Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Neuroimage. 2012 Dec;63(4):1854-63. doi: 10.1016/j.neuroimage.2012.08.028. Epub 2012 Aug 21.
BACKGROUND/AIMS: Alterations in noradrenergic (NE) signaling have been implicated in the pathophysiology of irritable bowel syndrome (IBS), and adrenergic receptors are potential treatment targets.
To characterize central NE signaling in IBS, 11 patients and 11 healthy controls (HCs) were studied 3 times during an auditory oddball vigilance task after double-blind ingestion of the α2-adrenoreceptor (α2AR) antagonist yohimbine (YOH), the α2AR agonist clonidine (CLO), or placebo (PLA). Regional cerebral glucose metabolism was measured with [¹⁸F] fluorodeoxyglucose (FDG) positron emission tomography (PET). Measures of anxiety, early-life trauma, plasma NE and blood pressure were acquired.
Patients had higher plasma NE levels than HCs before and after ingestion of all drugs (all p<0.05). YOH increased plasma NE and more anxiety in patients than in HCs. After YOH, NE levels directly correlated with drug-induced increases in anxiety in IBS patients (r=0.61), but not in HCs. IBS patients showed less YOH-mediated reduction of activity in a central arousal circuit, consistent with fewer functional presynaptic α2AR. In HCs, but not in patients, activation of amygdala and subgenual anterior cingulate cortex (sgACC) was inversely correlated with activation of anterior mid cingulate cortex (aMCC), and state anxiety covaried directly with activity in limbic and right frontotemporal cortices, but indirectly with activity in the left frontotemporal cortex. YOH-mediated reduction of activity in brainstem and amygdala inversely correlated with early life trauma.
IBS patients showed evidence for increased noradrenergic activity consistent with downregulation of presynaptic inhibitory α2ARs. Activity within central arousal circuits was biased toward greater excitability and reduced corticolimbic inhibition in IBS. Early life trauma may be one mediator of these abnormalities.
背景/目的：去甲肾上腺素（NE）信号的改变与肠易激综合征（IBS）的病理生理学有关，肾上腺素能受体是潜在的治疗靶点。
为了描述 IBS 患者中枢 NE 信号，在双盲给予α2-肾上腺素能受体（α2AR）拮抗剂育亨宾（YOH）、α2AR 激动剂可乐定（CLO）或安慰剂（PLA）后，11 名 IBS 患者和 11 名健康对照者（HCs）在听觉Oddball 警觉任务中进行了 3 次研究。采用[¹⁸F]氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET）测量脑局部葡萄糖代谢。获得焦虑、早年创伤、血浆 NE 和血压等指标。
与 HCs 相比，患者在服用所有药物前后的血浆 NE 水平均升高（均<0.05）。与 HCs 相比，YOH 增加了患者的血浆 NE 和焦虑。在 YOH 后，NE 水平与 IBS 患者的药物诱导性焦虑增加直接相关（r=0.61），但在 HCs 中则不相关。与 HCs 相比，IBS 患者在 YOH 介导的中枢觉醒回路活性降低方面表现出较少的功能，与较少的功能性突触前α2AR 一致。在 HCs 中，但在患者中没有，杏仁核和扣带回前部皮质（sgACC）的激活与前扣带中部（aMCC）的激活呈负相关，状态焦虑与边缘和右侧额颞叶皮质的活动直接相关，而与左侧额颞叶皮质的活动间接相关。YOH 介导的脑干和杏仁核活性降低与早年创伤呈负相关。
IBS 患者表现出与突触前抑制性α2AR 下调一致的去甲肾上腺素活性增加的证据。中枢觉醒回路内的活动偏向于更大的兴奋性和减少皮质边缘抑制。早年创伤可能是这些异常的一个介导因素。
