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Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors
Yvette Tach, Vicente Martinez, Mulugeta Million and Lixin Wang
Am J Physiol Gastrointest Liver Physiol 280:G173-G177, 2001. You might find this additional info useful... This article cites 29 articles, 7 of which can be accessed free at: http://ajpgi.physiology.org/content/280/2/G173.full.html#ref-list-1 This article has been cited by 24 other HighWire hosted articles, the first 5 are: Effects of cold stress on nitric oxide in duodenum of chicks Z. W. Zhang, Z. H. Lv, J. L. Li, S. Li, S. W. Xu and X. L. Wang Poult Sci, July , 2011; 90 (7): 1555-1561. [Abstract] [Full Text] [PDF] Corticotropin-releasing factor signaling and visceral response to stress Andreas Stengel and Yvette Tach Experimental Biology and Medicine, October , 2010; 235 (10): 1168-1178. [Abstract] [Full Text] [PDF] Norepinephrine mediates the transcriptional effects of heterotypic chronic stress on colonic motor function Barun K. Choudhury, Xuan-Zheng Shi and Sushil K. Sarna Am J Physiol Gastrointest Liver Physiol 2009; 296 (6): G1238-G1247. [Abstract] [Full Text] [PDF] Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats Sylvie Bradesi, Vicente Martinez, Lijun Lao, Hkan Larsson and Emeran A. Mayer Am J Physiol Gastrointest Liver Physiol 2009; 296 (2): G302-G309. [Abstract] [Full Text] [PDF] Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats Muriel Larauche, Sylvie Bradesi, Mulugeta Million, Peter McLean, Yvette Tach, Emeran A. Mayer and James A. McRoberts Am J Physiol Gastrointest Liver Physiol 2008; 294 (4): G1033-G1040. [Abstract] [Full Text] [PDF] Updated information and services including high resolution figures, can be found at: http://ajpgi.physiology.org/content/280/2/G173.full.html Additional material and information about AJP - Gastrointestinal and Liver Physiology can be found at: http://www.the-aps.org/publications/ajpgi

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AJP - Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright 2001 by the American Physiological Society. ISSN: 0193-1857, ESSN: 1522-1547. Visit our website at http://www.the-aps.org/.

Am J Physiol Gastrointest Liver Physiol 280: G173G177, 2001.

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Stress and the Gastrointestinal Tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors
YVETTE TACHE, VICENTE MARTINEZ, MULUGETA MILLION, AND LIXIN WANG CURE: Digestive Diseases Research Center, Department of Veterans Affairs Greater Los Angeles Healthcare System, and Department of Medicine, Digestive Diseases Division, University of California, Los Angeles, California 90073
Downloaded from ajpgi.physiology.org on June 3, 2012 Tache, Yvette, Vicente Martinez, Mulugeta Million, and Lixin Wang. Stress and the Gastrointestinal Tract. III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors. Am J Physiol Gastrointest Liver Physiol 280: G173G177, 2001.Alterations of gastrointestinal (GI) motor function are part of the visceral responses to stress. Inhibition of gastric emptying and stimulation of colonic motor function are the commonly encountered patterns induced by various stressors. Activation of brain corticotropin-releasing factor (CRF) receptors mediates stress-related inhibition of upper GI and stimulation of lower GI motor function through interaction with different CRF receptor subtypes. CRF subtype 1 receptors are involved in the colonic and anxiogenic responses to stress and may have clinical relevance in the comorbidity of anxiety/depression and irritable bowel syndrome. astressin; corticotropin-releasing factor antagonist; gastric emptying; colonic transit; defecation; paraventricular nucleus of the hypothalamus; locus ceruleus

