opioid receptor (KOR) system, in particular, stands apart due to its unique contribution to stress response, aversive behaviors, and dysphoric states. This paper aims to provide an understanding of the neural activity underlying the aversion-associated effects of the KOR agonist U-50488.

Materials and Methods: Rats underwent stereotaxic surgery to implant electrodes into the amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens. The rats were subjected to conditioned place preference test to measure aversion to U-50488. After that, local field potential (LFP) recordings were made. LFP data were processed and analyzed using spectral and coherence analysis methods. A stepwise multiple linear regression was employed to identify the LFP features most significantly correlated with aversion to U-50488.

Results: The administration of U-50488 resulted in significant changes in LFP signals across multiple brain regions. These changes were particularly notable in the theta, gamma, and delta bands of brain waves (p<0.05). Theta and gamma activities were especially sensitive to the effects of U-50488. Connectivity calculations revealed shifts in coherence between brain regions, particularly highlighting the amygdala's involvement. While changes were also observed in the ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens (p<0.05), they contributed less to aversion. Using the stepwise multiple linear regression method, we established a final model with the 3 most significant variables: (1) coherence between the amygdala and medial prefrontal cortex, (2) coherence between the amygdala and hippocampus, and (3) theta power in the amygdala.

Conclusion: Overall, the data provided insights into how electrical neural activity mediates aversion in response to KOR activation. The results showed that the severity of aversion can be reasonably predicted (r = 0.72±0.02, p = 0.0099) using LFP band power and functional connectivity data. We concluded that the amygdala is a brain region that contributes the most to the KOR agonist-induced aversion.

Graphical Abstract


Selective kappa-opioid agonist, U-50488, aversion, dysphoria, amygdala, LFP, analysis, coherence, machine learning


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Author Contribution

Konstantin Y. Kalitin, Volgograd State Medical University

PhD, Associate Professor of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; Senior Researcher, Laboratory of Metabotropic Drugs, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd, Russia; Researcher, Laboratory of experimental pharmacology, Volgograd Medical Research Center, Volgograd, Russia; e-mail: kkonst8@yandex.ru; ORCID ID https://orcid.org/0000-0002-0079-853X. Conceptualization, setting primary objectives, carrying out experimental procedures, literature review, analyzing and interpreting the data, writing the initial draft of the article, contributing to the overall structure and design, finalizing the article for submission, designing visual data representations, applying statistical, mathematical, and computational methods for data analysis.

Alexander A. Spasov, Volgograd State Medical University

PhD, Professor, Academician of the Russian Academy of Sciences; Head of the Department ofPharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; Head of theLaboratory of experimental pharmacology, Volgograd Medical Research Center, Volgograd, Russia; Head of the Department of Pharmacology and Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd, Russia; e-mail: aaspasov@volgmed.ru; ORCID ID https://orcid.org/0000-0002-7185-4826. Concept statement, supervision and mentorship, workflow control, critical revision with valuable intellectual investment, contributing to the overall structure and design, ensuring the integrity and consistency of the entire article.

Olga Y. Mukha, Volgograd State Medical University

Teaching fellow of the Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Volgograd, Russia; e-mail: olay.myha14@gmail.com; ORCID ID https://orcid.org/0000-0002-0429-905X. Task management, experimental work, literature review, data collection, drafting the manuscript, contributing to the scientific layout, ensuring the integrity and consistency of the entire article, including its final version, application of statistical, mathematical, and computational methods for data analysis, preparation of the final manuscript, interaction with the editors and reviewers.




How to Cite

Kalitin KY, Spasov AA, Mukha OY (2023) Aversion-related effects of kappa-opioid agonist U-50488 on neural activity and functional connectivity between amygdala, ventral tegmental area, prefrontal cortex, hippocampus, and nucleus accumbens. Research Results in Pharmacology 9(4): 21–29. https://doi.org/10.18413/rrpharmacology.9.10051



Experimental Pharmacology

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