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1
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Lai TT, Liou CW, Tsai YH, Lin YY, Wu WL. Butterflies in the gut: the interplay between intestinal microbiota and stress. J Biomed Sci 2023; 30:92. [PMID: 38012609 PMCID: PMC10683179 DOI: 10.1186/s12929-023-00984-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 11/29/2023] Open
Abstract
Psychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host's complex behavior.
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Affiliation(s)
- Tzu-Ting Lai
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Chia-Wei Liou
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Yu-Hsuan Tsai
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Yuan-Yuan Lin
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan
| | - Wei-Li Wu
- Department of Physiology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan.
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan, 70101, Taiwan.
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2
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Armario A, Belda X, Gagliano H, Fuentes S, Molina P, Serrano S, Nadal R. Differential Hypothalamic-pituitary-adrenal Response to Stress among Rat Strains: Methodological Considerations and Relevance for Neuropsychiatric Research. Curr Neuropharmacol 2023; 21:1906-1923. [PMID: 36453492 PMCID: PMC10514526 DOI: 10.2174/1570159x21666221129102852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/21/2022] [Accepted: 10/24/2022] [Indexed: 12/03/2022] Open
Abstract
The hormones of the hypothalamic-pituitary-adrenal (HPA) axis, particularly glucocorticoids (GCs), play a critical role in the behavioral and physiological consequences of exposure to stress. For this reason, numerous studies have described differences in HPA function between different rodent strains/lines obtained by genetic selection of certain characteristics not directly related to the HPA axis. These studies have demonstrated a complex and poorly understood relationship between HPA function and certain relevant behavioral characteristics. The present review first remarks important methodological considerations regarding the evaluation and interpretation of resting and stress levels of HPA hormones. Then, it presents works in which differences in HPA function between Lewis and Fischer rats were explored as a model for how to approach other strain comparisons. After that, differences in the HPA axis between classical strain pairs (e.g. High and Low anxiety rats, Roman high- and low-avoidance, Wistar Kyoto versus Spontaneously Hypertensive or other strains, Flinder Sensitive and Flinder Resistant lines) are described. Finally, after discussing the relationship between HPA differences and relevant behavioral traits (anxiety-like and depression-like behavior and coping style), an example for main methodological and interpretative concerns and how to test strain differences is offered.
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Affiliation(s)
- Antonio Armario
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Traslational Neuroscience Unit, UAB-Parc Taulí, Sabadell, Spain
- Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain
- CIBERSAM, ISCIII, Madrid, Spain
| | - Xavier Belda
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain
| | - Humberto Gagliano
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain
| | - Silvia Fuentes
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Psychobiology, Faculty of Psychology, Universidad de Granada, Granada, Spain
| | - Patricia Molina
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain
| | - Sara Serrano
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Biosciences, Universitat Autònoma de Barcelona, Spain
| | - Roser Nadal
- Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain
- Traslational Neuroscience Unit, UAB-Parc Taulí, Sabadell, Spain
- CIBERSAM, ISCIII, Madrid, Spain
- Psychobiology Unit, Faculty of Psychology, Universitat Autònoma de Barcelona, Barcelona, Spain
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3
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Louwies T, Orock A, Greenwood-Van Meerveld B. Stress-induced visceral pain in female rats is associated with epigenetic remodeling in the central nucleus of the amygdala. Neurobiol Stress 2021; 15:100386. [PMID: 34584907 PMCID: PMC8456109 DOI: 10.1016/j.ynstr.2021.100386] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/23/2021] [Accepted: 08/28/2021] [Indexed: 12/19/2022] Open
Abstract
Stress and anxiety contribute to the pathophysiology of irritable bowel syndrome (IBS), a female-predominant disorder of the gut-brain axis, characterized by abdominal pain due to heightened visceral sensitivity. In the current study, we aimed to evaluate in female rats whether epigenetic remodeling in the limbic brain, specifically in the central nucleus of the amygdala (CeA), is a contributing factor in stress-induced visceral hypersensitivity. Our results showed that 1 h exposure to water avoidance stress (WAS) for 7 consecutive days decreased histone acetylation at the GR promoter and increased histone acetylation at the CRH promoter in the CeA. Changes in histone acetylation were mediated by the histone deacetylase (HDAC) SIRT-6 and the histone acetyltransferase CBP, respectively. Administration of the HDAC inhibitor trichostatin A (TSA) into the CeA prevented stress-induced visceral hypersensitivity through blockade of SIRT-6 mediated histone acetylation at the GR promoter. In addition, HDAC inhibition within the CeA prevented stress-induced histone acetylation of the CRH promoter. Our results suggest that, in females, epigenetic modifications in the limbic brain regulating GR and CRH expression contribute to stress-induced visceral hypersensitivity and offer a potential explanation of how stress can trigger symptoms in IBS patients.
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Affiliation(s)
- Tijs Louwies
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Albert Orock
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Beverley Greenwood-Van Meerveld
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma City VA Medical Center, Oklahoma City, OK, USA
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4
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Elfers K, Armbrecht Y, Mazzuoli-Weber G. Good to Know: Baseline Data on Feed Intake, Fecal Pellet Output and Intestinal Transit Time in Guinea Pig as a Frequently Used Model in Gastrointestinal Research. Animals (Basel) 2021; 11:1593. [PMID: 34071498 PMCID: PMC8227794 DOI: 10.3390/ani11061593] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/13/2021] [Accepted: 05/26/2021] [Indexed: 12/11/2022] Open
Abstract
Guinea pigs are a traditional and frequently used species in gastrointestinal research. Comprehensive knowledge of basic parameters connected with their intestinal function, such as feed intake, fecal pellet output and gastrointestinal transit time, is important for evaluating results from basic gastrointestinal research that may be applied to practical problems in human and veterinary medicine, for example, when establishing diagnostic tools. Our study revealed that over a 24-h period, single-housed guinea pigs showed a continual but day-accentuated feeding activity, consuming 57% of the total feed during the light period, with pronounced peaks of feed intake during the beginning and end of the light period. This was mirrored by fecal pellet output during the light period and almost no defecation during the dark period, while potential coprophagy not measured in this study needs to be considered. A highly comparable feeding activity was recorded in pair-housed guinea pigs, with 60% of overall feed intake within the light period, indicating that such differences in housing conditions did not influence guinea pigs' feeding behavior. Intestinal transit time was successfully recorded by oral administration of carmine red and counted 5 h on average. Hence, this study provides important information on the basic functional parameters of guinea pigs' gastrointestinal tract physiology.
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Affiliation(s)
- Kristin Elfers
- Institute for Physiology and Cell Biology, University of Veterinary Medicine Hannover, Foundation, 30173 Hannover, Germany; (Y.A.); (G.M.-W.)
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5
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Furness JB, Pustovit RV, Syder AJ, Ringuet MT, Yoo EJ, Fanjul A, Wykosky J, Fothergill LJ, Whitfield EA, Furness SGB. Dopamine and ghrelin receptor co-expression and interaction in the spinal defecation centers. Neurogastroenterol Motil 2021; 33:e14051. [PMID: 33264473 DOI: 10.1111/nmo.14051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/20/2020] [Accepted: 11/12/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Dopamine receptor 2 (DRD2) and ghrelin receptor (GHSR1a) agonists both stimulate defecation by actions at the lumbosacral defecation center. Dopamine is in nerve terminals surrounding autonomic neurons of the defecation center, whereas ghrelin is not present in the spinal cord. Dopamine at D2 receptors generally inhibits neurons, but at the defecation center, its effect is excitatory. METHODS In vivo recording of defecation and colorectal propulsion was used to investigate interaction between DRD2 and GHSR1a. Localization studies were used to determine sites of receptor expression in rat and human spinal cord. KEY RESULTS Dopamine, and the DRD2 agonist, quinpirole, directly applied to the lumbosacral cord, caused defecation. The effect of intrathecal dopamine was inhibited by the GHSR1a antagonist, YIL781, given systemically, but YIL781 was not an antagonist at DRD2. The DRD2 agonist, pramipexole, administered systemically caused colorectal propulsion that was prevented when the pelvic nerves were cut. Drd2 and Ghsr were expressed together in autonomic preganglionic neurons at the level of the defecation centers in rat and human. Behaviorally induced defecation (caused by water avoidance stress) was reduced by the DRD2 antagonist, sulpiride. We had previously shown it is reduced by YIL781. CONCLUSIONS AND INFERENCES Our observations imply that dopamine is a transmitter of the defecation pathways whose actions are exerted through interacting dopamine (D2) and ghrelin receptors on lumbosacral autonomic neurons that project to the colorectum. The results explain the excitation by dopamine agonists and the conservation of GHSR1a in the absence of ghrelin.
