Upregulation of phosphodiesterase 7A leads to the downregulation of cAMP-PKA-CREB-BDNF signaling and neuroinflammation in the hippocampus and contributes to concurrent chronic pain and depression in two mouse models

Abstract Background 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. Methods 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. 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.