Color profile: Generic offset separations profile Black 133 lpi at 45 degrees GUT DYSFUNCTION IN IBS Corticotropin-releasing factor and the brain-gut motor response to stress 1 1 1 2 Yvette Taché PhD , Vicente Martinez DVM PhD , Mulugeta Million DVM PhD , Jean Rivier PhD Y Taché, V Martinez, M Million, J Rivier. Corticotropin- La corticolibérine (CRF) et la réponse de l’axe releasing factor and the brain-gut motor response to stress. Can J Gastroenterol 1999;13(Suppl A):18A-25A. The character- cerveau-intestin au stress ization of corticotropin-releasing factor (CRF) and CRF recep- RÉSUMÉ : La caractérisation de la corticolibérine (ou CRF, pour cortico- tors, and the development of specific CRF receptor antagonists tropin-releasing factor) et de ses récepteurs, ainsi que le développement selective for the receptor subtypes have paved the way to the un- d’antagonistes spécifiques du CRF manifestant une sélectivité à l’endroit derstanding of the biochemical coding of stress-related alterations de certains sous-types des récepteurs, ont pavé la voie à une meilleure com- of gut motor function. Reports have consistently established that préhension de l’encodage biochimique de la dysmotilité intestinale liée au central administration of CRF acts in the brain to inhibit gastric stress. Les rapports ont toujours confirmé que l’administration centrale de emptying while stimulating colonic motor function through mod- CRF agit sur le cerveau pour inhiber la vidange gastrique tout en stimulant ulation of the vagal and sacral parasympathetic outflow in rodents. la motricité du côlon par l’entremise d’une modulation de l’influx vagal et Endogenous CRF in the brain plays a role in mediating various parasympathique sacré chez le rat. Au niveau cérébral, le CRF endogène forms of stressor-induced gastric stasis, including postoperative joue un rôle de médiateur sur diverses formes de stases gastriques dues au gastric ileus, and activates colonic transit and fecal excretion elic- stress, notamment l’iléus gastrique post-opératoire; et il active le transit co- ited by psychologically aversive or fearful stimuli. It is known that lique et l’émission des selles déclenchée par des stimuli aversifs ou terri- brain CRF is involved in the cross-talk between the immune and fiants. On sait que le CRF cérébral participe aux échanges entre les gastrointestinal systems because systemic or central administra- systèmes immunitaire et gastro-intestinal parce que l’administration systé- tion of interleukin-1-beta delays gastric emptying while stimulat- mique ou centrale d’interleukine-1-bêta retarde la vidange gastrique tout en stimulant l’activité motrice colique par le biais de la sécrétion de CRF ing colonic motor activity through activation of CRF release in dans le cerveau. Le noyau paraventriculaire de l’hypothalamus et le the brain. The paraventricular nucleus of the hypothalamus and complexe vagal dorsal sont d’importants sièges de l’action inhibitrice du the dorsal vagal complex are important sites of action for CRF to CRF sur la motricité gastrique, alors que le noyau paraventriculaire de inhibit gastric motor function, while the paraventricular nucleus l’hypothalamus et le complexe du locus cœruleus sont d’importants sièges of the hypothalamus and the locus coeruleus complex are sites of de l’action stimulante du CRF sur la motricité colique. L’inhibition de la action for CRF to stimulate colonic motor function. The inhibi- vidange gastrique par le CRF est amenée par l’interaction avec les récep- tion of gastric emptying by CRF may be mediated by the interac- teurs du CRF2, alors que les réponses motrices anxiogènes et coliques met- tion with the CRF2 receptors, while the anxiogenic and colonic tent en cause les récepteurs CRF1. On se demande si l’hypersécrétion de motor responses may involve CRF1 receptors. Hypersecretion of CRF au cerveau ne contribuerait pas à la physiopathologie de CRF in the brain may contribute to the pathophysiology of l’exacerbation du syndrome du côlon irritable liée au stress. stress-related exacerbation of irritable bowel syndrome. 