Hisaoka-Nakashima Kazue, Tokuda Shintarou, Goto Tatsuki, Yoshii Nanako, Nakamura Yoki, Ago Yukio, Morioka Norimitsu
Department of Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
Department of Cellular and Molecular Pharmacology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima, Japan.
Behav Brain Res. 2025 Jun 25;488:115590. doi: 10.1016/j.bbr.2025.115590. Epub 2025 Apr 18.
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.
临床证据表明，认知障碍是慢性疼痛（包括神经性疼痛）的常见合并症，但这种合并症的潜在机制仍不清楚。神经炎症在神经性疼痛和认知障碍的发展中起关键作用。先前的一项研究表明，小胶质细胞抑制剂米诺环素可改善部分坐骨神经结扎（PSNL）小鼠的痛觉过敏和认知障碍。因此，本研究探讨了脑小胶质细胞在PSNL所致雄性神经性疼痛小鼠的痛觉过敏和认知障碍中的潜在作用。通过对小胶质细胞标志物离子钙结合衔接分子1（Iba1）、跨膜蛋白119（TMEM119）和嘌呤能受体P2Y12（P2RY12）进行免疫组织化学检测来检查小胶质细胞状态。PSNL两周后，在海马体和杏仁核中观察到明显的小胶质细胞激活，但在嗅周皮质中未观察到。通过局部注射氯膦酸盐脂质体抑制脑区特异性小胶质细胞，以阐明这些小胶质细胞在PSNL诱导的痛觉过敏和认知障碍中的作用。向海马体而非杏仁核局部注射氯膦酸盐脂质体可改善痛觉过敏和认知障碍。PSNL小鼠海马体的其他变化，如海马体树突长度和交叉数减少，可通过注射氯膦酸盐脂质体来预防。目前的研究结果表明，海马体小胶质细胞通过PSNL小鼠中观察到的神经元可塑性变化与认知障碍和痛觉过敏有关。阻断海马体小胶质细胞介导的神经炎症可能是减少诸如与神经性疼痛相关的认知障碍等合并症的一种新方法。