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Affiliation(s)
- John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Ruslan V Pustovit
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Andrew J Syder
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, San Diego, CA, USA
| | - Mitchell T Ringuet
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Eun Ji Yoo
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, San Diego, CA, USA
| | - Andrea Fanjul
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, San Diego, CA, USA
| | - Jill Wykosky
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, San Diego, CA, USA
| | - Linda J Fothergill
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia
| | - Emily A Whitfield
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia
| | - Sebastian G B Furness
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic., Australia
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Ueda HH, Naitou K, Nakamori H, Horii K, Shiina T, Masatani T, Shiraishi M, Shimizu Y. α-MSH-induced activation of spinal MC1R but not MC4R enhances colorectal motility in anaesthetised rats. Sci Rep 2021; 11:487. [PMID: 33436759 PMCID: PMC7803980 DOI: 10.1038/s41598-020-80020-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022] Open
Abstract
The central nervous system is involved in regulation of defaecation. It is generally considered that supraspinal regions control the spinal defaecation centre. However, signal transmission from supraspinal regions to the spinal defaecation centre is still unclear. In this study, we investigated the regulatory role of an anorexigenic neuropeptide, α-MSH, in the spinal defaecation centre in rats. Intrathecal administration of α-MSH to the L6-S1 spinal cord enhanced colorectal motility. The prokinetic effect of α-MSH was abolished by severing the pelvic nerves. In contrast, severing the colonic nerves or thoracic cord transection at the T4 level had no impact on the effect of α-MSH. RT-PCR analysis revealed MC1R mRNA and MC4R mRNA expression in the L6-S1 spinal cord. Intrathecally administered MC1R agonists, BMS470539 and SHU9119, mimicked the α-MSH effect, but a MC4R agonist, THIQ, had no effect. These results demonstrate that α-MSH binds to MC1R in the spinal defaecation centre and activates pelvic nerves, leading to enhancement of colorectal motility. This is, to our knowledge, the first report showing the functional role of α-MSH in the spinal cord. In conclusion, our findings suggest that α-MSH is a candidate for a neurotransmitter from supraspinal regions to the spinal defaecation centre.
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Affiliation(s)
- Hiromi H Ueda
- Department of Basic Veterinary Science, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan
| | - Kiyotada Naitou
- Department of Basic Veterinary Science, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan
| | - Hiroyuki Nakamori
- Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kazuhiro Horii
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Takahiko Shiina
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan
| | - Tatsunori Masatani
- Transboundary Animal Diseases Research Center, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, 890-0065, Japan
| | - Mitsuya Shiraishi
- Department of Basic Veterinary Science, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-0065, Japan
| | - Yasutake Shimizu
- Laboratory of Physiology, Department of Basic Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. .,Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University (G-CHAIN), Gifu, Japan.
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7
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Gonkowski S, Rytel L. Somatostatin as an Active Substance in the Mammalian Enteric Nervous System. Int J Mol Sci 2019; 20:ijms20184461. [PMID: 31510021 PMCID: PMC6769505 DOI: 10.3390/ijms20184461] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/22/2019] [Accepted: 09/08/2019] [Indexed: 12/12/2022] Open
Abstract
Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous system (ENS), located in the wall of the gastrointestinal (GI) tract. It regulates most of the functions of the stomach and intestine and it is characterized by complex organization and a high degree of independence from the central nervous system. SOM has been described in the ENS of numerous mammal species and its main functions in the GI tract are connected with the inhibition of the intestinal motility and secretory activity. Moreover, SOM participates in sensory and pain stimuli conduction, modulation of the release of other neuronal factors, and regulation of blood flow in the intestinal vessels. This peptide is also involved in the pathological processes in the GI tract and is known as an anti-inflammatory agent. This paper, which focuses primarily on the distribution of SOM in the ENS and extrinsic intestinal innervation in various mammalian species, is a review of studies concerning this issue published from 1973 to the present.
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Affiliation(s)
- Slawomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 13, 10-718 Olsztyn, Poland.
| | - Liliana Rytel
- Department and Clinic of Internal Diseases, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 14, 10-718 Olsztyn, Poland.
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8
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Tache Y, Larauche M, Yuan PQ, Million M. Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol 2018; 11:51-71. [PMID: 28240194 DOI: 10.2174/1874467210666170224095741] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/16/2016] [Accepted: 08/03/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Corticotropin-releasing factor (CRF) pathways coordinate behavioral, endocrine, autonomic and visceral responses to stress. Convergent anatomical, molecular, pharmacological and functional experimental evidence supports a key role of brain CRF receptor (CRF-R) signaling in stress-related alterations of gastrointestinal functions. These include the inhibition of gastric acid secretion and gastric-small intestinal transit, stimulation of colonic enteric nervous system and secretorymotor function, increase intestinal permeability, and visceral hypersensitivity. Brain sites of CRF actions to alter gut motility encompass the paraventricular nucleus of the hypothalamus, locus coeruleus complex and the dorsal motor nucleus while those modulating visceral pain are localized in the hippocampus and central amygdala. Brain CRF actions are mediated through the autonomic nervous system (decreased gastric vagal and increased sacral parasympathetic and sympathetic activities). The activation of brain CRF-R2 subtype inhibits gastric motor function while CRF-R1 stimulates colonic secretomotor function and induces visceral hypersensitivity. CRF signaling is also located within the gut where CRF-R1 activates colonic myenteric neurons, mucosal cells secreting serotonin, mucus, prostaglandin E2, induces mast cell degranulation, enhances mucosal permeability and propulsive motor functions and induces visceral hyperalgesia in animals and humans. CRF-R1 antagonists prevent CRF- and stressrelated gut alterations in rodents while not influencing basal state. DISCUSSION These preclinical studies contrast with the limited clinical positive outcome of CRF-R1 antagonists to alleviate stress-sensitive functional bowel diseases such as irritable bowel syndrome. CONCLUSION The translational potential of CRF-R1 antagonists in gut diseases will require additional studies directed to novel anti-CRF therapies and the neurobiology of brain-gut interactions under chronic stress.
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Affiliation(s)
- Yvette Tache
- CURE/Digestive Diseases Research Center, G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073. United States
| | - Muriel Larauche
- CURE/Digestive Diseases Research Center, G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073. United States
| | - Pu-Qing Yuan
- CURE/Digestive Diseases Research Center, G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073. United States
| | - Mulugeta Million
- CURE/Digestive Diseases Research Center, G Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Digestive Diseases Division, David Geffen School of Medicine at UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073. United States
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9
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Pustovit RV, Callaghan B, Ringuet MT, Kerr NF, Hunne B, Smyth IM, Pietra C, Furness JB. Evidence that central pathways that mediate defecation utilize ghrelin receptors but do not require endogenous ghrelin. Physiol Rep 2018; 5:5/15/e13385. [PMID: 28801520 PMCID: PMC5555902 DOI: 10.14814/phy2.13385] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 01/24/2023] Open
Abstract
In laboratory animals and in human, centrally penetrant ghrelin receptor agonists, given systemically or orally, cause defecation. Animal studies show that the effect is due to activation of ghrelin receptors in the spinal lumbosacral defecation centers. However, it is not known whether there is a physiological role of ghrelin or the ghrelin receptor in the control of defecation. Using immunohistochemistry and immunoassay, we detected and measured ghrelin in the stomach, but were unable to detect ghrelin by either method in the lumbosacral spinal cord, or other regions of the CNS. In rats in which the thoracic spinal cord was transected 5 weeks before, the effects of a ghrelin agonist on colorectal propulsion were significantly enhanced, but defecation caused by water avoidance stress (WAS) was reduced. In knockout rats that expressed no ghrelin and in wild‐type rats, WAS‐induced defecation was reduced by a ghrelin receptor antagonist, to similar extents. We conclude that the ghrelin receptors of the lumbosacral defecation centers have a physiological role in the control of defecation, but that their role is not dependent on ghrelin. This implies that a transmitter other than ghrelin engages the ghrelin receptor or a ghrelin receptor complex.
