King's Laboratory, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China.
J Neurosci. 2014 Apr 9;34(15):5322-34. doi: 10.1523/JNEUROSCI.4703-13.2014.
This study aims to identify the inhibitory role of the spinal glucagon like peptide-1 receptor (GLP-1R) signaling in pain hypersensitivity and its mechanism of action in rats and mice. First, GLP-1Rs were identified to be specifically expressed on microglial cells in the spinal dorsal horn, and profoundly upregulated after peripheral nerve injury. In addition, intrathecal GLP-1R agonists GLP-1(7-36) and exenatide potently alleviated formalin-, peripheral nerve injury-, bone cancer-, and diabetes-induced hypersensitivity states by 60-90%, without affecting acute nociceptive responses. The antihypersensitive effects of exenatide and GLP-1 were completely prevented by GLP-1R antagonism and GLP-1R gene knockdown. Furthermore, exenatide evoked β-endorphin release from both the spinal cord and cultured microglia. Exenatide antiallodynia was completely prevented by the microglial inhibitor minocycline, β-endorphin antiserum, and opioid receptor antagonist naloxone. Our results illustrate a novel spinal dorsal horn microglial GLP-1R/β-endorphin inhibitory pathway in a variety of pain hypersensitivity states.
本研究旨在确定脊髓胰高血糖素样肽-1 受体（GLP-1R）信号在痛觉过敏中的抑制作用及其在大鼠和小鼠中的作用机制。首先，鉴定出 GLP-1R 特异性表达于脊髓背角的小胶质细胞，在外周神经损伤后显著上调。此外，鞘内给予 GLP-1R 激动剂 GLP-1(7-36)和 exenatide 可分别强力缓解福尔马林、外周神经损伤、骨癌和糖尿病引起的痛觉过敏状态达 60-90%，而不影响急性痛觉反应。GLP-1R 拮抗剂和 GLP-1R 基因敲低完全阻止了 exenatide 和 GLP-1 的抗敏作用。此外，exenatide 可从脊髓和培养的小胶质细胞中释放β-内啡肽。小胶质细胞抑制剂米诺环素、β-内啡肽抗血清和阿片受体拮抗剂纳洛酮完全阻止了 exenatide 的抗痛觉过敏作用。我们的结果说明了在各种痛觉过敏状态下，一种新型的脊髓背角小胶质细胞 GLP-1R/β-内啡肽抑制通路。