THE INFLUENCE OF EMOTION ON gastric motor function was rst described as anecdotal clinical observations by Cabanis and Beaumont followed by Pavlovs and Cannons pioneering experimental studies in cats and dogs at the beginning of the 1900s (see Ref. 32). Although Selyes original concept of stress appeared as a short letter in Nature in 1936, in 1934 Hall established the use of defecation score as an index of emotionality in rats exposed to unfamiliar surroundings (9). Alterations of the gastrointestinal (GI) motility pattern and transit by various stressors were thereafter well documented with the development of quantitative techniques to monitor GI motility and transit in experimental animals and humans. However, it was only during the past two decades that attempts were made

to unravel the mechanisms underlying the gut motor response to stressful stimuli. In particular, the characterization of the 41-amino acid peptide corticotropinreleasing factor (CRF) and a related family member, urocortin, the cloning of CRF receptor subtypes 1 (CRF-R1) and 2 (CRF-R2), and the development of specic CRF-R1 and CRF-R2 receptor antagonists, namely, -helical CRF-(941), [D-Phe12,Nle21,38]h/rCRF(1241), and, more recently, astressin {cyclo(3033)[D-Phe12,Nle21,38,Glu30,Lys33]CRF-(1241)} (15, 18) provided relevant novel tools to characterize the neurochemical basis of the stress response. Evidence has emerged that activation of CRF receptors in the brain mediates almost the entire repertoire of behavioral, neuroendocrine, autonomic, immunologic, and visceral responses characteristic of stress in rodents and primates (8, 11, 29). We review here the patterns of stress-related disturbances in GI motor function and recent advances made in the understanding of the central nervous system mechanisms underlying stressinduced alterations of gastric and colonic motor function, with particular emphasis on the role of brain CRF receptors.
PATTERNS OF GASTROINTESTINAL MOTOR RESPONSES TO VARIOUS STRESSORS

Address for reprint requests and other correspondence: Yvette Tache, CURE: DDRC, VA Greater Los Angeles Healthcare System, Bldg. 115, Rm. 203, 11301 Wilshire Blvd, Los Angeles, CA 90073 (E-mail: ytache@ucla.edu). http://www.ajpgi.org

Acute stress induces differential motor effects in the upper and lower GI tract. Delayed gastric emptying is commonly induced by various acute stressors such as operant avoidance, water avoidance, radiation, handling, acoustic stimulation, hemorrhage, abdominal or cranial surgery, tail shock, trunk clamping, wrap restraint at room temperature, swimming, and anesthetic exposure in experimental animals (mice, rats, guinea pigs, dogs, and/or monkeys) (5, 24, 26). Likewise, in healthy human subjects, anger, fear, labyrinthine stimulation, painful stimuli, preoperative anxiety, or intense exercise results in a slowing of gastric emptying (19, 24, 26). Acute exposure to wrap restraint, cold water swim, or ether also slows down
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intestinal transit in the rat (30). In contrast, colonic motility, transit, and/or defecation are stimulated by conditioned fear to inescapable foot shocks and exposure to water avoidance, tail shock, loud noise, open eld test, and restraint at room temperature or in a cold environment, (5, 24). Similarly, in healthy human volunteers, painful stimuli, dichotomous listening test, fear, anxiety, anger or a stressful interview enhances colonic motor activity (19). Although the above gut motor changes represent the most characteristic patterns induced by various stressors, differential responses are also encountered after specic stimuli. In particular, acute exposure to cold, which is largely used to study gastric erosion formation induced by stress, activates both gastric and colonic motility and transit in rats (14, 24). Gastrointestinal motor responsiveness to acute stress is affected by previous stress experiences and intrinsic biological factors such as the animal species, strain, gender, estrus cycles, circadian pattern, and regions of the GI tract. For instance, a short session of inescapable foot shocks induces long-term sensitization of the colonic contractile response to a novel stressor applied 2 wk later (21). Fischer rats are more sensitive than Sprague-Dawley rats to acute wrap restraint-induced inhibition of small intestinal transit (30) and more sensitive than Lewis rats to water avoidance-induced defecation (16). Female rats are also more sensitive than males to the small intestinal inhibitory effect of chronic wrap restraint (30). Circadian variations with a greater sensitivity to the effects of stress on intestinal transit were observed in the late afternoon in rats (30). With regard to regional differences, the colon is more responsive to stress than the upper gut (5, 22). However, reports on the modulation of the gut motor response to acute stress by these factors are relatively scarce, and underlying mechanisms remain poorly characterized. Another important limitation of studies on stress-related alterations of GI motility is their focus on short-term stress while the consequences of long-term exposure to homotypic or heterotypic stressors have received little attention (31).
BRAIN CRF RECEPTORS AND STRESS-RELATED INHIBITION OF GASTRIC MOTOR FUNCTION