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Affiliation(s)
- Ruslan V Pustovit
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Brid Callaghan
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Mitchell T Ringuet
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Nicole F Kerr
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Billie Hunne
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Ian M Smyth
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
| | - Claudio Pietra
- Helsinn Research and Preclinical Department, Lugano, Switzerland
| | - John B Furness
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, Australia .,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
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10
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Gil DW, Wang J, Gu C, Donello JE, Cabrera S, Al-Chaer ED. Role of sympathetic nervous system in rat model of chronic visceral pain. Neurogastroenterol Motil 2016; 28:423-31. [PMID: 26670784 DOI: 10.1111/nmo.12742] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 10/31/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Changes in central pain modulation have been implicated in generalized pain syndromes such as irritable bowel syndrome (IBS). We have previously demonstrated that reduced descending inhibition unveils a role of sympathoneuronal outflow in decreasing peripheral sensory thresholds, resulting in stress-induced hyperalgesia. We investigated whether sympathetic nervous system (SNS) exacerbation of pain sensation when central pain inhibition is reduced is relevant to chronic pain disorders using a rat colon irritation (CI) model of chronic visceral hypersensitivity with hallmarks of IBS. METHODS Rats were treated to a series of colorectal balloon distensions (CRD) as neonates resulting in visceral and somatic hypersensitivity and altered stool function that persists into adulthood. The visceral sensitivity was assessed by recording electromyographic (EMG) responses to CRD. Somatic sensitivity was assessed by paw withdrawal thresholds to radiant heat. The effects on the hypersensitivity of (i) inhibiting sympathoneuronal outflow with pharmacological and surgical interventions and (ii) enhancing the outflow with water avoidance stress (WAS) were tested. KEY RESULTS The alpha2-adrenergic agonist, clonidine, and the alpha1-adrenergic antagonist, prazosin, reduced the visceral hypersensitivity and WAS enhanced the pain. Chemical sympathectomy with guanethidine and surgical sympathectomy resulted in a loss of the chronic visceral hypersensitivity. CONCLUSIONS & INFERENCES The results support a role of the SNS in driving the chronic visceral and somatic hypersensitivity seen in CI rats. The findings further suggest that treatments that decrease sympathetic outflow or block activation of adrenergic receptors on sensory nerves could be beneficial in the treatment of generalized pain syndromes.
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Affiliation(s)
| | - J Wang
- University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | - C Gu
- University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
| | | | | | - E D Al-Chaer
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut (AUB), Beirut, Lebanon.,Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA
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11
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12
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Corticotropin-releasing factor receptor type 1 and type 2 interaction in irritable bowel syndrome. J Gastroenterol 2015; 50:819-30. [PMID: 25962711 DOI: 10.1007/s00535-015-1086-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 04/25/2015] [Indexed: 02/06/2023]
Abstract
Irritable bowel syndrome (IBS) displays chronic abdominal pain or discomfort with altered defecation, and stress-induced altered gut motility and visceral sensation play an important role in the pathophysiology. Corticotropin-releasing factor (CRF) is a main mediator of stress responses and mediates these gastrointestinal functional changes. CRF in brain and periphery acts through two subtype receptors such as CRF receptor type 1 (CRF1) and type 2 (CRF2), and activating CRF1 exclusively stimulates colonic motor function and induces visceral hypersensitivity. Meanwhile, several recent studies have demonstrated that CRF2 has a counter regulatory action against CRF1, which may imply that CRF2 inhibits stress response induced by CRF1 in order to prevent it from going into an overdrive state. Colonic contractility and sensation may be explained by the state of the intensity of CRF1 signaling. CRF2 signaling may play a role in CRF1-triggered enhanced colonic functions through modulation of CRF1 activity. Blocking CRF2 further enhances CRF-induced stimulation of colonic contractility and activating CRF2 inhibits stress-induced visceral sensitization. Therefore, we proposed the hypothesis, i.e., balance theory of CRF1 and CRF2 signaling as follows. Both CRF receptors may be activated simultaneously and the signaling balance of CRF1 and CRF2 may determine the functional changes of gastrointestinal tract induced by stress. CRF signaling balance might be abnormally shifted toward CRF1, leading to enhanced colonic motility and visceral sensitization in IBS. This theory may lead to understanding the pathophysiology and provide the novel therapeutic options targeting altered signaling balance of CRF1 and CRF2 in IBS.
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Browning KN, Travagli RA. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol 2015; 4:1339-68. [PMID: 25428846 DOI: 10.1002/cphy.c130055] [Citation(s) in RCA: 360] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Although the gastrointestinal (GI) tract possesses intrinsic neural plexuses that allow a significant degree of autonomy over GI functions, the central nervous system (CNS) provides extrinsic neural inputs that regulate, modulate, and control these functions. While the intestines are capable of functioning in the absence of extrinsic inputs, the stomach and esophagus are much more dependent upon extrinsic neural inputs, particularly from parasympathetic and sympathetic pathways. The sympathetic nervous system exerts a predominantly inhibitory effect upon GI muscle and provides a tonic inhibitory influence over mucosal secretion while, at the same time, regulates GI blood flow via neurally mediated vasoconstriction. The parasympathetic nervous system, in contrast, exerts both excitatory and inhibitory control over gastric and intestinal tone and motility. Although GI functions are controlled by the autonomic nervous system and occur, by and large, independently of conscious perception, it is clear that the higher CNS centers influence homeostatic control as well as cognitive and behavioral functions. This review will describe the basic neural circuitry of extrinsic inputs to the GI tract as well as the major CNS nuclei that innervate and modulate the activity of these pathways. The role of CNS-centered reflexes in the regulation of GI functions will be discussed as will modulation of these reflexes under both physiological and pathophysiological conditions. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide these answers.
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Affiliation(s)
- Kirsteen N Browning
- Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, Pennsylvania
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Pustovit RV, Furness JB, Rivera LR. A ghrelin receptor agonist is an effective colokinetic in rats with diet-induced constipation. Neurogastroenterol Motil 2015; 27:610-7. [PMID: 25616061 DOI: 10.1111/nmo.12517] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 12/24/2014] [Indexed: 01/06/2023]
Abstract
BACKGROUND Despite constipation being a common problem, the treatments that are available have side effects and are only partly effective. Recent studies show that centrally penetrant ghrelin receptor agonists cause defecation in humans and other species. Here, we describe some features of a rat model of low fiber-induced constipation, and investigate the effectiveness of the ghrelin agonist, capromorelin. METHODS Rats were given low-fiber diets for 5 weeks. Their colorectal responsiveness to distension and to a behavioral test, water avoidance and colon histology were compared to those of rats on a standard diet. KEY RESULTS After the low-fiber diet, distension of the colon produced fewer propulsive contractions, behaviorally induced defecation was reduced, and the lining of the colorectum was inflamed. However, capromorelin was similarly effective in causing defecation in constipated and non-constipated rats. CONCLUSIONS & INFERENCES Low-fiber diet in rats produces a constipation phenotype, characterized by reduced responsiveness of the colorectum to distension and to a behavioral stimulus of defecation, water avoidance. The effectiveness of capromorelin suggests that centrally penetrant ghrelin receptor stimulants may be effective in treating constipation.
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Affiliation(s)
- R V Pustovit
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia
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Taché Y, Million M. Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. J Neurogastroenterol Motil 2015; 21:8-24. [PMID: 25611064 PMCID: PMC4288101 DOI: 10.5056/jnm14162] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 12/28/2014] [Indexed: 12/13/2022] Open
Abstract
The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.
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Affiliation(s)
- Yvette Taché
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Mulugeta Million
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
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Post RJ, Dahlborg KM, O'Loughlin LE, Bloom CM. Effects of juvenile exposure to predator odor on adolescent and adult anxiety and pain nociception. Physiol Behav 2014; 131:57-61. [PMID: 24732419 DOI: 10.1016/j.physbeh.2014.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 03/11/2014] [Accepted: 04/04/2014] [Indexed: 01/07/2023]
Abstract
Clinical researchers have tracked patients with early life trauma and noted generalized anxiety disorder, unipolar depression, and risk-taking behaviors developing in late adolescence and into early adulthood. Animal models provide an opportunity to investigate the neural and developmental processes that underlie the relationship between early stress and later abnormal behavior. The present model used repeated exposure to 2,3,5-trimethyl-3-thiazoline (TMT), a component of fox feces, as an unconditioned fear-eliciting stimulus in order to induce stress in juvenile rats aged postnatal day (PND) 23 through 27. After further physical maturation characteristic of the adolescent stage (PND 42), animals were tested using an elevated plus maze (EPM) for anxiety and plantar test (Hargreaves method) for pain to assess any lingering effects of the juvenile stress. To assess how an additional stress later in life affects anxiety and pain nociception, PND 43 rats were exposed to inescapable shock (0.8mA) and again tested on EPM and plantar test. A final testing period was conducted in the adult (PND 63) rats to assess resulting changes in adult behaviors. TMT-exposed rats were significantly more anxious in adolescence than controls, but this difference disappeared after exposure to the secondary stressor. In adulthood, but not in adolescence, TMT-exposed rats demonstrated lower pain sensitivity than controls. These results suggest that early life stress can play a significant role in later anxiety and pain nociception, and offer insight into the development and manifestation of anxiety- and trauma-related disorders.
