AV-608

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.Aim  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.

The selective non-peptide NK(1) receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC(50) values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003-10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001-10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK(1) receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK(1) receptor antagonists to their potency at NK(1) receptors.