Abstract
Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67–87% and decreased WAS-induced-FPO by 23–53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.
Highlights
Corticotropin releasing factor (CRF), a 41-amino acid peptide originally isolated from ovine brain extract, is the principal mediator of the hypothalamic-pituitary-adrenal (HPA) stress– response [1,2] CRF exerts its biological functions by activating two classes of B subfamily G-protein coupled receptors, Corticotropin releasing factor receptor 1 (CRF1) and CRF2 receptors [3]
Acute stressors and CRF injected into the brain or the periphery induces a rapid onset stimulation of colonic motor function in rodents, a response that is largely mediated by activating CRF1 receptors in both the brain and the colon and reproducing symptoms of irritable bowel syndrome (IBS) with diarrhea (IBS-D) [8,9]
We previously reported the efficacy of CP 154,526 (20 mg/kg) against ip CRF (10 mg/kg) -induced stimulation of defecation in rats [39] and this CRF1 antagonist at such a dose was used as a positive control
Summary
Corticotropin releasing factor (CRF), a 41-amino acid peptide originally isolated from ovine brain extract, is the principal mediator of the hypothalamic-pituitary-adrenal (HPA) stress– response [1,2] CRF exerts its biological functions by activating two classes of B subfamily G-protein coupled receptors, CRF1 and CRF2 receptors [3]. Chronic administration of a selective CRF1 antagonist, R121919/NBI 30775, showed anxiolytic and antidepressant effects in the first open-label clinical study in patients with major depressive episodes [16]. NBI-34041 showed efficacy against the Trier social stress-induced endocrine response in placebo-controlled phase I and II clinical trials performed in healthy subjects [11]. In a recent randomized, double-blind, placebo-controlled study, the selective CRF1 antagonist GSKGW876008 decreased brain regional activity associated with the emotional-arousal network during expectation of abdominal pain in IBS patients [14]. With regard to IBS, a double blind placebo-controlled clinical report showed the lack of effect of the CRF1 selective antagonist BMS-562086 in ameliorating gastrointestinal symptoms in IBS-D patients [15]
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