Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Ji'nan, China.
Department of Pharmacy, Taian Maternal and Child Health Hospital, Tai'an, China.
Int J Neuropsychopharmacol. 2024 Oct 1;27(10). doi: 10.1093/ijnp/pyae040.
Phosphodiesterases (PDEs) are enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate AMP (cAMP) and/or cyclic guanosine monophosphate (cGMP). 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.
C57BL/6J mice were subjected to partial sciatic nerve ligation (PSNL) to induce chronic neuropathic pain or injected with complete Freund's adjuvant (CFA) 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 (PKA)-cAMP response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling and neuroinflammation in the effect of PDE7A inhibition on PSNL- or CFA-induced chronic pain and depression-like behavior.
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.
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.
磷酸二酯酶（PDEs）是催化环腺苷酸单磷酸（cAMP）和/或环鸟苷酸（cGMP）水解的酶。当这些疾病单独发生时，PDE 抑制剂可以减轻慢性疼痛和抑郁；然而，对于它们在同时发生的慢性疼痛和抑郁中的作用，人们的了解有限。我们旨在使用 2 种同时发生慢性疼痛和抑郁的小鼠模型来评估 PDE 的作用机制。
C57BL/6J 小鼠接受坐骨神经部分结扎（PSNL）以诱导慢性神经病理性疼痛，或注射完全弗氏佐剂（CFA）以诱导炎性疼痛，两种动物均表现出抑郁样行为。首先，我们确定了两种动物模型中 PDE 表达的变化。接下来，我们确定了 PDE7 抑制剂 BRL50481 或海马 PDE7A 敲低对 PSNL 或 CFA 诱导的慢性疼痛和抑郁样行为的影响。我们还研究了 cAMP-蛋白激酶 A（PKA）-cAMP 反应元件结合蛋白（CREB）-脑源性神经营养因子（BDNF）信号和神经炎症在 PDE7A 抑制对 PSNL 或 CFA 诱导的慢性疼痛和抑郁样行为中的作用。
这两种动物模型中慢性疼痛和抑郁的诱导上调了海马 PDE7A。口服 PDE7 抑制剂 BRL50481 或海马 PDE7A 敲低显著减轻机械性超敏反应和抑郁样行为。海马 PDE7 抑制逆转了 PSNL 或 CFA 诱导的 cAMP 和 BDNF 下调以及 PKA、CREB 和 p65 的磷酸化。cAMP 激动剂 forskolin 逆转了这些变化，并导致疼痛和抑郁的行为症状更轻微。BRL50481 逆转了 PSNL 小鼠海马中的神经炎症。
海马 PDE7A 通过抑制 cAMP-PKA-CREB-BDNF 信号转导介导了两种小鼠模型中同时发生的慢性疼痛和抑郁。抑制 PDE7A 或激活 cAMP-PKA-CREB-BDNF 信号转导可能是治疗同时发生的慢性疼痛和抑郁的潜在策略。
