Hippocampal microglial activation induces cognitive impairment and allodynia through neuronal plasticity changes in male mice with neuropathic pain

Clinical evidence indicates that cognitive impairment is a common comorbidity of chronic pain, including neuropathic pain, but the mechanism underlying this comorbidity remains unclear. Neuroinflammation plays a critical role in the development of both neuropathic pain and cognitive impairment. A previous study showed that minocycline, an inhibitor of microglia, ameliorated allodynia and cognitive impairment in partial sciatic nerve ligation (PSNL) mice. Therefore, the current study examined a potential role of brain microglia in allodynia and cognitive impairment in male mice with neuropathic pain due to PSNL. Immunohistochemistry of the microglial markers ionized calcium-binding adapter molecule 1 (Iba1), transmembrane protein 119 (TMEM119), and purinergic receptor P2Y12 (P2RY12) was performed to examine microglial status. Two weeks after PSNL, significant microglial activation was observed in the hippocampus and amygdala, but not in the perirhinal cortex. Inhibition of brain-region-specific microglia with a local microinjection of clodronate liposomes was examined to elucidate the involvement of these microglia in PSNL-induced allodynia and cognitive impairment. Local clodronate liposome microinjection to the hippocampus, but not the amygdala, ameliorated allodynia and cognitive impairment. Other changes in the hippocampus of PSNL mice, e.g., decreased hippocampal dendrite length and intersections number, were prevented by microinjection of clodronate liposomes. The current findings suggest hippocampal microglia are related to cognitive impairment and allodynia through neuronal plasticity changes observed in PSNL mice. Blocking hippocampal microglia-mediated neuroinflammation may be a novel approach for reducing comorbidities such as cognitive impairment associated with neuropathic pain.