Several reports consistently established that CRF injected into the cerebrospinal uid (CSF) acts in the brain to inhibit gastric emptying of a solid or liquid meal and contractility in rats and dogs (25, 26). The paraventricular nucleus of the hypothalamus (PVN) is a responsive site for CRF-induced delayed gastric emptying (26). In addition, CRF in the dorsal vagal complex (DVC) inhibits central vagal stimulation of gastric motility in rats (26). The central action of CRF is receptor mediated, as shown by the use of CRF antagonists, of which the recently developed astressin is 16- and 6-fold more potent than -helical CRF-(941) and [D-Phe12,Nle21,38]h/rCRF-(1241), respectively (26). Indirect pharmacological evidence suggests that intracis-

ternal CRF-induced inhibition of gastric emptying involves interaction with CRF-R2 in rats (13, 25). The CRF receptor antagonists -helical CRF-(941), [D-Phe12, Nle21,38]h/rCRF-(1241), and astressin, injected into the CSF or the PVN at doses preventing gastric response to centrally injected CRF, block the delayed gastric emptying induced by various forms of stress, immunologic (intravenous or intracisternal injection of interleukin-1 ), physicopsychological (partial restraint, forced swimming), chemical (ether), or visceral (abdominal or cranial surgery or peritoneal irritation induced by intraperitoneal injection of acetic acid) (Ref. 26; Fig. 1). Astressin is more potent and efcacious than previously developed CRF antagonists (26). In contrast, peripheral administration of these CRF antagonists has no effect on the gastric response to stress except for abdominal surgery (26). These ndings opened new venues for understanding brain and peripheral pathways contributing to postoperative ileus (2). It also revealed that the intercommunications between the immune and hypothalamic CRF systems impact on the central regulation of gastric motor function. The relationship between the immune and neuroendocrine systems has been well dened with respect to mechanisms and neuronal circuitries through which immune signals activate the hypothalamic-pituitaryadrenal axis (20). However, central CRF-induced delayed gastric emptying is independent from the activation of pituitary-adrenal hormone release. It is related to the alterations of autonomic nervous system activity, in which the decrease in gastric vagal outow plays a role (26). The cellular mechanisms through which cytokines of peripheral or central origin activate brain CRF pathways involved in the autonomic regulation of gastric motor function require elucidation. Different stress paradigms, in addition to CRF, produce diverse neurochemical alterations and dissimilar changes in circulating hormone levels (10). For instance, cold exposure in rodents illustrates a stressorspecic activation of thyrotrophin-releasing hormone (TRH)-containing neurons in the PVN and medulla designed to coordinate thermoregulatory adaptive processes through stimulation of the autonomic nervous system (1, 33). Of relevance to GI function, TRH exerts a direct postsynaptic excitatory effect on dorsal motor nucleus (DMN) neurons through interaction with TRH receptors, leading to increased gastric vagal efferent discharges (33). Activation of medullary TRH receptors mediates the stimulation of gastric contractility and emptying induced by acute exposure to cold (14). The cold-specic activation of medullary TRH neurons (33) and related vagal activation to the gut provide insight to the differential gastric motor response to cold (stimulatory) compared with other stressors (inhibitory) (14). However, central CRF inhibits DMN neurons activated by TRH (26). Such interplay may modulate the outcome of gastric response to sustained cold as indicated by the dampening of gastric contractile response under these conditions.

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Fig. 1. Various stressors induce inhibition of gastric emptying and stimulation of colonic motor function. Blockade by central administration of specic nonselective corticotropin-releasing factor (CRF) receptor subtype 1 (CRFR1)/subtype 2 (CRF-R2) peptide antagonists and prevention of the colonic but not gastric response by selective CRF-R1 antagonists. CSF, cerebrospinal uid; DVC, dorsal vagal complex; IL-1 , interleukin-1 ; ic, intracisternal; icv, intracerebroventricular; iv, intravenous; GLP-1, glucagon-like peptide 1; LCC, locus ceruleus complex; NPY, neuropeptide Y; PVN, paraventricular nucleus of the hypothalamus.

