Pain-relieving drugs and the brain histaminergic system: multiple analgesic mechanisms from histamine, improgan and cimetidine.
Pain-relieving drugs and the brain histaminergic system: multiple analgesic mechanisms from histamine, improgan and cimetidine.
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止痛药物和大脑组胺能系统：组胺、伊普甘和西咪替丁的多种镇痛机制。
DOI：
10.1007/s00011-003-0320-7
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Timmermann,H
中科院分区：
文献类型：
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作者：
Hough,LB;Nalwalk,JW;Svokos,K;Leurs,R;Timmermann,H
将组胺注射到中枢神经系统会产生强大的镇痛作用[1]，但大脑组胺能系统在缓解疼痛中的作用仍然知之甚少。导水管周围灰质 (PAG) 由组胺能神经元支配，已知是多个下行阿片类和非阿片类止痛系统的重要组成部分，这些系统与情绪状态相关并由环境变量激活 [2]。在 PAG 中，组胺激活 H1 和 H2 受体以减少疼痛传递 [1]，但该区域的 H2 受体对于吗啡镇痛和非阿片类应激诱导的镇痛是必需的 [3]。与 H2 受体相关的镇痛反应的表征导致了意外的发现，即中枢给药的 H2 拮抗剂（如西咪替丁）具有镇痛活性 [4]。对与 H2 和 H3 拮抗剂化学相关的化合物进行测试后发现了 improgan，这是一种西咪替丁衍生物，可诱导强大的 CNS 镇痛作用，但不会阻断 H2 受体 [4]。组胺、西咪替丁和 improgan 的化学结构如图 1 所示。与吗啡一样，improgan 可以减弱热和机械伤害性反应，并显示出高效镇痛药物的特性 [5]。然而，improgan 并不通过已知的阿片类药物或组胺受体发挥作用 [5]。尽管体外研究已经排除了 50 多种 CNS 受体和离子通道 [5]，但对 improgan 受体的研究仍在继续。在体内，improgan 似乎激活 PAG 和中缝大肌中的下行脑干疼痛缓解回路，可能涉及脊髓上 GABA 能和大麻素系统，以及脊髓去甲肾上腺素能系统 [5-7]。然而，该药物并不直接作用于任何这些受体。
Injections of histamine into the CNS produce powerful antinociception [1], but the role of the brain histaminergic system in pain relief has remained poorly understood. The periaqueductal grey (PAG), innervated by histaminergic neurons, is known to be an essential component of multiple, descending opioid and non-opioid pain-relieving systems which are linked to emotional states and are activated by environmental variables [2]. In the PAG, histamine activates both H1 and H2 receptors to reduce pain transmission [1], but H2 receptors in this region are necessary for morphine antinociception and for non-opioid stress-induced antinociception [3].Characterization of antinociceptive responses related to H2 receptors led to the unexpected discovery that centrallyadministered H2 antagonists such as cimetidine have antinociceptive activity [4]. Testing of compounds chemically related to H2 and H3 antagonists led to the discovery of improgan, a cimetidine derivative which induces powerful CNS antinociception, but does not block the H2 receptor [4]. Chemical structures of histamine, cimetidine and improgan are given in Fig. 1. Like morphine, improgan attenuates thermal and mechanical nociceptive responses, and shows the profile of a highly effective analgesic drug [5]. However, improgan does not act through known opioid or histamine receptors [5]. Although in vitro studies have excluded over 50 CNS receptors and ion channels [5], the search for the improgan receptor continues. In vivo, improgan seems to activate descending, brain stem pain-relieving circuitry in the PAG and raphe magnus which may involve supraspinal GABAergic and cannabinoid systems, as well as spinal noradrenergic systems [5–7]. The drug does not act directly on any of these receptors, however.