Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron
Condition-specific deactivation of brain regions by 5-HT3 receptor antagonist Alosetron
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DOI：
10.1053/gast.2002.35990
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发表时间：
2002-10-01
期刊：
影响因子：
29.4
通讯作者：
Mayer, EA
中科院分区：
文献类型：
--
作者：
Berman, SM;Chang, L;Mayer, EA
背景与目的：5-羟色胺受体(5-HT3R)拮抗剂阿洛司琼(alosetron，ALOS)可减轻女性腹泻型肠易激综合征患者的症状，但其作用机制(S)尚不完全清楚。我们测定了在没有或存在直肠或乙状结肠刺激的情况下，ALOS对局部脑血流量(RCBF)的影响，以评估两种假想的治疗作用机制：外周抗伤害性感觉和抑制大脑中的情绪运动系统(EMS)区域。方法：49例非便秘型肠易激综合征(IBS)患者(26例女性)接受(H2O)-O-15正电子发射断层扫描(PET)，然后进行为期3周的随机、安慰剂对照试验，每天2次，每次1-4 mg。37例完全者在治疗后再次进行PET扫描。我们评估了基线、直肠扩张和预计未交付直肠扩张期间的rCBF。在一系列有害的乙状结肠扩张后，重复这3种情况。使用计算机控制的恒压装置进行直肠(45 Mm Hg)和乙状结肠(60 Mm Hg)扩张术。结果：与安慰剂相比，ALOS治疗改善了IBS症状，减少了EMS内含有5-HT3R的区域的rCBF，但对疼痛激活的区域没有影响。无内脏刺激时rCBF下降最明显，直肠或乙状结肠扩张可部分逆转rCBF的下降。症状的改善与富含5-HT3R的杏仁核、腹侧纹状体和桥脑背侧rCBF的减少显著相关。结论：IBS症状的减轻与药物引起的调节情绪表达的中枢自主神经网络活性的降低有关，在没有伤害性输入的情况下，这种活性最大。
Background & Aims: The 5-HT3 receptor (5-HT3R) antagonist Alosetron (Alos) reduces the symptoms of female patients with diarrhea-predominant irritable bowel syndrome (IBS); yet, the mechanism(s) underlying this effect remains incompletely understood. We determined the effect of Alos on regional cerebral blood flow (rCBF) in the absence and presence of rectal or sigmoid stimulation to evaluate 2 hypothesized mechanisms of therapeutic action: peripheral antinociception and inhibition of emotional motor system (EMS) regions in the brain. Methods: Forty-nine nonconstipated irritable bowel syndrome (IBS) patients (26 female) received (H2O)-O-15 positron emission tomography (PET) brain scans before a randomized, placebo-controlled, 3-week trial with Alos (1-4 mg twice daily). PET scans were repeated after treatment in 37 completers. We assessed rCBF during baseline, rectal distention, and anticipation of undelivered rectal distention. The 3 conditions were repeated after a series of noxious sigmoid distentions. Rectal (45 mm Hg) and sigmoid (60 mm Hg) distentions were performed with a computer-controlled barostat device. Results: Alos treatment, as compared with placebo, improved IBS symptoms and reduced rCBF in 5-HT3R containing regions of the EMS, but not in areas activated by pain. Reduction of rCBF appeared greatest in the absence of visceral stimulation, and was partially reversed by rectal or sigmoid distention. Symptom improvement across sessions was significantly correlated with rCBF decreases in the 5-HT3R-rich amygdala, ventral striatum, and dorsal pons. Conclusions: Reduction in IBS symptoms correlated with a drug-induced reduction in the activity of central autonomic networks mediating emotional expression that was maximal in the absence of nociceptive input.