Department of Physiology and Medical Science, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon, South Korea.
Department of Pharmacology, Catholic Kwandong University College of Medicine, Gangneung, South Korea.
Brain Res Bull. 2022 Jan;178:69-81. doi: 10.1016/j.brainresbull.2021.11.010. Epub 2021 Nov 20.
Recent studies have revealed that glial sigma-1 receptor (Sig-1R) in the spinal cord may be a critical factor to mediate sensory function. However, the functional role of Sig-1R in astrocyte has not been clearly elucidated. Here, we determined whether Sig-1Rs modulate calcium responses in primary cultured astrocytes and pathological changes in spinal astrocytes, and whether they contribute to pain hypersensitivity in naïve mice and neuropathic pain following chronic constriction injury (CCI) of the sciatic nerve in mice. Sig-1R was expressed in glial fibrillary acidic protein (GFAP)-positive cultured astrocytes. Treatment with the Sig-1R agonist, PRE-084 or neurosteroid dehydroepiandrosterone (DHEA) increased intracellular calcium responses in cultured astrocytes, and this increase was blocked by the pretreatment with the Sig-1R antagonist, BD-1047 or neurosteroid progesterone. Intrathecal administration of PRE-084 or DHEA for 10 days induced mechanical and thermal hypersensitivity and increased the number of Sig-1R-immunostained GFAP-positive cells in the superficial dorsal horn (SDH) region of the spinal cord in naïve mice, and these changes were inhibited by administration with BD-1047 or progesterone. In CCI mice, intrathecal administration of BD-1047 or progesterone at post-operative day 14 suppressed the developed mechanical allodynia and the number of Sig-1R-immunostained GFAP-positive cells that were increased in the SDH region of the spinal cord following CCI of the sciatic nerve. These results demonstrate that Sig-1Rs play an important role in the modulation of intracellular calcium responses in cultured astrocytes and pathological changes in spinal astrocytes and that administration of BD-1047 or progesterone alleviates the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced mechanical allodynia.
最近的研究表明，脊髓中的神经胶质西格玛-1 受体（Sig-1R）可能是介导感觉功能的关键因素。然而，Sig-1R 在星形胶质细胞中的功能作用尚未得到明确阐明。在这里，我们确定 Sig-1R 是否调节原代培养的星形胶质细胞中的钙反应和脊髓星形胶质细胞中的病理变化，以及它们是否导致未受伤的小鼠的疼痛过敏和慢性缩窄性坐骨神经损伤（CCI）后小鼠的神经性疼痛。Sig-1R 在胶质纤维酸性蛋白（GFAP）阳性培养的星形胶质细胞中表达。用 Sig-1R 激动剂 PRE-084 或神经甾体脱氢表雄酮（DHEA）处理可增加培养的星形胶质细胞中的细胞内钙反应，并且该增加可被 Sig-1R 拮抗剂 BD-1047 或神经甾体孕酮预处理所阻断。鞘内给予 PRE-084 或 DHEA 10 天会导致机械性和热敏感性，并增加未受伤小鼠脊髓背角浅层（SDH）区域中 Sig-1R 免疫染色 GFAP 阳性细胞的数量，而这些变化可通过给予 BD-1047 或孕酮来抑制。在 CCI 小鼠中，在术后第 14 天鞘内给予 BD-1047 或孕酮可抑制机械性痛觉过敏的发展以及坐骨神经 CCI 后脊髓背角 SDH 区域中增加的 Sig-1R 免疫染色 GFAP 阳性细胞的数量。这些结果表明 Sig-1R 在培养的星形胶质细胞中的细胞内钙反应和脊髓星形胶质细胞中的病理变化的调节中起重要作用，并且给予 BD-1047 或孕酮可减轻 Sig-1R 诱导的疼痛过敏和周围神经损伤诱导的机械性痛觉过敏。
