7 The Peripheral Histamine 1-Receptor Antagonist Fexofenadine Effectively Reverses Stress-Induced Visceral Hypersensitivity in a Rat Model of Maternal Separation

Abstract

BACKGROUND: We previously showed that the mast cell stabilizer ketotifen reduces IBS symptoms and increases the threshold of discomfort in hypersensitive IBS-patients. However, as ketotifen also has Histamine 1-receptor antagonistic properties and is known to penetrate the blood-brain barrier, its beneficial effect observed in this trial could also result from H1 receptor blockade, either at the peripheral or central level. AIM: To establish whether fexofenadine, a peripherally restricted 2nd generation Histamine 1-receptor antagonist, can mimic the effect of ketotifen and A) reverse stress-induced, mast cell dependent visceral hypersensitivity in a rat model of maternal separation (MS), and B) modulate gastrointestinal transit in MS and non-handled (NH) rats. METHODS: Adult MS and NH rats (n=9 in all groups) were subjected to acute stress (1 hr water avoidance,WA). The visceromotor response (VMR) to colorectal distension (1, 11⁄2, 2ml) was established preand 24 hours post-WA and expressed as area-under-curve (AUC, volume-vs-response, significant difference when P<0.05: Wilcoxon). Rats were then treated with fexofenadine (1,8 mg/kg or 18 mg/kg) or vehicle and re-evaluated 48 hrs post-WA. Pre-WA transit was measured in NH (n=4) and MS (n=5) rats treated with fexofenadine or vehicle by evaluating the transit (geometric centre or GC) of orally administered fluorescein-labeled dextran (MW=70.000) (1 is stomach, 2 most proximal small bowel, 11 most distal, 12 cecum, 13-15 colon). RESULTS: WA induced an increased VMR to distension in MS rats (pre-WA vs post-WA, 64±4 vs 98±6 (mean±SEM), P=0.012) which was reversed by 1.8 mg/kg fexofenadine (post-WA vs post-fexofenadine, 98±6 vs 69±5, P=0.012). High concentration fexofenadine (18 mg/kg) showed similar results (pre-WA vs post-WA, 72±4 vs 97±6, P=0.012 and post-WA vs post fexofenadine 97±6 vs 60±6, P=0.008). NH rats remained normo-sensitive under all conditions. Baseline pre-WA transit times of NH and MS were equal (10±0.2 vs 9.6±0.4). Administration of high-dose fexofenadine decreased transit time in NH (vehicle vs fexofenadine, 10±0.2 vs 6.4±1.1, P= 0.028) and MS-rats (9.6±0.4 vs 6.9±0.2, P=0.008). CONCLUSION: The peripheral H1 receptor antagonist fexofenadine effectively reverses stress-induced visceral hypersensitivity and decreases intestinal transit. As low dose fexofenadine does not cross the blood brain barrier, these data justify future IBS patient trials with 2nd generationH1-receptor antagonists.