cGMP-dependent protein kinase I in the dorsal hippocampus protects against synaptic plasticity and cognitive deficit induced by chronic pain

Patients with chronic pain often experience an exacerbated pain response and complain of memory deficits. However, the mechanistic link between pain and cognitive function remains unclear. The dorsal hippocampus (dHPC), a well-defined region responsible for learning and memory, displays maladaptive plasticity upon injury, which involves the activation of N-methyl-d-aspartic acid receptors. Mounting evidence has shown that cyclic guanosine cGMP-dependent protein kinase I (PKG-I) serves as a key downstream target of the N-methyl-d-aspartic acid receptors-NO-cGMP signaling pathway, regulating neuronal plasticity, pain hypersensitivity, and pain-related affective disorders. Despite these advances, it has remained elusive whether and how PKG-I in the dHPC contributes to hippocampal plasticity, as well as to chronic pain and pain-related cognitive deficits. In this study, we disclosed the crucial role of PKG-I in the dHPC in chronic pain and pain-related cognitive deficits. Following nerve injury, mice exhibited mechanical allodynia and thermal hyperalgesia, along with pain-related cognitive impairments; these changes were accompanied by the downregulation of PKG-I at both mRNA and protein levels in the dHPC. Overexpression of PKG-I in the dHPC alleviated pain hypersensitivity and associated cognitive deficits. Further mechanistic analysis revealed that PKG-I contributes to modulating Ca2+ mobilization in hippocampal pyramidal neurons, which brings about the production and secretion of a brain-derived neurotrophic factor in the dHPC. The resultant increase of the brain-derived neurotrophic factor in turn enhanced hippocampal neuronal excitability and synaptic plasticity and thus relieved pain hypersensitivity and pain-related cognitive impairment. Our findings extended the functional capability of hippocampal PKG-I on chronic pain and pain-related cognitive impairment. Hippocampal PKG-I may represent a novel therapeutic target for the treatment of chronic pain and pain-related memory deficits.