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Affiliation(s)
- Ryan J Post
- Providence College, 1 Cunningham Sq., Providence, RI 02918, USA
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Fukudo S. Stress and visceral pain: focusing on irritable bowel syndrome. Pain 2013; 154 Suppl 1:S63-S70. [PMID: 24021863 DOI: 10.1016/j.pain.2013.09.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 08/08/2013] [Accepted: 09/04/2013] [Indexed: 12/14/2022]
Abstract
Recent advances in brain science have shown that the brain function encoding emotion depends on interoceptive signals such as visceral pain. Visceral pain arose early in our evolutionary history. Bottom-up processing from gut-to-brain and top-down autonomic/neuroendocrine mechanisms in brain-to-gut signaling constitute a circuit. Brain imaging techniques have enabled us to depict the visceral pain pathway as well as the related emotional circuit. Irritable bowel syndrome (IBS) is characterized by chronic recurrent abdominal pain or abdominal discomfort associated with bowel dysfunction. It is also thought to be a disorder of the brain-gut link associated with an exaggerated response to stress. Corticotropin-releasing hormone (CRH), a major mediator of the stress response in the brain-gut axis, is an obvious candidate in the pathophysiology of IBS. Indeed, administration of CRH has been shown to aggravate the visceral sensorimotor response in IBS patients, and the administration of peptidergic CRH antagonists seems to alleviate IBS pathophysiology. Serotonin (5-HT) is another likely candidate associated with brain-gut function in IBS, as 5-HT3 antagonists, 5-HT4 agonists, and antidepressants were demonstrated to regulate 5-HT neurotransmission in IBS patients. Autonomic nervous system function, the neuroimmune axis, and the brain-gut-microbiota axis show specific profiles in IBS patients. Further studies on stress and visceral pain neuropathways in IBS patients are warranted.
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Affiliation(s)
- Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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Suda K, Setoyama H, Nanno M, Matsumoto S, Kawai M. Involvement of parasympathetic pelvic efferent pathway in psychological stress-induced defecation. World J Gastroenterol 2013; 19:1200-1209. [PMID: 23482518 PMCID: PMC3587476 DOI: 10.3748/wjg.v19.i8.1200] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Revised: 09/28/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of the pelvic nerve pathway in stress-induced acceleration of colorectal transit and defecation in rats.
METHODS: Surgical transection of rectal nerves (rectal branches of the pelvic nerve), vagotomy (Vag) or adrenalectomy (Adx) were performed bilaterally in rats. Number of fecal pellet output of these rats was measured during 1-h water avoidance stress (WAS). To evaluate the colonic transit, rats were given phenol red through the catheter indwelled in the proximal colon and subjected to WAS. After WAS session, entire colon and rectum were isolated and distribution of phenol red was measured. Distal colonic and rectal transit was evaluated using glass bead. Rats were inserted the glass bead into the distal colon and evacuation rate of the bead was measured. Neural activation was assessed by immunohistochemical staining of c-Fos and PGP9.5 in colonic whole-mount preparations of longitudinal muscle myenteric plexus (LMMP).
RESULTS: In the sham-operated rats (sham op), WAS significantly increased defecation and accelerated colorectal transit with marked elevation of plasma corticosterone level. Compared with sham-operated rats, increase in the excretion of fecal pellets during WAS was significantly reduced by rectal nerve transection (RNT) (sham op: 6.9 ± 0.8 vs RNT: 4.3 ± 0.6, P < 0.05) or Vag (sham op: 6.4 ± 0.8 vs Vag: 3.7 ± 1.1, P < 0.05), although corticosterone level remained elevated. Adx-rats significantly increased the defecation despite the lower corticosterone level. Distribution pattern of phenol red showed RNT inhibited distal colonic and rectal transit accelerated by WAS, while Vag inhibited proximal colonic transit. Suppression of distal colonic and rectal transit by RNT was further confirmed by the bead evacuation rate (sham op: 80.0% vs RNT: 53.8%). WAS significantly increased the number of c-Fos-immunoreactive neural cells in the LMMP of the proximal and distal colon, whereas c-Fos expression was decreased by RNT in the distal colon (sham op: 9.0 ± 2.0 vs RNT: 4.4 ± 1.0, P < 0.05) and decreased by Vag in the proximal colon.
CONCLUSION: Pelvic nerve conveys WAS stimuli from the brain to the distal colon, and directly activate the myenteric neurons, followed by the increase of its motility.
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WANG L, MAGEN I, YUAN PQ, SUBRAMANIAM SR, RICHTER F, CHESSELET MF, TACHÉ Y. Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol Motil 2012; 24:e425-36. [PMID: 22779732 PMCID: PMC3712640 DOI: 10.1111/j.1365-2982.2012.01974.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prevalent non-motor symptoms of Parkinson's disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α-synuclein in colonic enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α-synuclein under the Thy1 promoter (Thy1-aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates. METHODS Defecation, gastric emptying (GE), and immunostaining for α-synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1-aSyn compared to littermate WT mice. KEY RESULTS Thy1-aSyn mice aged 2.5-3 or 7-8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2-h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1-aSyn mice (8-10 months) displayed increased α-synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT-immunoreactive (ir) neurons, and only a few, nNOS-ir neurons. There were no conspicuous changes in pChAT- and nNOS-ir neurons, or TH- and VIP-ir nerve fibers. Thy1-aSyn mice aged 4-18 months had normal GE. CONCLUSIONS & INFERENCES The occurrence of over-production of pre-synaptic α-synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.
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Affiliation(s)
- L. WANG
- CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles and Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, USA
| | - I. MAGEN
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - P-Q YUAN
- CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles and Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, USA
| | - S. R. SUBRAMANIAM
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - F. RICHTER
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - M-F CHESSELET
- Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Y. TACHÉ
- CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles and Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, USA
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Yoshimoto S, Cerjak D, Babygirija R, Bulbul M, Ludwig K, Takahashi T. Hypothalamic circuit regulating colonic transit following chronic stress in rats. Stress 2012; 15:227-36. [PMID: 21936687 DOI: 10.3109/10253890.2011.614297] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Although acute stress accelerates colonic transit, the effect of chronic stress on colonic transit remains unclear. In this study, rats received repeated restraint stress (chronic homotypic stress) or various types of stress (chronic heterotypic stress) for 5 and 7 days, respectively. Vehicle saline, oxytocin (OXT), OXT receptor antagonist or corticotropin-releasing factor (CRF) receptor antagonists were administered by intracerebroventricular (ICV) injection prior to restraint stress for 90 min. Immediately after the stress exposure, the entire colon was removed and the geometric center (GC) of Na51CrO4 (a nonabsorbable radioactive marker; 0.5 μCi) distribution was calculated to measure the transit. Gene expression of OXT and CRF in the paraventricular nucleus (PVN) was evaluated by in situ hybridization. Accelerated colonic transit with the acute stressor was no longer observed following chronic homotypic stress. This restored colonic transit was reversed by ICV injection of an OXT antagonist. In contrast, chronic heterotypic stress significantly accelerated colonic transit, which was attenuated by ICV injection of OXT and by a CRF receptor 1 antagonist. OXT mRNA expression in the PVN was significantly increased following chronic homotypic stress, but not chronic heterotypic stress. However, CRF mRNA expression in the PVN was significantly increased following acute and chronic heterotypic stress, but not chronic homotypic stress. These results indicate that central OXT and CRF play a pivotal role in mediating the colonic dysmotility following chronic stress in rats.
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Affiliation(s)
- Sazu Yoshimoto
- Department of Surgery, Medical College of Wisconsin, Zablocki VA Medical Center, Milwaukee, WI 53295, USA
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21
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Bian ZX, Qin HY, Tian SL, Qi SD. Combined effect of early life stress and acute stress on colonic sensory and motor responses through serotonin pathways: differences between proximal and distal colon in rats. Stress 2011; 14:448-58. [PMID: 21438781 DOI: 10.3109/10253890.2011.558604] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Clinically, adults who have experienced stresses in childhood present with episodes of serious symptoms of irritable bowel syndrome that are associated with acute stress, but the mechanism is not well understood. This study aimed to investigate the colonic sensory/motor responses to acute water avoidance stress (WAS) in male adult rats subjected to neonatal maternal separation (NMS), and the underlying mechanism of sensory/motor responses. Effects of the combined acute and early life stress on visceral sensation, colonic motility, and the tissue and luminal content of serotonin (5-hydroxytryptamine, 5-HT) in the proximal and distal colon were evaluated using the abdominal withdrawal reflex test, faecal pellet output measurement and capillary electrophoresis analysis, respectively. Results showed that WAS significantly increased not only visceral sensitivity but also colonic motility in NMS rats compared to the normal rats. These alterations were accompanied by significant increase in 5-HT content in the proximal but not the distal colonic tissues; these alterations were also associated with increased density of enterochromaffin (EC) cells in the proximal segment. In contrast, the faecal content of 5-HT increased similarly in both segments. Consecutive administration of parachlorophenylalanine to NMS rats was more potent at 500 mg kg⁻¹ day⁻¹ than at 150 mg kg⁻¹ day⁻¹ in suppressing colonic sensory/motor responses to WAS, corresponding to the greater reduction of the tissue and faecal content of 5-HT and of EC cell density in the colon. These data indicate that combined early life stress and acute stress effectively induce visceral hyperalgesia and motility disorder through 5-HT pathways in the colon of rats, and the proximal and distal colon have different responses towards the combined stressors.
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Affiliation(s)
- Zhao-Xiang Bian
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, People's Republic of China.