BRAIN CRF RECEPTORS IN STRESS-RELATED STIMULATION OF COLONIC MOTOR FUNCTION

CRF injected into the CSF increases colonic motility, decreases colonic transit time, and induces fecal excretion, reproducing colonic motor response to various stressors. CRF brain sites of action characterized so far are the PVN and locus ceruleus complex (26). Transneuronal retrograde tracing studies with pseudorabies virus inoculated into the distal colon provide neuroanatomic support that these sites are synaptically connected to regulate colonic function through bulbospinal pathways (28). An interesting novel report showed that CRF projections from the Barrington nucleus innervate sacral parasympathetic preganglionic neurons that are synaptically linked to the distal colon (27). This suggests another potential sacral spinal site of action for CRF to inuence colonic motility. The role of CRF receptors in mediating stress-related activation of colonic motor function is supported by the demonstration that -helical CRF-(941), [D-Phe12,Nle21,38]h/rCRF-(1241), and more potently, astressin injected into the lateral ventricle, PVN, or locus ceruleus complex abolished partial wrap restraint- or water avoidance-induced stimulation of co-

lonic transit and defecation as well as conditioned fear-induced increase in cecal and colonic spike burst frequency (16, 26) (Fig. 1). Likewise, interleukin-1 and neuropeptides such as glucagon-like peptide-1 and neuropeptide Y, all known to act in the brain to activate hypothalamic CRF-containing neurons when administered into the brain, stimulate colonic motor function as assessed by decrease in colonic transit time, increase in defecation, or enhanced spike burst frequency, through central CRF receptor-dependent mechanisms (7, 17, 26). Conversely, Lewis rats with a defective hypothalamic CRF response to immune challenges and other stressors exhibit a 50% reduction in pellet output induced by water avoidance stress that is associated with a decrease in neuronal activation in the PVN and sacral parasympathetic nucleus (16). Pharmacological characterization of CRF receptor subtype using selective nonpeptide CRF-R1 antagonists, namely CP-154526 and NBI-27914, indicates that the CRF-R1 subtype is primarily involved in the stimulation of colonic propulsion induced by central administration of CRF and one stressor tested so far, water avoidance in rats (12, 13). Of signicant relevance is that the anxiogenic behavioral response to

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central administration of CRF or stress is also mediated by brain CRF-R1. This was established by the use of selective CRF-R1 antagonists, CRF-R1 antisense, and CRF-R1 knockouts (23). In addition, there is an overlap between hypothalamic and pontine nuclei responsive to CRF that mediate the anxiogenic behavior and stimulation of colonic motor function through CRF-R1 (11, 13, 26). Brain circuitries that activate anxiogenic and colonic motor function under stress through CRF-R1-dependent pathways may provide the neurobiological basis for the observed relationship between emotionality and defecation in rats. Such mechanisms may also have clinical relevance in the context of established association between anxiety/depression and irritable bowel syndrome (IBS) (3). Recent ndings in monkeys and humans indicate that the CRF-R1 antagonists antalarmine and R-121919 alleviate manifestations of anxiety and depression (8, 34). This preliminary report of benecial effects of CRF-R1 antagonist treatment on depressive symptoms in patients with major depression (34) suggests a therapeutic potential for CRF-R1 antagonists, particularly in subsets of IBS patients who have psychiatric illness and GI symptoms of enhanced bowel motor function.
CONCLUSIONS

