Drug discovery and the mechanism of neuropathic pain targeting central cholinergic systems

(1) 在本研究中，我们检查了脊髓和大脑中神经性疼痛的机制。特别是，我们证明了脊髓和大脑中的毒蕈碱受体如何参与神经性疼痛。脊髓毒蕈碱 M_1 受体的激活对伤害性刺激产生镇痛作用，并且至少部分通过涉及脊髓 GABA_A 受体的神经元通路产生镇痛作用。此外，激活扣带皮质中的毒蕈碱 M_1 受体可以减轻神经性疼痛，并且镇痛作用是由 GABA_A 和 GABA_B 受体介导的。 (2)此外，我们还研究了趋化因子在神经性疼痛中的功能作用。预先给予小胶质细胞抑制剂米诺环素可抑制异常性疼痛。这一结果支持脊髓中的趋化细胞因子配体 (CCL)-1 有助于神经性疼痛的发生。

(1) In this study, we examined the mechanism of neuropathic pain in spinal cord and brain. Especially, we demonstrated how the muscarinic receptors in spinal cord and brain involve in neuropathic pain. Activation of spinal muscarinic M_1, receptors produces analgesic effect to nociceptive stimulation and, at least in part, through neuronal pathways involving spinal GABA_A receptors. In addition, Activation of muscarinic M_1 receptors in the the cinglate cortex attenuated the neuropathic pain and the analgesic effect was mediated by both GABA_A and GABA_B receptors. (2) In addition, we examined the functional role of chemokines in neuropathic pain. Pre-administrations of microglia inhibitor minocycline inhibited the allodynia. This result supports that Chemotactic Cytokine Ligand (CCL)-1 in the spinal cord contributes to the development of neuropathic pain.