Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors
Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors
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DOI：
10.1113/jphysiol.2007.139352
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发表时间：
2007-09-01
影响因子：
5.5
通讯作者：
Schemann, Michael
中科院分区：
文献类型：
--
作者：
Breunig, Eva;Michel, Klaus;Schemann, Michael
组胺是肠道中免疫神经信号传导的主要肥大细胞介质，肥大细胞在功能性和炎性肠病的病理生理学中发挥作用。因此，组胺受体是治疗肠道疾病的有前途的药物靶点。我们的目的是研究迄今未知的组胺对人类肠神经系统（ENS）的神经活动的影响，并确定组胺反应的药理学。我们使用快速成像技术结合电位染料二-8-ANEPPS直接监测膜电位的变化，从而在人类粘膜下神经丛的神经元兴奋性从手术标本的110例（2137神经元，273神经节）。局部微喷射组胺导致37%的神经元动作电位放电。这种兴奋作用被H-1激动剂HTMT-dimaleat、H-2激动剂dimaleat、H-3激动剂（R）-（-）-α-甲基组胺和H-4激动剂4-甲基组胺模拟。H-1、H-2、H-3或H-4受体拮抗剂吡拉明、雷尼替丁、氯苄丙酸或J1-[（5-氯-1H-吲哚-2-基）羰基]-4-甲基哌嗪（JNJ 7777120）分别特异性和选择性地阻断激动剂的兴奋作用。Clobenproprit减少组胺的兴奋性反应。与豚鼠不同，ENS（R）-（-）-α-甲基组胺在人粘膜下神经丛中无突触前作用。激动剂的应用显示受体聚集如下：29%H-1/H-3、27%H-2、20%H-1/H-2/H-3、10%H-3、7%H-1/H-2和7%H-2/H-3。组胺兴奋人肠神经元，这种作用涉及所有四种组胺受体;最引人注目的是兴奋性H3介导的组分的鉴定和H4介导的神经元兴奋的发现。这些数据可能构成识别治疗炎症性和功能性肠道疾病的新靶点的基础。
Histamine is a major mast cell mediator of immunoneural signalling in the gut and mast cells play a role in the pathophysiology of functional and inflammatory bowel diseases. Histamine receptors are therefore promising drug targets to treat gut disorders. We aimed to study the so far unknown effect of histamine on neural activity in the human enteric nervous system (ENS) and to identify the pharmacology of histamine response. We used fast imaging techniques in combination with the potentiometric dye di-8-ANEPPS to monitor directly membrane potential changes and thereby neuronal excitability in the human submucous plexus from surgical specimens of 110 patients (2137 neurones, 273 ganglia). Local microejection of histamine resulted in action potential discharge in 37% of neurones. This excitatory effect was mimicked by the H, agonist HTMT-dimaleat, H-2 agonist dimaprit, H-3 agonist (R)-(-)-alpha-methylhistamine and H-4 agonist 4-methylhistamine. The excitatory actions of the agonists were specifically and selectively blocked by the H-1, H-2, H-3 or H-4 receptor antagonists pyrilamine, ranitidine, clobenpropit or J1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine (JNJ7777120), respectively. Clobenproprit reduced the excitatory response to histamine. Unlike in the guinea-pig ENS (R)-(-)-a-methylhistamine had no presynaptic actions in human submucous plexus. Application of agonists revealed receptor clustering which was as follows: 29% H-1/H-3, 27% H-2, 20% H-1/H-2/H-3, 10% H-3, 7% H-1/H-2 and 7% H-2/H-3. Histamine excites human enteric neurones and this effect involves all four histamine receptors; most striking was the identification of an excitatory H3 mediated component and the discovery of H4 mediated neuronal excitation. These data may form the basis of identification of new targets to treat inflammatory and functional gut disorders.