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Goebel-Stengel M, Wang L, Stengel A, Taché Y. Localization of nesfatin-1 neurons in the mouse brain and functional implication. Brain Res 2011; 1396:20-34. [PMID: 21555116 PMCID: PMC3104076 DOI: 10.1016/j.brainres.2011.04.031] [Citation(s) in RCA: 112] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Revised: 03/30/2011] [Accepted: 04/17/2011] [Indexed: 12/17/2022]
Abstract
Nesfatin-1 reduces food intake when injected centrally in rodents. We recently described wide distribution of nucleobindin2 (NUCB2)/nesfatin-1 immunoreactivity in rat brain autonomic nuclei activated by various stressors. We used C57BL/6 mice to localize brain NUCB2/nesfatin-1 immunoreactivity and assessed activation of NUCB2/nesfatin 1 neurons after water avoidance stress (WAS). Gastric emptying of a non-nutrient liquid was also determined. NUCB2/nesfatin-1 immunoreactivity was detected in cortical areas including piriform, insular, cingulate and somatomotor cortices, the limbic system including amygdaloid nuclei, hippocampus and septum, the basal ganglia, bed nucleus of the stria terminalis, the thalamus including paraventricular and parafascicular nuclei, the hypothalamus including supraoptic, periventricular, paraventricular (PVN), arcuate nuclei and ventromedial and lateral hypothalamic areas. Intensely labeled NUCB2/nesfatin-1 neurons were detected in a previously undefined region which we named intermediate dorsomedial hypothalamus. In the brainstem, NUCB2/nesfatin-1 immunoreactivity was detected in the raphe nuclei, Edinger-Westphal nucleus, locus coeruleus (LC), lateral parabrachial nucleus, ventrolateral medulla (VLM) and dorsal vagal complex. WAS induced Fos expression in 35% of NUCB2/nesfatin-1-immunoreactive neurons in the PVN, 50% in the LC, 54% in the rostral raphe pallidus, 58% in the VLM, 39% in the middle part of the nucleus of the solitary tract (NTS) and 33% in the caudal NTS. Nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying. These data showed that NUCB2/nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that nesfatin-1 might play a role in the efferent component of the stress response.
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Affiliation(s)
- Miriam Goebel-Stengel
- CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Lixin Wang
- CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Andreas Stengel
- CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Yvette Taché
- CURE/Digestive Diseases Research Center, Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
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Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice. Neurosci Lett 2011; 495:77-81. [PMID: 21439349 DOI: 10.1016/j.neulet.2011.03.045] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Revised: 01/20/2011] [Accepted: 03/01/2011] [Indexed: 12/12/2022]
Abstract
Acute restraint stress delays gastric emptying and accelerates colonic transit via central corticotropin releasing factor (CRF) in rats. In contrast, central oxytocin has anxiolytic effects and attenuates the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Our recent study showed that up regulated oxytocin expression attenuates hypothalamic CRF expression and restores impaired gastric motility following chronic homotypic stress in mice. We studied the effects of acute and chronic homotypic stress on colonic transit and hypothalamic CRF mRNA expression in wild type (WT) and oxytocin knockout (OXT-KO) mice. Colonic transit was measured following acute restraint stress or chronic homotypic stress (repeated restraint stress for 5 consecutive days). (51)Cr was injected via a catheter into the proximal colon. Ninety minutes after restraint stress loading, the entire colon was removed. The geometric center (GC) was calculated to evaluate colonic transit. Expression of CRF mRNA in the supraoptic nucleus (SON) was measured by real time RT-PCR. Colonic transit was significantly accelerated following acute stress in WT (GC=8.1±0.8; n=7) and OXT KO mice (GC=9.4±0.3; n=7). The accelerated colonic transit was significantly attenuated in WT mice (GC=6.6±0.5; n=9) following chronic homotypic stress while it was still accelerated in OXT KO mice (GC=9.3±0.5; n=8). The increase in CRF mRNA expression at the SON was much greater in OXT-KO mice, compared to WT mice following chronic homotypic stress. It is suggested that oxytocin plays a pivotal role in mediating the adaptation mechanism following chronic homotypic stress in mice.
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Yang YJ, Lv SY, Xiu MH, Xu N, Chen Q. Intracerebroventricular administration of apelin-13 inhibits distal colonic transit in mice. Peptides 2010; 31:2241-6. [PMID: 20849897 DOI: 10.1016/j.peptides.2010.09.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 09/04/2010] [Accepted: 09/04/2010] [Indexed: 01/17/2023]
Abstract
Apelin is a novel bioactive peptide as the endogenous ligand for the orphan G-protein-coupled receptor (GPCR), APJ, a receptor distributed in various tissues such as the hypothalamus and the gastrointestinal tract. Recent reports showed that apelin regulated many biological functions, including blood pressure, neuroendocrine, drinking behavior and food intake. However, the role of apelin in regulating gastrointestinal motility remains unknown. The present study aimed to investigate the actions of intracerebroventricularly administered apelin-13 on colonic transit as well as the actions of apelin-13 on the contraction of isolated distal colon in vitro. Intracerebroventricular (i.c.v.) injection of apelin-13 (0.3, 0.5, 1 and 3 μg/mouse) dose-dependently inhibited fecal pellet output and bead expulsion. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A), indicating an APJ receptor-mediated mechanism. Furthermore, naloxone could also reverse the inhibitory effect of apelin-13 on fecal pellet output and bead expulsion, suggesting the involvement of opioid receptors in the suppressive effect of apelin-13 on distal colon transit. However, apelin-13 (10⁻⁸-10⁻⁶ M) did not affect distal colonic contractions in vitro.
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Affiliation(s)
- Yan-Jie Yang
- Institute of Biochemistry and Molecular Biology, School of Life Science, Lanzhou University, 222 Tian Shui South Road, Lanzhou 730000, PR China
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Stengel A, Taché Y. Corticotropin-releasing factor signaling and visceral response to stress. Exp Biol Med (Maywood) 2010; 235:1168-78. [PMID: 20881321 PMCID: PMC3169435 DOI: 10.1258/ebm.2010.009347] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Stress may cause behavioral and/or psychiatric manifestations such as anxiety and depression and also impact on the function of different visceral organs, namely the gastrointestinal and cardiovascular systems. During the past years substantial progress has been made in the understanding of the underlying mechanisms recruited by stressors. Activation of the corticotropin-releasing factor (CRF) signaling system is recognized to be involved in a large number of stress-related behavioral and somatic disorders. This review will outline the present knowledge on the distribution of the CRF system (ligands and receptors) expressed in the brain and peripheral viscera and its relevance in stress-induced alterations of gastrointestinal and cardiovascular functions and the therapeutic potential of CRF(1) receptor antagonists.
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Affiliation(s)
- Andreas Stengel
- CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division, David Geffen School of Medicine at University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
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26
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Matsunaga M, Konagaya T, Nogimori T, Yoneda M, Kasugai K, Ohira H, Kaneko H. Inhibitory effect of oxytocin on accelerated colonic motility induced by water-avoidance stress in rats. Neurogastroenterol Motil 2009; 21:856-e59. [PMID: 19298230 DOI: 10.1111/j.1365-2982.2009.01286.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Recent studies have indicated that brain and gut activities are interrelated and exposure to several stressors, such as water-avoidance stress, stimulates the motor function of the gut through corticotropin-releasing factor (CRF)-signalling pathways in the brain. Central oxytocin is known to attenuate stress responses, including CRF expression in the brain. Here, we examined whether central oxytocin attenuated the acceleration of colonic motility induced by water-avoidance stress. A force transducer was attached to the distal colon of male rat, and the colonic motility and faecal pellet output were recorded while the rats were exposed to water-avoidance stress. Intracerebroventricular (i.c.v.) injections of oxytocin (5, 50 and 500 pmol) and the oxytocin receptor antagonist tocinoic acid (25 microg) were administered before exposure to water-avoidance stress, and the effect of oxytocin on colonic motor function was determined. Centrally administered oxytocin inhibited the accelerated colonic motility induced by water-avoidance stress. The effective dose ranged between 5 and 50 pmol on i.c.v. injection. Oxytocin also decreased the number of CRF-positive cells in the paraventricular nucleus and corticosterone release. The inhibitory effect of oxytocin on accelerated colonic motility was blocked by pretreatment with oxytocin receptor antagonist. Furthermore, centrally administered tocinoic acid enhanced the acceleration of colonic motility. These results suggested that endogenous central oxytocin may contribute to the regulation of colonic function and inhibit the brain CRF-signalling pathways targeting the gut, resulting in the inhibition of stress-induced colonic contractions.
