组胺H3受体拮抗剂对II型复杂性区域疼痛综合征的镇痛作用及机制

II型复杂性区域疼痛综合征(CRPS-2)是一种与自主神经系统障碍相关的神经痛，因其对常规镇痛药不敏感，迫切需要寻找新的药物与靶点。课题组前期研究发现中枢组胺可以抑制CRPS-2的神经痛，但因组胺不能通过血脑屏障而无法成药。组胺H3受体(H3R)主要分布在中枢神经系统，负反馈调节组胺的合成与释放。预实验发现，H3R拮抗剂噻普酰胺(Thio)可以有效干预CRPS-2神经痛的发生与维持。然而，预实验意外地发现阻断组胺功能并不能阻断其作用，提示其作用可能是组胺非依赖的。预实验还发现电毁损或药物阻断蓝斑-去甲肾上腺素(LC-NA)系统可以阻断Thio的作用，Thio还可以增强蓝斑神经元的兴奋性，提示H3R拮抗剂的镇痛作用可能是通过LC-NA来发挥的。本课题拟利用多种转基因小鼠、病毒转染，结合膜片钳、在体微电极记录等技术，阐明H3R拮抗剂对CRPS-2神经痛的作用和机制，为临床提供新策略和理论依据。

Complex regional pain syndrome II (CRPS-2) is an neuropathic pain associated with autonomic nervous system disorders. Because it is not sensitive to conventional analgesics, more efficacious drugs and targets are urgently required. Our previous studies have found that central histamine can inhibit the CRPS-2's neuralgia. However, histamine does not cross the blood brain barrier. Histamine H3 receptors (H3R) are predominantly expressed in the central nervous system, where they negatively regulate histamine release. Our preliminary experiments found that administration of thioperamide significantly attenuated the allodynia and hyperalgesia induced by partial sciatic nerve ligation (PSL) in a dose-dependent manner. However, to our surprise, the hypersensitivity of HDC-/- mice induced by PSL was also attenuated by thioperamide administration, suggesting that the analgesic effect may be histamine-independent. We also found that intervention of locus coeruleus - noradrenergic (LC-NA) system with electrical damage or drugs blocked the analgesic effect of thioperamide in CRPS-2. Thioperamide also enhanced the locus coeruleus neuronal excitability, suggesting that the H3R antagonists may have an analgesic effect in CRPS-2 by intervention of descending noradrenergic pathways. So, in this project, we intends to clarify the role of H3R antagonists on CRPS-2 neuralgia and its underling mechanism by using a variety of transgenic mice, viral transfection, combined with patch clamp and microelectrode recording technologies, and provide a new theoretical basis for clinical strategies.