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作者

Shi-Cai Chen, Yan-Han Chen, Yan Song, Shu-Hua Zong, Ming-Xia Wu, Wei Wang, Hao Wang, Feng Zhang, Yan-Meng Zhou, Hai-Yang Yu, Han-Ting Zhang, Fang-Fang Zhang

作者单位

Affiliations ¹ Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji'nan, China. ² Department of Pharmacy, Taian Maternal and Child Health Hospital, Tai'an, China. ³ Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, China.

刊名

The international journal of neuropsychopharmacology

年份

2024

卷号

Vol.27 No.10

页码

pyae040

ISSN

1469-5111

关键词

Chronic pain cyclic adenosine monophosphate depression neuroinflammation phosphodiesterase7A.

摘要

Background: Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP and/or cyclic guanosine monophosphate . PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression. Methods: C57BL/6J mice were subjected...更多

Background: Phosphodiesterases are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP and/or cyclic guanosine monophosphate . PDE inhibitors can mitigate chronic pain and depression when these disorders occur individually; however, there is limited understanding of their role in concurrent chronic pain and depression. We aimed to evaluate the mechanisms of action of PDE using 2 mouse models of concurrent chronic pain and depression. Methods: C57BL/6J mice were subjected to partial sciatic nerve ligation to induce chronic neuropathic pain or injected with complete Freund's adjuvant to induce inflammatory pain, and both animals showed depression-like behavior. First, we determined the change in PDE expression in both animal models. Next, we determined the effect of PDE7 inhibitor BRL50481 or hippocampal PDE7A knockdown on PSNL- or CFA-induced chronic pain and depression-like behavior. We also investigated the role of cAMP-protein kinase A -cAMP response element binding protein -brain-derived neurotrophic factor signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior. Results: This induction of chronic pain and depression in the 2 animal models upregulated hippocampal PDE7A. Oral administration of PDE7 inhibitor, BRL50481, or hippocampal PDE7A knockdown significantly reduced mechanical hypersensitivity and depression-like behavior. Hippocampal PDE7 inhibition reversed PSNL- or CFA-induced downregulation of cAMP and BDNF and the phosphorylation of PKA, CREB, and p65. cAMP agonist forskolin reversed these changes and caused milder behavioral symptoms of pain and depression. BRL50481 reversed neuroinflammation in the hippocampus in PSNL mice. Conclusions: Hippocampal PDE7A mediated concurrent chronic pain and depression in both mouse models by inhibiting cAMP-PKA-CREB-BDNF signaling. Inhibiting PDE7A or activating cAMP-PKA-CREB-BDNF signaling are potential strategies to treat concurrent chronic pain and depression.收起

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期刊