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Affiliation(s)
- M Matsunaga
- Department of Neurology, Ban Buntane Hotokukai Hospital, Fujita Health University, Aichi, Japan
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Han RW, Chang M, Peng YL, Qiao LY, Yin XQ, Li W, Wang R. Central Neuropeptide S inhibits distal colonic transit through activation of central Neuropeptide S receptor in mice. Peptides 2009; 30:1313-7. [PMID: 19540430 DOI: 10.1016/j.peptides.2009.03.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 03/17/2009] [Accepted: 03/17/2009] [Indexed: 10/21/2022]
Abstract
Neuropeptide S (NPS), the endogenous ligand of NPS receptor (NPSR), regulates many biological functions, including arousal, anxiety, locomotion and food intake. NPSR mRNA is expressed in several regions of central autonomic network through which the brain controls visceromotor and other responses essential for survival. However, the role of NPS/NPSR system in regulating gastrointestinal motor is still unknown. Here, we studied the effects of NPS on distal colonic transit in mice. Intracerebroventricular (i.c.v.) injection of NPS (1-1000 pmol) inhibited fecal pellet output and bead expulsion in a dose-dependent manner. However, intraperitoneal injection of NPS (1000 and 10000 pmol) did not affect fecal pellet output and bead expulsion. In vitro, NPS (0.1-10 microM) also did not modulate distal colonic contractions. Furthermore, i.c.v. co-administration of [D-Val(5)]NPS, a pure and potent NPSR antagonist, dose-dependently antagonized the inhibitory effects of NPS on fecal pellet output and bead expulsion. In conclusion, our results firstly indicate that central NPS inhibits distal colonic transit through the activation of central NPSR, which implicate that NPS/NPSR system might be a new target to treat function disorder of distal colon.
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Affiliation(s)
- Ren-Wen Han
- Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, PR China
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28
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Gourcerol G, Wang L, Adelson DW, Larauche M, Taché Y, Million M. Cholinergic giant migrating contractions in conscious mouse colon assessed by using a novel noninvasive solid-state manometry method: modulation by stressors. Am J Physiol Gastrointest Liver Physiol 2009; 296:G992-G1002. [PMID: 19299579 PMCID: PMC2696213 DOI: 10.1152/ajpgi.90436.2008] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
There is a glaring lack of knowledge on mouse colonic motility in vivo, primarily due to unavailability of adequate recording methods. Using a noninvasive miniature catheter pressure transducer inserted into the distal colon, we assessed changes in colonic motility in conscious mice induced by various acute or chronic stressors and determined the neurotransmitters mediating these changes. Mice exposed to restraint stress (RS) for 60 min displayed distal colonic phasic contractions including high-amplitude giant migrating contractions (GMCs), which had peak amplitudes >25 mmHg and occurred at a rate of 15-25 h(-1) of which over 50% were aborally propagative. Responses during the first 20-min of RS were characterized by high-frequency and high-amplitude contractions that were correlated with defecation. RS-induced GMCs and fecal pellet output were blocked by atropine (0.5 mg/kg ip) or the corticotrophin releasing factor (CRF) receptor antagonist astressin-B (100 microg/kg ip). RS activated colonic myenteric neurons as shown by Fos immunoreactivity. In mice previously exposed to repeated RS (60 min/day, 14 days), or in transgenic mice that overexpress CRF, the duration of stimulation of phasic colonic contractions was significantly shorter (10 vs. 20 min). In contrast to RS, abdominal surgery abolished colonic contractions including GMCs. These findings provide the first evidence for the presence of frequent cholinergic-dependent GMCs in the distal colon of conscious mice and their modulation by acute and chronic stressors. Noninvasive colonic manometry opens new venues to investigate colonic motor function in genetically modified mice relevant to diseases that involve colonic motility alterations.
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Affiliation(s)
- G. Gourcerol
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - L. Wang
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - D. W. Adelson
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - M. Larauche
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Y. Taché
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - M. Million
- CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
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29
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Bradesi S, Martinez V, Lao L, Larsson H, Mayer EA. Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats. Am J Physiol Gastrointest Liver Physiol 2009; 296:G302-9. [PMID: 19033533 DOI: 10.1152/ajpgi.90557.2008] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Visceral hypersensitivity and stress have been implicated in the pathophysiology of functional gastrointestinal disorders. We used a selective vasopressin 3 (V(3)) receptor antagonist SSR149415 to investigate the involvement of the vasopressin (AVP)/V(3) signaling system in the development of stress-induced visceral hyperalgesia in rats. Rats were exposed to a daily 1-h session of water avoidance stress (WAS) or sham WAS for 10 consecutive days. The visceromotor response to phasic colorectal distension (CRD, 10-60 mmHg) was assessed before and after stress. Animals were treated daily with SSR149415 (0.3, 1, or 3 mg/kg ip 30 min before each WAS or sham WAS session), with a single dose of SSR149415 (1 mg/kg ip), or the selective corticotropin-releasing factor 1 (CRF(1)) antagonist DMP-696 (30 mg/kg po) before CRD at day 11. Effects of a single dose of SSR149415 (10 mg/kg iv) on acute mechanical sensitization during repetitive CRD (12 distensions at 80 mmHg) were also assessed. In vehicle-treated rats, repeated WAS increased the response to CRD, indicating visceral hypersensitivity. Repeated administration of SSR149415 at 1 or 3 mg/kg completely prevented stress-induced visceral hyperalgesia. Similarly, a single dose of DMP-696 or SSR149415 completely blocked hyperalgesic responses during CRD. In contrast, a single dose of SSR149415 did not affect the acute hyperalgesic responses induced by repeated, noxious distension. These data support a major role for V(3) receptors in repeated psychological stress-induced visceral hyperalgesia and suggest that pharmacological manipulation of the AVP/V(3) pathway might represent an attractive alternative to the CRF/CRF(1) pathway for the treatment of chronic stress-related gastrointestinal disorders.
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Affiliation(s)
- Sylvie Bradesi
- University of California Los Angeles Center for Neurobiology of Stress, Departments of Medicine, Physiology, and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90073.
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30
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Stengel A, Taché Y. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight. Annu Rev Physiol 2009; 71:219-39. [PMID: 18928406 PMCID: PMC2714186 DOI: 10.1146/annurev.physiol.010908.163221] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems.
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Affiliation(s)
- Andreas Stengel
- Department of Medicine and CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California 90073;
| | - Yvette Taché
- Department of Medicine and CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California 90073;
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31
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Taché Y, Brunnhuber S. From Hans Selye's discovery of biological stress to the identification of corticotropin-releasing factor signaling pathways: implication in stress-related functional bowel diseases. Ann N Y Acad Sci 2008; 1148:29-41. [PMID: 19120089 PMCID: PMC2993154 DOI: 10.1196/annals.1410.007] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Selye pioneered the concept of biological stress in 1936, culminating in the identification of the corticotropin-releasing factor (CRF) signaling pathways by Vale's group in the last two decades. The characterization of the 41 amino-acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2, and urocortin 3, and the cloning of CRF(1) and CRF(2) receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable us to unravel the importance of CRF(1) receptor in the stress-related endocrine (activation of pituitary-adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (activation of sympathetic nervous system), and immune responses. The activation of CRF(1) receptors is also one of the key mechanisms through which various stressors impact the gut to stimulate colonic propulsive motor function and to induce hypersensitivity to colorectal distension as shown by the efficacy of the CRF(1) receptor antagonists in blunting these stress-related components. The importance of CRF(1) signaling pathway in the visceral response to stress in experimental animals provided new therapeutic approaches for treatment of functional bowel disorder such as irritable bowel syndrome, a multifactor functional disorder characterized by altered bowel habits and visceral pain, for which stress has been implicated in the pathophysiology and is associated with anxiety-depression in a subset of patients.
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Affiliation(s)
- Yvette Taché
- Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
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Abstract
To use sheep and rat models and demonstrate that stressors activate fetal glucocorticoid (GC) system, corticotrophin-releasing factor (CRF) system and cholinergic neurotransmitter system (ChNS) leading to propulsive colonic motility and in utero meconium passage. Immunohistochemical studies (IHS) were performed to localize GC-Receptors, CRF-receptors and key molecules of ChNS in sheep fetal distal colon. CRF expression in placenta and enteric endocrine cells in fetal rat system were examined and the effects of acute hypoxia on in utero meconium passage was tested. IHS confirmed localization and gestation dependent changes in GC-Rs, CRF-Rs and cholinergic markers in sheep fetal colon. Rat placenta and enteric endocrine cells express CRF and gastrointestinal tract express CRF-Rs. Hypoxia is a potent inducer of meconium passage in term fetal rats. Stress is a risk factor for in utero meconium passage and laboratory animal models can be used to develop pharmacotherapy to prevent stress-induced in utero meconium passage.
