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Repeated Use of Morphine Induces Anxiety by Affecting a Proinflammatory Cytokine Signaling Pathway in the Prefrontal Cortex in Rats

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Abstract

We examined the role of toll-like receptors (TLRs) and proinflammatory cytokine signaling pathways in the prefrontal cortex (PFC) in anxiety-like behaviors after repeated use of morphine. Morphine (10 mg/kg) was used twice daily for 8 days to induce morphine dependence in male Wistar rats. On day 8, opioid dependence was confirmed by measuring naloxone-precipitated withdrawal signs. On days 1 and 8, anxiety-like behaviors were evaluated using a light/dark box test. Expression of TLR1 and 4, proinflammatory cytokines, and some of the downstream signaling molecules was also evaluated in the bilateral PFC at mRNA and protein levels following morphine dependence. The results revealed that morphine caused anxiolytic-like effects on day 1 while induced anxiety following 8 days of repeated injection. On day 8, a significant decrease in TLR1 expression was detected in the PFC in morphine-dependent rats, but TLR4 remained unaffected. Repeated morphine injection significantly increased IL1-β, TNFα, and IL6 expression, but decreased IL1R and TNFR at mRNA and protein levels except for IL6R at the protein level in the PFC. The p38α mitogen-activated protein (MAP) kinase expression significantly increased but the JNK3 expression decreased in the PFC in morphine-dependent rats. Repeated injection of morphine also significantly increased the NF-κB expression in the PFC. Further, significant increases in Let-7c, mir-133b, and mir-365 were detected in the PFC in morphine-dependent rats. We conclude that TLR1 and proinflammatory cytokines signaling pathways in the PFC are associated with the anxiogenic-like effects of morphine following its chronic use in rats via a MAP kinase/NF-κB pathway.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was funded by the Cognitive Sciences and Technologies Council of Iran (Contract No. D/100/11988).

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This study was funded by the Cognitive Sciences and Technologies Council of Iran (Contract No. D/100/11988).

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  1. Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran

    Shamseddin Ahmadi, Shiva Mohammadi Talvar, Kayvan Masoudi & Mohammad Zobeiri

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Shamseddin Ahmadi: conceptualization and design of the work, writing—original draft preparation, writing—reviewing and editing, supervision, project administration, and funding acquisition. Mohammad Zobeiri, Shiva Mohammadi Talvar, and Kayvan Masoudi: acquisition, analysis, interpretation of data, and writing—original draft preparation. All authors approved the final version for publication.

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All procedures were done according to the Guide for the Care and Use of Laboratory Animals (2011) prepared by the National Academy of Sciences’ Institute for Laboratory Animal Research. The Research Ethics Committee (REC) at the University of Kurdistan approved the study protocol (IR.UOK.REC.1398.021).

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Ahmadi, S., Mohammadi Talvar, S., Masoudi, K. et al. Repeated Use of Morphine Induces Anxiety by Affecting a Proinflammatory Cytokine Signaling Pathway in the Prefrontal Cortex in Rats. Mol Neurobiol 60, 1425–1439 (2023). https://doi.org/10.1007/s12035-022-03144-3

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