Chen S-R, Pan H-L
Department of Anesthesiology, H187, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850, USA.
Neuroscience. 2004;125(1):141-8. doi: 10.1016/j.neuroscience.2004.01.015.
Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce efficacious analgesia. However, the mechanisms of the antinociceptive actions of muscarinic agonists in the spinal cord are not fully known. Previous in vitro studies have shown that muscarinic agonists increase GABA release and reduce the glutamatergic synaptic input to lamina II interneurons through GABAB receptors in the spinal cord. In the present study, we studied the effect of muscarinic agents on dorsal horn projection neurons and the role of spinal GABAB receptors in their action. Single-unit activity of ascending dorsal horn neurons was recorded in the lumbar spinal cord of anesthetized rats. The responses of dorsal horn neurons to graded mechanical stimuli were determined before and after topical spinal application of muscarine and neostigmine. We found that topical application of 0.1-5 microM muscarine or 0.5-5 microM neostigmine significantly suppressed the evoked response of dorsal horn neurons in a concentration-dependent manner. The inhibitory effect of muscarine or neostigmine on dorsal horn neurons was completely abolished in the presence of 1 microM atropine and by intrathecal pretreatment with 1 microg pertussis toxin to inactivate inhibitory G proteins. Furthermore, the inhibitory effect of both muscarine and neostigmine on the evoked response of dorsal horn neurons was significantly attenuated in the presence of 1 microM CGP55845, a GABAB receptor antagonist. Collectively, these data suggest that muscarinic agents inhibit dorsal horn projection neurons through muscarinic receptors coupled to pertussis toxin-sensitive Gi/o proteins. The inhibitory action of muscarinic agonists on these dorsal horn neurons is mediated in part by spinal GABAB receptors.
脊髓给予毒蕈碱受体激动剂或乙酰胆碱酯酶抑制剂可产生有效的镇痛作用。然而，毒蕈碱激动剂在脊髓中抗伤害感受作用的机制尚不完全清楚。先前的体外研究表明，毒蕈碱激动剂可增加γ-氨基丁酸（GABA）释放，并通过脊髓中的GABAB受体减少对Ⅱ层中间神经元的谷氨酸能突触输入。在本研究中，我们研究了毒蕈碱药物对背角投射神经元的作用以及脊髓GABAB受体在其作用中的作用。在麻醉大鼠的腰脊髓中记录背角神经元的单单位活动。在脊髓局部应用毒蕈碱和新斯的明之前和之后，测定背角神经元对分级机械刺激的反应。我们发现，局部应用0.1 - 5微摩尔/升的毒蕈碱或0.5 - 5微摩尔/升的新斯的明以浓度依赖性方式显著抑制背角神经元的诱发反应。在存在1微摩尔/升阿托品的情况下以及通过鞘内预处理1微克百日咳毒素使抑制性G蛋白失活后，毒蕈碱或新斯的明对背角神经元的抑制作用完全消除。此外，在存在1微摩尔/升GABAB受体拮抗剂CGP55845的情况下，毒蕈碱和新斯的明对背角神经元诱发反应的抑制作用均显著减弱。总体而言，这些数据表明，毒蕈碱药物通过与百日咳毒素敏感的Gi/o蛋白偶联的毒蕈碱受体抑制背角投射神经元。毒蕈碱激动剂对这些背角神经元的抑制作用部分由脊髓GABAB受体介导。
