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

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ABSTRACT: 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 Ca 2+ 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.

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