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Affiliation(s)
- J Lakshmanan
- Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA 90502, USA
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33
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Broccardo M, Agostini S, Petrella C, Guerrini R, Improta G. Central and peripheral role of the nociceptin/orphaninFQ system on normal and disturbed colonic motor function and faecal pellet output in the rat. Neurogastroenterol Motil 2008; 20:939-48. [PMID: 18410266 DOI: 10.1111/j.1365-2982.2008.01120.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this study, seeking further information on the role of the nociceptin/orphanin FQ (N/OFQ)-ergic system in normal and disturbed colonic motor function in rats, we compared the colonic effects of UFP-112, a novel highly potent agonist, with those of N/OFQ. When injected intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.), UFP-112 and N/OFQ increased bead expulsion time in a statistically significant and dose-related manner and reduced the percentage of rats with castor oil-induced diarrhoea. UFP-112 showed greater efficacy, higher potency and longer-lasting inhibitory effects than N/OFQ, and pretreatment with UFP-101, a selective antagonist, blocked the N/OFQ analogue-induced responses in both tests. When injected i.c.v., UFP-112 and N/OFQ inhibited corticotrophin releasing factor- and restrain stress-stimulated faecal pellet excretion significantly and in a dose-related manner. Conversely, when injected peripherally both peptides significantly inhibited colonic propulsive motility but did so in a non-dose-related manner. In conclusion, these findings indicate that, in the rat, the central and peripheral N/OFQ systems have an inhibitory role in modulating distal colonic propulsive motility under physiological and pathological conditions. UFP-112 therefore promises to be a useful pharmacological tool for investigating the role of the N/OFQ system in motor functions in the distal colonic tract under physiological and pathological conditions.
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Affiliation(s)
- M Broccardo
- Department of Human Physiology and Pharmacology "V. Erspamer", University of Rome "Sapienza", Rome, Italy.
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Miampamba M, Million M, Yuan PQ, Larauche M, Taché Y. Water avoidance stress activates colonic myenteric neurons in female rats. Neuroreport 2007; 18:679-82. [PMID: 17426598 PMCID: PMC8082807 DOI: 10.1097/wnr.0b013e3280bef7f8] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Stress stimulates colonic motor function and plays a role in functional bowel disorders, prevalently in women. We examined, in conscious female rats, the influence of water avoidance stress for 60 min on colonic myenteric neuron activity using immunohistochemical detection of Fos as a marker of neuronal activity. In control rats, Fos immunoreactive nuclei were rare in proximal and distal colon and no defecation was observed. Water avoidance stimulated fecal pellet output, which was associated with Fos expression in myenteric ganglia of proximal and distal colon including in a population of peripheral choline acetyltransferase-immunoreactive neurons. Atropine blocked fecal pellet output but not Fos expression in myenteric ganglia. These results indicate that psychological stress stimulates the activity of colonic cholinergic myenteric neurons.
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Affiliation(s)
- Marcel Miampamba
- Department of Medicine, Center for Neurovisceral Sciences and Women's Health and CURE: Digestive Diseases Research Center and Brain Research Institute, University of California, Los Angeles, California, USA.
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35
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Nakade Y, Fukuda H, Iwa M, Tsukamoto K, Yanagi H, Yamamura T, Mantyh C, Pappas TN, Takahashi T. Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1037-44. [PMID: 17158256 DOI: 10.1152/ajpgi.00419.2006] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although restraint stress accelerates colonic transit via a central corticotropin-releasing factor (CRF), the precise mechanism still remains unclear. We tested the hypothesis that restraint stress and central CRF stimulate colonic motility and transit via a vagal pathway and 5-HT(3) receptors of the proximal colon in rats. (51)Cr was injected via the catheter positioned in the proximal colon to measure colonic transit. The rats were subjected to a restraint stress for 90 min or received intracisternal injection of CRF. Ninety minutes after the administration of (51)Cr, the entire colon was removed, and the geometric center (GC) was calculated. Four force transducers were sutured on the proximal, mid, and distal colon to record colonic motility. Restraint stress accelerated colonic transit (GC of 6.7 +/- 0.4, n=6) compared with nonrestraint controls (GC of 5.1 +/- 0.2, n=6). Intracisternal injection of CRF (1.0 microg) also accelerated colonic transit (GC of 7.0 +/- 0.2, n=6) compared with saline-injected group (GC of 4.6 +/- 0.5, n=6). Restraint stress-induced acceleration of colonic transit was reduced by perivagal capsaicin treatment. Intracisternal injection of CRF antagonists (10 microg astressin) abolished restraint stress-induced acceleration of colonic transit. Stimulated colonic transit and motility induced by restraint stress and CRF were significantly reduced by the intraluminal administration of 5-HT(3) antagonist ondansetron (5 x 10(-6) M; 1 ml) into the proximal colon. Restraint stress and intracisternal injection of CRF significantly increased the luminal content of 5-HT of the proximal colon. It is suggested that restraint stress stimulates colonic motility via central CRF and peripheral 5-HT(3) receptors in conscious rats.
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MESH Headings
- Animals
- Capsaicin/pharmacology
- Central Nervous System/metabolism
- Colon/drug effects
- Colon/innervation
- Colon/metabolism
- Colon/physiopathology
- Consciousness
- Corticotropin-Releasing Hormone/antagonists & inhibitors
- Corticotropin-Releasing Hormone/metabolism
- Corticotropin-Releasing Hormone/pharmacology
- Disease Models, Animal
- Feces/chemistry
- Gastrointestinal Motility/drug effects
- Male
- Ondansetron/pharmacology
- Peptide Fragments/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Corticotropin-Releasing Hormone/metabolism
- Receptors, Serotonin, 5-HT3/metabolism
- Restraint, Physical/adverse effects
- Serotonin/metabolism
- Serotonin 5-HT3 Receptor Antagonists
- Serotonin Antagonists/pharmacology
- Stress, Psychological/etiology
- Stress, Psychological/metabolism
- Stress, Psychological/physiopathology
- Time Factors
- Vagotomy, Truncal
- Vagus Nerve/metabolism
- Vagus Nerve/surgery
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Affiliation(s)
- Yukiomi Nakade
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
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36
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Nakade Y, Mantyh C, Pappas TN, Takahashi T. Fecal pellet output does not always correlate with colonic transit in response to restraint stress and corticotropin-releasing factor in rats. J Gastroenterol 2007; 42:279-82. [PMID: 17464456 DOI: 10.1007/s00535-006-1947-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2006] [Accepted: 12/18/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Fecal pellet output has been assessed as a colonic motor activity because of its simplicity. However, it remains unclear whether an acceleration of colonic transit correlates well with an increase in fecal pellet output. We examined the causal relationship between colonic transit and fecal pellet output stimulated by the central application of corticotropin-releasing factor (CRF) and restraint stress. METHODS Immediately after intracisternal injection of CRF, (51)Cr was injected via a catheter positioned in the proximal colon. Ninety minutes after (51)Cr injection, the total number of excreted feces was counted, and then the rats were killed. The radioactivity of each colonic segment was evaluated, and the geometric center (GC) of the distribution of (51)Cr was calculated. For the restraint stress study, after administration of (51)Cr into the proximal colon, rats were submitted to wrapping restraint stress for 90 min. Then they were killed, and GC was calculated. RESULTS Both restraint stress and CRF significantly accelerated colonic transit. There was a positive correlation observed between fecal pellet output and GC of colonic transit in response to restraint stress, but not CRF, when the number of excreted feces was more than three. In contrast, there was no significant correlation observed between the two in stress and CRF when the number of excreted feces was less than two. CONCLUSIONS The acceleration of colonic transit in response to restraint stress and central administration of CRF does not always correlate with an increase in fecal pellet output.
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Affiliation(s)
- Yukiomi Nakade
- Department of Surgery, Duke University Medical Center and Durham Veterans Affairs Medical Center, Durham, NC, USA
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37
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Taché Y, Bonaz B. Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. J Clin Invest 2007; 117:33-40. [PMID: 17200704 PMCID: PMC1716215 DOI: 10.1172/jci30085] [Citation(s) in RCA: 266] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, corticotropin-releasing factor (CRF) signaling pathways have been shown to be the main coordinators of the endocrine, behavioral, and immune responses to stress. Emerging evidence also links the activation of CRF receptors type 1 and type 2 with stress-related alterations of gut motor function. Here, we review the role of CRF receptors in both the brain and the gut as part of key mechanisms through which various stressors impact propulsive activity of the gastrointestinal system. We also examine how these mechanisms translate into the development of new approaches for irritable bowel syndrome, a multifactorial disorder for which stress has been implicated in the pathophysiology.
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Affiliation(s)
- Yvette Taché
- CURE: Digestive Diseases Research Center, and Center for Neurovisceral Sciences & Women's Health, Department of Medicine, Division of Digestive Diseases, UCLA, Los Angeles, California 90073, USA.
