Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, China.
Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
Neuropharmacology. 2018 May 1;133:224-232. doi: 10.1016/j.neuropharm.2018.01.041. Epub 2018 Feb 1.
Some cannabinoids have been shown to suppress chronic pain by targeting glycine receptors (GlyRs). Although cannabinoid potentiation of α3 GlyRs is thought to contribute to cannabinoid-induced analgesia, the role of cannabinoid potentiation of α1 GlyRs in cannabinoid suppression of chronic pain remains unclear. Here we report that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, significantly suppresses chronic inflammatory pain caused by noxious heat stimulation. This effect may involve spinal α1 GlyRs since the expression level of α1 subunits in the spinal cord is positively correlated with CFA-induced inflammatory pain and the GlyRs antagonist strychnine blocks the DH-CBD-induced analgesia. A point-mutation of S296A in TM3 of α1 GlyRs significantly inhibits DH-CBD potentiation of glycine currents (I) in HEK-293 cells and neurons in lamina I-II of spinal cord slices. To explore the in vivo consequence of DH-CBD potentiation of α1 GlyRs, we generated a GlyRα1 knock-in mouse line. We observed that DH-CBD-induced potentiation of I and analgesia for inflammatory pain was absent in GlyRα1 knock-in mice. These findings suggest that spinal α1 GlyR is a potential target for cannabinoid analgesia in chronic inflammatory pain.
一些大麻素通过靶向甘氨酸受体（GlyRs）来抑制慢性疼痛。虽然大麻素对 α3 GlyRs 的增强被认为有助于大麻素诱导的镇痛，但大麻素对 α1 GlyRs 的增强在大麻素抑制慢性疼痛中的作用仍不清楚。在这里，我们报告说，去羟基大麻素（DH-CBD），一种非精神活性大麻素，可显著抑制由有害热刺激引起的慢性炎症性疼痛。这种作用可能涉及脊髓 α1 GlyRs，因为脊髓中 α1 亚基的表达水平与 CFA 诱导的炎症性疼痛呈正相关，而 GlyRs 拮抗剂士的宁可阻断 DH-CBD 诱导的镇痛。TM3 中的 S296A 点突变显著抑制 DH-CBD 对 HEK-293 细胞和脊髓切片 I-II 层神经元中甘氨酸电流（I）的增强。为了探索 DH-CBD 增强 α1 GlyRs 的体内后果，我们生成了 GlyRα1 敲入小鼠品系。我们观察到，DH-CBD 诱导的 I 增强和炎症性疼痛的镇痛在 GlyRα1 敲入小鼠中不存在。这些发现表明，脊髓 α1 GlyR 是慢性炎症性疼痛中大麻素镇痛的潜在靶点。
