Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study.
BACKGROUND
Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P ⁄ neurokinin-1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS.


OBJECTIVE
To determine whether inhibition of the neurokinin-1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not.


METHODS
Rome II positive IBS women were recruited for a double-blind, placebo-controlled, cross-over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2-week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed.


RESULTS
Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid-cingulate gyrus).


CONCLUSIONS
Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.
Center for Neurobiology of Stress, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. ktillisch@mednet.ucla.edu
K
K
Tillisch
J
J
Labus
B
B
Nam
J
J
Bueller
S
S
Smith
B
B
Suyenobu
J
J
Siffert
J
J
McKelvy
B
B
Naliboff
E
E
Mayer
D015746:Abdominal Pain / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D001007:Anxiety / Q000523:psychology*; D001143:Arousal / Q000502:physiology*; D018592:Cross-Over Studies; D004108:Dilatation, Pathologic; D004311:Double-Blind Method; D004644:Emotions / Q000502:physiology*; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000503:physiopathology*; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010865:Pilot Projects; D010880:Piperidines; D018040:Receptors, Neurokinin-1 / Q000627:therapeutic use; D013315:Stress, Psychological; D059265:Visceral Pain / Q000503:physiopathology*; D055815:Young Adult
C481395:4-aminopiperidine; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1