Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome

Abstract

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Fig. 1

Drug and group effects on relative glucose metabolism. Upper panel depicts p<0.005 statistical interactions in the regions of interest (ROIs – outlined in green) between group and drug effects (compared to placebo), superimposed on a structural MRI representing atlas space. Lower panel depicts individual group effects responsible for the interaction above. Other possible interactions and contributing group effects were insignificant. Yohimbine effects are depicted on slices 6 mm to the left, 2 mm anterior, and 14 mm inferior to the anterior commissure (i.e., MNI coordinates −6, 2, −14). Clonidine effects are depicted at MNI −4, 24, −8. All figures depict neurological orientation (left=left). sgACC = subgenual cingulate, pgACC = pregenual cingulate, MCC = mid cingulate cortex, aINS = anterior insula, pINS = posterior insula, amyg = amygdala, DBS = dorsal brainstem, and vlPFC = ventrolateral prefrontal cortex.

Fig. 2

Covariance of relative glucose metabolism with self-rated anxiety by group. Upper panel depicts areas of p<0.005 statistical interaction in the ROIs between the slopes of covariation between metabolism and anxiety in the two groups. Lower panel depicts positive and negative covariations with anxiety in the control group, the major contributor to these interactions (see Table 2 for effects, Fig. 1 for format and abbreviations).

Fig. 3

Functional connectivity of relative glucose metabolism in other regions of interest with activity in sgACC, and amygdala. Depicts areas of covariation across all scans between metabolism in other ROIs and seed regions within (A) sgACC depicted on sagittal slices 4 mm to the right of the anterior commissure, and (B) amygdala depicted on sagittal slices 6 mm to the right of the anterior commissure (see Fig. 1 for format and abbreviations).

Fig. 4

Covariation (p<0.005) of early life trauma with Yohimbine effects on relative glucose metabolism. Covariance between early life trauma and the ability of YOH, as compared to placebo, to downregulate relative glucose metabolism is depicted at coordinates −6, − 26, −24 (see Fig. 1 for format and abbreviations).