Abstract
Neuropathic pain (NP) is an intractable pain that results from primary nervous system injury and dysfunction. Herein, we demonstrated in animal models that peripheral nerve injury induced enhanced pain perception and anxiety-like behaviors. According to previous reports, nucleus accumbens (NAc) shell is required for complete expression of neuropathic pain behaviors and mood alternations, we found the elevated mRNA and protein level of Prokineticin-2 (Prok2) in the NAc shell after Chronic Constriction Injury (CCI). Prok2 knockdown in the NAc shell reversed NP and anxiety-like behaviors in rats, indicating that Prok2 might play a fundamental role in NP and anxiety co-morbidity. CCI significantly enhanced Prok2 co-expression with NF-κB P-p65 in comparison with control animals. In addition to reversing the established nociceptive hypersensitivities and anxiety simultaneously, NAc microinjection of NF-κB siRNA or specific inhibitor PDTC reversed Prok2 upregulation. Besides, Prok2 was significantly decreased in vitro when co-transfected with si-NF-κB. Dual-Luciferase assay showed NF-κB directly activated Prok2 gene transcriptional activity. Overall, these findings provide new insights into the neurobiological mechanisms behind NP and comorbid anxiety. The NF-κB/Prok2 pathway could be a potential therapeutic target for NP and anxiety disorders.
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Acknowledgements
We sincerely appreciate the well-equipped Scientific and Research Platform and experimental animal center provided by the Institute of Neuroscience of Zhengzhou University. We would also like to thank our colleagues at the First Affiliated Hospital of Zhengzhou University and the School of Basic Medicine of Zhengzhou University for full support. We would acknowledge the valuable reviewer comments on this paper.
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This study was supported by grants from the National Natural Science Foundation of China Youth Project (Grant number: 82001191), and The Henan Medical Science and Technology Research Youth Project Co-Sponsored by the Province and Ministry in China (Grant number: SBGJ2021030880), and the Henan province young and middle-aged health science and technology innovation outstanding young talent training project (NO: YXKC2020059, YXKC2021018).
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WW, YX and MY: conceptualization. WW, YX and JY: designed and implemented of experiments; XW, YZ and ZY: data collection and analysis; YW, ZL and CH: preparation of articles and references; WW: first draft writing; QB and ZL: study design, experimental supervision, experimental administration, and revision of the manuscript. All of the authors participated in manuscript revision, and acknowledged the final version of the manuscript.
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Wang, W., Yuan, M., Xu, Y. et al. Prokineticin-2 Participates in Chronic Constriction Injury-Triggered Neuropathic Pain and Anxiety via Regulated by NF-κB in Nucleus Accumbens Shell in Rats. Mol Neurobiol 61, 2764–2783 (2024). https://doi.org/10.1007/s12035-023-03680-6
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DOI: https://doi.org/10.1007/s12035-023-03680-6