Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome.
OBJECTIVE
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.
Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Steven
S
Berman
Brandall
B
Suyenobu
Bruce D
BD
Naliboff
Joshua
J
Bueller
Jean
J
Stains
Heng
H
Wong
Mark
M
Mandelkern
Leah
L
Fitzgerald
Gordon
G
Ohning
Arpana
A
Gupta
Jennifer S
JS
Labus
Kirsten
K
Tillisch
Emeran A
EA
Mayer
D000328:Adult; D001007:Anxiety / Q000150:complications / Q000523:psychology; D001143:Arousal / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005221:Fatigue / Q000523:psychology; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D043183:Irritable Bowel Syndrome / Q000000981:diagnostic imaging / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000502:physiology; D009638:Norepinephrine / Q000502:physiology*; D049268:Positron-Emission Tomography; D011597:Psychomotor Performance / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D011795:Surveys and Questionnaires; D013564:Sympathetic Nervous System / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013565:Sympatholytics; D014947:Wounds and Injuries / Q000523:psychology; D015016:Yohimbine; D055815:Young Adult
D018341:Receptors, Adrenergic, alpha-2; D013565:Sympatholytics; D015016:Yohimbine; D009638:Norepinephrine