神经痛的药物治疗.pptVIP

* Calcium current reduced, NT release is reduced, postsynaptic eletrophys is reduced, a2d sticks to main Ca conducting subunit allosteric modulation of channel, reduces influc of Ca, this reduces NT release. UK-464,273 displaces binding of 3H-gabapentin from pig brain membranes (IC50 = 46.8nM). Activity at this binding site represents an interaction with the ?2? subunit of voltage-gated calcium channels. The mechanism of action of gaba-analogues is related to binding at the ?2? site, which is up-regulated in animal models of neuropathic pain. Displacement of 3H-gabapentin binding predicts analgesic effects in vivo resulting from modulation of voltage-dependent calcium channels and subsequent neurotransmitter release. It displaces 3H-gabapentin from the truncated, porcine, soluble isoform of the ?2?-1 subunit of voltage-activated calcium channels (IC50 = 13.45 nM). Studies with recombinant ?2?-1 and ?2?-2 proteins and subtype-specific binding methods suggest that UK-464,273 (like pregabalin and gabapentin) has no selectivity between the two isoforms. Modulation of GABA synapses -Benzodiazepines inrease the affinity of agonist binding to GABA-A receptors and enhance GABAergic inhibition. -Barbiturates bind to GABA receptors, increasing the time that the ion-conducting channel stays open. -Vigabatrin inhibits GABA transaminase enzyme, reducing GABA degradation. -Tiagabine competes with GABA for GABA transporter sites on neurons and glial cells. -Gabapentin may increase cytosolic GABA formed by glutamic acid decarboxylase (GAD) from glutamate. 癌性神经痛的药物治疗 神经病理性疼痛的定义 定义：神经系统损伤或功能障碍（失调）所致的疼痛。（国际疼痛学会，IASP ） 分类： 中枢性 周围性 神经病理性疼痛的形成机制 Diseases Syndromes Symptoms Mechanisms 肿瘤浸润或外压、创伤、代谢异常、 缺血、免疫、感染、神经毒性药物等 外周敏化及中枢敏化 自发性疼痛及诱发痛 神经病理性疼痛 神经病理性疼痛的形成机制 组织损伤 炎 症 交感神经末梢 H+,K+,5-HT,PG，缓激肽, 去甲肾上腺素,白细胞介素， 嘌呤,细胞因子,神经生长因子,神经肽等 痛阈下降，异位放电，Na+通道上调 NP的外周敏化机制 Neural Blockade 1998；675-699 神经病理性疼痛的形成机制 脊髓背角c纤维持续兴奋传入， 背角细胞反应性增强，“上发条”现象 （同突触机制） 相同刺激作用于不同的传人纤维， 改变了A-β机械