Department of Toxicology, Hoshi University, School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York City, NY 10065-6399, USA Cancer Pathophysiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan Division of Palliative Medicine, Wakayama Medical University Hospital, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8510, Japan Department of Psychiatry, Nihon University, School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8601, Japan Palliative Care Unit, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan Department of Palliative Medicine, Palliative Care Team, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Pain. 2011 Jun;152(6):1358-1372. doi: 10.1016/j.pain.2011.02.016. Epub 2011 Mar 10.
Insomnia is a common problem for people with chronic pain. Cortical GABAergic neurons are part of the neurobiological substrate that underlies homeostatic sleep regulation. In the present study, we confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, we found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. Under these conditions, membrane-bound GABA (γ-aminobutyric acid) transporters (GATs) on activated glial fibrillary acidic protein-positive astrocytes were significantly increased in the cingulate cortex, and extracellular GABA levels in this area after depolarization were rapidly decreased by nerve injury. Furthermore, sleep disturbance induced by sciatic nerve ligation was improved by the intracingulate cortex injection of a GAT-3 inhibitor. These findings provide novel evidence that sciatic nerve ligation decreases extracellular-released GABA in the cingulate cortex of mice. These phenomena may, at least in part, explain the insomnia in patients with neuropathic pain. Neuropathic pain-like stimuli suppress the GABAergic transmission with increased GABA (γ-aminobutyric acid) transporters located on activated astrocytes in the cingulate cortex related to sleep disturbance.
失眠是慢性疼痛患者常见的问题。皮质 GABA 能神经元是构成稳态睡眠调节神经生物学基础的一部分。在本研究中，我们证实了坐骨神经结扎会导致小鼠出现热痛觉过敏和触觉异常性疼痛。在这个用于神经病理性疼痛的实验模型中，我们发现，在类似神经病理性疼痛的状态下，清醒时间增加，非快速眼动睡眠减少。在这些条件下，激活的神经胶质纤维酸性蛋白阳性星形胶质细胞上的膜结合 GABA（γ-氨基丁酸）转运体（GATs）在扣带皮质中显著增加，并且该区域的细胞外 GABA 水平在神经损伤后迅速下降。此外，通过扣带皮质内注射 GAT-3 抑制剂可以改善坐骨神经结扎引起的睡眠障碍。这些发现为坐骨神经结扎会减少小鼠扣带皮质细胞外释放 GABA 提供了新的证据。这些现象至少部分解释了神经病理性疼痛患者的失眠。神经病理性疼痛样刺激通过位于与睡眠障碍相关的扣带皮质中激活的星形胶质细胞上的增加的 GABA（γ-氨基丁酸）转运体抑制 GABA 能传递。