100 Key Words: Brain-gut interactions, Colonic motor function, Cortico- 95 tropin-releasing factor, Irritable bowel syndrome 75 1CURE: Digestive Diseases Research Center, West Los Angeles VA Medical Center and Departments of Medicine and Brain Research Institute, 2 University of California, Los Angeles, and Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California, USA 25 Correspondence and reprints: Dr Yvette Taché, Building 115, Room 203, West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. Telephone 310-312-9275, fax 310-268-4963, e-mail [email protected] 5 0 18A Can J Gastroenterol Vol 13 Suppl A March 1999 1 G:\GASTRO\GUT DYSFUNCTION\Tache\tache.vp Thursday, March 11, 1999 10:05:34 AM Plate: 1 of 8 Color profile: Generic offset separations profile Black 133 lpi at 45 degrees Brain CRF and gut motor response to stress “…Should this man receive bad news, or should sad and projects to the portal capillary zone of the median eminence baneful passions suddenly arise in his soul, his stomach to stimulate the secretion of ACTH from the anterior pitu- and intestine will immediately cease to act on the foods itary gland. The subsequent ACTH-induced release of adre- contained in them. The very juices in which the foods nal glucocorticoids is part of the response of the peripheral are already almost entirely dissolved will remain as limb of the hypothalamic-pituitary axis (HPA) to stress though struck by a moral stupor.” (15,16). In addition to its neuroendocrine role, CRF, when injected centrally, elicits a wide spectrum of behavioural, au- abanis’ statement in 1802 (1) is among the first tonomic and visceral responses, including anxiogenic be- Cprescientific recognitions that the brain affects gut haviour and inhibition of food intake, increases in function. A few years later, Beaumont (2) reported clinical sympathetic outflow, decreases in vagal activity, and alter- observations that emotional states linked with fear or anger ations in cardiovascular and immunological function that disturbed gastric function. Pioneer experimental reports of mimic the bodily alterations induced by various stressors brain-gut interactions by Pavlov (3) and Cannon (4) dem- (17-23). onstrated that psychological stimuli such as sham feeding CRF mediates its actions through interaction with spe- and fear influence gastric secretory and motor function in cific, high affinity, membrane-bound receptors that are cou- dogs and cats. Hall (5) established in rodents that defecation pled to a guanine nucleotide stimulatory factor-signalling scores are a means of measuring the fearfulness response to protein, resulting in increased intracellular cAMP levels unfamiliar surroundings or arousing situations. (19,24,25). Two different CRF receptors, CRF1 and CRF2 Selye (6,7), while working at McGill University, Mon- subtypes, have been cloned and characterized in rats as well treal, fathered the unifying concept of stress initially re- as in humans (24-26). These receptors show an overall 71% ported in 1936 as a “syndrome produced by diverse nocuous identity and differential pharmacological and anatomical agents” and later defined as the “nonspecific response of the profiles, indicative of distinct functional roles (26,27). Bind- body to any demand”. The activation of the pituitary adrenal ing constants in transfected cells indicate that rat/human axis induced by exposure to various stressors (7) stimulated CRF (r/hCRF) exhibits a higher affinity for the CRF1 recep- research on the biochemical coding of the hypothalamic fac- tor than the CRF2 subtype (25,26,28). By contrast, tors triggering the endocrine response. In the 1960s, CRF-related peptides, sharing a 40% to 50% structural Guillemin (8) (a former doctoral student of Selye) observed homology with CRF, namely, sauvagine, a 40-amino acid independently the presence of a corticotropin-releasing fac- peptide isolated from the Phyllomedusa sauvagi amphibian’s tor (CRF) in hypothalamic extracts that stimulates adreno- skin, and urotensin-I, a 41-residue peptide isolated from tele- corticotrophic hormone (ACTH) release from anterior ost fish, as well as mammalian urocortin, display a higher af- pituitary cells. However, CRF eluded characterization until finity at the CRF2 receptor than CRF, while having a similar 1981, when Vale and coworkers (9) (former doctoral stu- affinity to CRF at the CRF1 subtype (25,26,28). The CRF1 dents of Guillemin) reported the isolation of the 41-amino receptor is the predominant form localized in the pituitary acid peptide involved in the pituitary stimulation of ACTH gland, olfactory bulb and cerebral cortex, while the CRF2 release. Recently, a new CRF-related mammalian peptide, subtype is found in the lateral septum, hypothalamus, urocortin, was identified in rats and humans, and the amygdala and brain stem (25,26). 40-amino acid peptide shares 45% homology with CRF (10). Since the discoveries of CRF-related peptides along with CRF RECEPTOR ANTAGONISTS the development of specific CRF receptor antagonists by Rivier et al (11), Gulyas et al (12), Hernandez et al (13), Rivier et al (11), Gulyas et al (12), Hernandez et al (13) and Miranda et al (14), Fisher et al (29) and Menzaghi et al (30) Miranda et al (14), significant advances have been made in developed three generations of CRF analogues with compet- the understanding of the neurobiological basis of the stress itive antagonistic