Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension:: role of afferent C-fibers and 5-HT3 receptors
Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distension:: role of afferent C-fibers and 5-HT3 receptors
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DOI：
10.1016/s0006-8993(02)04197-5
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发表时间：
2003-03-21
期刊：
影响因子：
2.9
通讯作者：
Tebbe, JJ
中科院分区：
文献类型：
--
作者：
Mönnikes, H;Rüter, J;Tebbe, JJ
为了深入了解肠易激综合征（IBS）内脏痛觉过敏的发病机制，建立了实验动物模型。然而，数据的机制和途径参与诱导神经元活动的前脑和中脑结构的生理胃肠道刺激，如结肠扩张（CD），在范围从非有害到有害的强度是稀缺的。因此，近端CD与非有害（10 mmHg）和有害（40和70 mmHg）刺激强度对脑核中神经元活动的影响，如通过c-fos表达所评估的。在另外的研究中，在该实验模型中，在伤害性结肠扩张（70 mmHg）下研究了迷走神经和非迷走神经传入感觉C纤维和5-HT 3受体在内脏伤害感受介导中的作用。在CD时，孤束核（NTS）、延髓头端腹外侧区（RVLM）、楔状核（NC）、中脑导水管周围灰质（PAG）和杏仁核（AM）内c-Fos样免疫反应（c-FLI）阳性神经元数量呈压力依赖性增加。在背内侧核（DMH）和腹内侧核（VMH）的下丘脑，以及在丘脑（TH），神经元的活动也增加后CD，但独立的刺激强度。CD诱导的c-fos表达减少后，感觉迷走神经周围辣椒素治疗只观察到在脑干核（NTS和RVLM）。在所有其他激活的脑核团检查，CD相关的诱导c-fos的表达减少后，系统的新生儿辣椒素治疗。在NTS和RVLM，c-fos的表达也观察到下降的趋势后，系统的新生儿辣椒素治疗。为了评估5-HT 3受体在CD诱导的脑核神经元活化中的作用，用5-HT 3受体拮抗剂格拉司琼（1250 μ g/kg，在CD前18 μ g内腹膜内）预处理动物。格拉司琼预处理可使孤束核c-FLI阳性细胞数减少40%，但对CD诱导的其他脑区c-fos表达无显著影响。这些数据表明，不同的传入通路和递质参与了近端结肠扩张激活的伤害性信息从结肠到脑核团的传递。NTS神经元在这种条件下的激活似乎部分介导辣椒素敏感的迷走神经传入和5-HT 3受体。与此相反，近端结肠的伤害性机械刺激，评估c-fos表达，激活的脑核在二和端脑，部分介导的辣椒素敏感，非迷走神经传入，并独立于通过5-HT 3受体的神经传递。CD诱导的c-fos表达的调制专门在NTS的格拉司琼点的作用，5-HT 3受体拮抗剂的调制迷走神经感觉运动反射，而不是影响前脑核参与伤害性感受。(C)2002 Elsevier Science B. V.保留所有权利。
Experimental animal models have been established to gain insight into the pathogenesis and the mechanisms of visceral hyperalgesia in the irritable bowel syndrome (IBS). However, data about the mechanisms and pathways involved in the induction of neuronal activity in forebrain and midbrain structures by a physiological GI stimulus, like colonic distension (CD), in the range from non-noxious to noxious intensities are scarce. Thus, the effect of proximal CD with non-noxious (10 mmHg) and noxious (40 and 70 mmHg) stimulus intensities on neuronal activity in brain nuclei, as assessed by c-fos expression, was established. In additional studies, the role of vagal and non-vagal afferent sensory C-fibers and 5-HT3 receptors in the mediation of visceral nociception was investigated in this experimental model at noxious colonic distension (70 mmHg). At CD, the number of c-Fos like immunoreactivity (c-FLI)-positive neurons increased pressure-dependently in the nucleus of the solitary tract (NTS), rostral ventrolateral medulla (RVLM), nucleus cuneiformis (NC), periaqueductal gray (PAG), and the amygdala (AM). In the dorsomedial (DMH) and ventromedial nucleus (VMH) of the hypothalamus, as well as in the thalamus (TH), neuronal activity was also increased after CD, but independently of stimulus intensities. A decrease of the CD-induced c-fos expression after sensory vagal denervation by perivagal capsaicin treatment was only observed in brainstem nuclei (NTS and RVLM). In all other activated brain nuclei examined, the CD-related induction of c-fos expression was diminished only after systemic neonatal capsaicin treatment. In the NTS and RVLM, a trend of decrease of c-fos expression was also observed after systemic neonatal capsaicin treatment. In order to assess the role of the 5-HT3 receptor in CD-induced neuronal activation of brain nuclei, animals were pretreated with the 5-HT3 receptor antagonist granisetron (1250 mug/kg, i.p. within 18 It before CD). Pretreatment with granisetron significantly reduced the number of c-FLI-positive cells/section in the NTS by 40%, but had no significant effect on the CD-induced c-fos expression in other brain areas. The data suggest that distinct afferent pathways and transmitters are involved in the transmission of nociceptive information from the colon to the brain nuclei activated by proximal colonic distension. Activation of NTS neurons at such a condition seems to be partially mediated via capsaicin-sensitive vagal afferents and 5-HT3 receptors. In contrast, activation of brain nuclei in the di- and telencephalon by nociceptive mechanical stimulation of the proximal colon, as assessed by c-fos expression, is partially mediated by capsaicin-sensitive, non-vagal afferents, and independent of neurotransmission via 5-HT3 receptors. The modulation of CD-induced c-fos expression exclusively in the NTS by granisetron points to a role of 5-HT3 receptor antagonists in the modulation of vago-vagal sensomotoric reflexes rather than an influence on forebrain nuclei involved in nociception. (C) 2002 Elsevier Science B.V. All rights reserved.