antagonist reduces depression and anxiety scores in depressed patients and the experimental evidence for a role of CRF-R1 in mediating stress-related anxiogenic behavior and stimulation of colonic motor function in rodents (12, 13) suggest a possible therapeutic value of CRF-R1 antagonists in the context of IBS patients with depression/anxiety or chronic stress.
We thank Dr. J. E. Rivier (Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA) for the generous donation of CRF and CRF antagonists and P. Kirsch for help in the preparation of the manuscript. The authors work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-30110, DK-33061, DK-57238, and DK-41301 (Animal Core). REFERENCES 1. Arancibia S, Rage F, Astier H, and Tapia-Arancibia L. Neuroendocrine and autonomous mechanisms underlying thermoregulation in cold environment. Neuroendocrinology 64: 257 267, 1996. 2. Barquist E, Bonaz B, Martinez V, Rivier J, Zinner MJ, and Tache Y. Neuronal pathways involved in abdominal surgery induced gastric ileus in rats. Am J Physiol Regulatory Integrative Comp Physiol 270: R888R894, 1996. 3. Bennett EJ, Tennant CC, Piesse C, Badcock J, and Kellow J. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut 43: 256261, 1998. 4. Bonaz B and Rivest S. Effect of a chronic stress on CRF neuronal activity and expression of its type 1 receptor in the rat brain. Am J Physiol Regulatory Integrative Comp Physiol 275: R1438R1449, 1998. 5. Enck P and Holtmann G. Stress and gastrointestinal motility in animals: a review of the literature. J Gastrointest Motil 1: 8390, 1992. 6. Francis DD, Caldji C, Champagne F, Plotsky PM, and Meaney MJ. The role of corticotropin-releasing factor-norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress. Biol Psychiatry 46: 11531166, 1999. 7. Gulpinar MA, Bozkurt A, Coskun T, Ulusoy NB, and Yegen BC. Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats. Am J Physiol Gastrointest Liver Physiol 278: G924G929, 2000. 8. Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, and Gold PW. Oral administration of a corticotropin-releasing hormone receptor antagonist signicantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci USA 97: 60796084, 2000. 9. Hall CS. Emotional behavior in the rat. 1. Defecation and urination as measures of individual differences in emotionality. J Comp Psychol 18: 385403, 1934. 10. Herman JP and Cullinan WE. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20: 7884, 1997. 11. Koob GF and Heinrichs SC. A role for corticotropin releasing factor and urocortin in behavioral responses to stressors. Brain Res 848: 141152, 1999. 12. Maillot C, Million M, Wei JY, Gauthier A, and Tache Y. Peripheral corticotropin-releasing factor and stress-stimulated colonic motor activity involve type 1 receptor in rats. Gastroenterology 119: 15691579, 2000. 13. Martinez V and Tache Y. Role of CRF receptor 1 in central CRF-induced stimulation of colonic propulsion in rats. Brain Res. In press. 14. Martinez V, Wu SV, and Tache Y. Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats. Endocrinology 139: 37303735, 1998.

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There is overwhelming experimental and clinical evidence that stress inuences GI motility. The most consistent pattern of GI motor alterations induced by various acute stressors is that of delaying gastric emptying while accelerating large bowel transit, which is mimicked by central administration of CRF. Several convergent ndings implicate the activation of brain CRF receptors in mediating the delayed gastric emptying and stimulation of colonic motor function resulting not only from acute exposure to psychological, physical, or chemical stress but also from activation of the immune system (Fig. 1). Novel ndings related to the differential CRF receptor subtypes involved in the central actions of CRF on upper and lower gut transit point to a role of medullary CRF-R2 in the inhibition of gastric emptying. In contrast, central injection of CRF and psychological stress act through CRF-R1 to induce anxiogenic and colonic motor responses. The exact neuronal circuitries whereby CRF interacts with CRF-R1 and CRF-R2 receptors and how it translates into autonomic-dependent alterations of GI motor function in response to various acute stressors must be further elucidated. Because most of the knowledge on stressrelated GI motor alterations is derived from acute exposure, the impact of chronic homotypic or heterotypic stressors must be characterized. Whether CRF-R1 in the PVN that are upregulated during chronic restraint (4) may have a bearing in the colonic sensitization after stressful experience (21) is worth exploring. Likewise, the inuence of early postnatal stressful life events that alter the central CRF response to stressors in adulthood (6) will be a relevant model to explore vulnerability to stress-related GI motor alterations. The rst clinical report that CRF-R1

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