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38
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Singewald N. Altered brain activity processing in high-anxiety rodents revealed by challenge paradigms and functional mapping. Neurosci Biobehav Rev 2007; 31:18-40. [PMID: 16620984 DOI: 10.1016/j.neubiorev.2006.02.003] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2005] [Revised: 02/10/2006] [Accepted: 02/15/2006] [Indexed: 12/21/2022]
Abstract
Pathological anxiety involves aberrant processing of emotional information that is hypothesized to reflect perturbations in fear/anxiety pathways. The affected neurobiological substrates in patients with different anxiety disorders are just beginning to be revealed. Important leads for this research can be derived from findings obtained in psychopathologically relevant rodent models of enhanced anxiety, by revealing where in the brain neuronal processing in response to diverse challenges is different to that in animals with lower anxiety levels. Different functional mapping methods in various rodent models, including psychogenetically selected lines or genetically modified animals, have been used for this purpose. These studies show that the divergent anxiety-related behavioral response of high-anxiety- vs. normal and/or low-anxiety rodents to emotional challenges is associated with differential neuronal activation in restricted parts of proposed fear/anxiety circuitries including brain areas thought to be important in stress, emotion and memory. The identification of neuronal populations showing differential activation depends in part on the applied emotional challenge, indicating that specific facets of elicited fear or anxiety preferentially engage particular parts of the fear/anxiety circuitry. Hence, only the use of an array of different challenges will reveal most affected brain areas. A number of the neuronal substrates identified are suggested as candidate mediators of dysfunctional brain activation in pathological anxiety. Indeed, key findings revealed in these rodent models show parallels to observations in human symptom provocation studies comparing anxiety disorder patients with healthy volunteers. Work to investigate exactly which of the changed neuronal activation patterns in high-anxiety rodents has to be modulated by therapeutic drugs to achieve effective anxiolysis and via which neurochemical pathways this can be accomplished is at its early stages but has identified a small number of promising candidates. Extending these approaches should help to provide further insight into these mechanisms, revealing new leads for therapeutic targets and strategies.
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Affiliation(s)
- Nicolas Singewald
- Department of Pharmacology & Toxicology, Institute of Pharmacy and Center of Molecular Biosciences, University of Innsbruck, A-6020 Innsbruck, Austria.
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39
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Iwa M, Nakade Y, Pappas TN, Takahashi T. Electroacupuncture elicits dual effects: stimulation of delayed gastric emptying and inhibition of accelerated colonic transit induced by restraint stress in rats. Dig Dis Sci 2006; 51:1493-500. [PMID: 16868821 DOI: 10.1007/s10620-006-9083-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2005] [Accepted: 10/07/2005] [Indexed: 12/11/2022]
Abstract
Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies have demonstrated that acupuncture antagonized various stress-induced responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced alteration of GI motor activities. Solid gastric emptying was significantly delayed by restraint stress (29.6+/-2.4%; n=7) compared to that of controls (60.0+/-2.5%; n=8). Delayed gastric emptying was significantly improved by EA at ST-36 (47.2+/-1.8%). Intracisternal (IC) injection of corticotropin releasing factor (CRF; 1 microg) delayed gastric emptying to 25.4+/-3.1%, which was also improved by EA at ST-36, to 53.0+/-7.1% (n=8). The stimulatory effect of EA on stress-induced delayed gastric emptying was abolished by atropine (17.6+/-1.9%) but not by guanethidine (42.2+/-2.3%). Colonic transit was significantly accelerated by restraint stress (GC=7.2+/-0.3; n=8) compared to that of controls (GC=5.2+/-0.2; n=8). Accelerated colonic transit was significantly reduced by EA at ST-36 (GC=4.9+/-0.3). IC injection of CRF accelerated colonic transit (GC=6.9+/-0.2), which was also normalized by EA at ST-36 (GC=4.7+/-0.2). The inhibitory effect of EA on stress-induced acceleration of colonic transit was not affected by guanethidine (GC=4.6+/-0.3). In conclusion, EA at ST-36 showed dual effects: stimulation of stress-induced delayed gastric emptying and inhibition of stress-induced acceleration of colonic transit. The stimulatory effect of EA on stress-induced delayed gastric emptying is mediated via cholinergic pathways. The inhibitory effect of EA on stress-induced acceleration of colonic transit is independent of the sympathetic pathway.
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Affiliation(s)
- Masahiro Iwa
- Department of Surgery, Duke University and Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, USA
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Trnecková L, Armario A, Hynie S, Sída P, Klenerová V. Differences in the brain expression of c-fos mRNA after restraint stress in Lewis compared to Sprague–Dawley rats. Brain Res 2006; 1077:7-15. [PMID: 16487948 DOI: 10.1016/j.brainres.2006.01.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2005] [Revised: 12/15/2005] [Accepted: 01/05/2006] [Indexed: 10/25/2022]
Abstract
In order to study the contribution of genetic factors to the pattern of stress-induced brain activation, we studied the expression of c-fos mRNA, a marker of neuronal activity, in male Sprague-Dawley and Lewis strains, the latter being known to have a deficient responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis. Immobilization (IMO) alone or combined with the immersion into water at 21 degrees C was applied for 15 or 60 min. The expression of c-fos mRNA was quantified by in situ hybridization in those brain areas that represent important parts of neuronal circuits activated by stress: medial prefrontal cortex, medial amygdala, lateral septum ventral part, paraventricular nucleus of the hypothalamus and locus coeruleus. While in controls, c-fos mRNA was not detectable in tested brain areas, both types of stressors induced a strong expression of this immediate early gene. There were only small differences in c-fos mRNA expression related to the type of stressor or the length of exposure to them. However, there were remarkable differences in the expression between the two rat strains. When compared to Sprague-Dawley rats, Lewis rats showed a reduced c-fos mRNA expression after both stressors in most brain areas, which may be related to the reduced responsiveness of HPA axis and also with other abnormal responses in this strain. However, this hyporesponsiveness was not observed in all brain areas studied, suggesting that there is not a generalized defective c-fos response to stress in Lewis rats and that some responses to stress may be normal in this strain.
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Affiliation(s)
- Lenka Trnecková
- Laboratory of Biochemical Neuropharmacology, Charles University in Prague, First Faculty of Medicine, Institute of Medical Biochemistry, Albertov 4, 128 00 Prague 2, Czech Republic
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Bradesi S, Schwetz I, Ennes HS, Lamy CMR, Ohning G, Fanselow M, Pothoulakis C, McRoberts JA, Mayer EA. Repeated exposure to water avoidance stress in rats: a new model for sustained visceral hyperalgesia. Am J Physiol Gastrointest Liver Physiol 2005; 289:G42-53. [PMID: 15746211 DOI: 10.1152/ajpgi.00500.2004] [Citation(s) in RCA: 226] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic stress plays an important role in the development and exacerbation of symptoms in functional gastrointestinal disorders. To better understand the mechanisms underlying this relationship, we aimed to characterize changes in visceral and somatic nociception, colonic motility, anxiety-related behavior, and mucosal immune activation in rats exposed to 10 days of chronic psychological stress. Male Wistar rats were submitted daily to either 1-h water avoidance (WA) stress or sham WA for 10 consecutive days. The visceromotor response to colorectal distension, thermal somatic nociception, and behavioral responses to an open field test were measured at baseline and after chronic WA. Fecal pellets were counted after each WA stress or sham WA session as a measure of stress-induced colonic motility. Colonic samples were collected from both groups and evaluated for structural changes and neutrophil infiltration, mast cell number by immunohistochemistry, and cytokine expression by quantitative RT-PCR. Rats exposed to chronic WA (but not sham stress) developed persistent visceral hyperalgesia, whereas only transient changes in somatic nociception were observed. Chronically stressed rats also exhibited anxiety-like behaviors, enhanced fecal pellet excretion, and small but significant increases in the mast cell numbers and the expression of IL-1beta and IFN-gamma. Visceral hyperalgesia following chronic stress persisted for at least a month. Chronic psychological stress in rats results in a robust and long-lasting alteration of visceral, but not somatic nociception. Visceral hyperalgesia is associated with other behavioral manifestations of stress sensitization but was only associated with minor colonic immune activation arguing against a primary role of mucosal immune activation in the maintenance of this phenomenon.
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Affiliation(s)
- Sylvie Bradesi
- Department of Medicine, Center for Neurovisceral Sciences and Women's Health, David Geffen School of Medicine at University of California, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, USA
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Million M, Maillot C, Adelson DA, Nozu T, Gauthier A, Rivier J, Chrousos GP, Bayati A, Mattsson H, Taché Y. Peripheral injection of sauvagine prevents repeated colorectal distension-induced visceral pain in female rats. Peptides 2005; 26:1188-95. [PMID: 15949637 DOI: 10.1016/j.peptides.2005.02.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2004] [Revised: 01/31/2005] [Accepted: 02/01/2005] [Indexed: 01/26/2023]
Abstract
We investigated the effects of peripheral injection of sauvagine, a CRF2>CRF1 receptor (corticotropin-releasing factor) agonist compared with CRF, on two sets of tonic colorectal distension (CRDs 30, 40, 50 mmHg, 3-min on/off)-induced visceromotor response (VMR) measured as area under the curve (AUC) of abdominal muscle contraction in conscious female rats. Sauvagine (10 or 20 microg/kg, s.c.) abolished the 226.7+/-64.3% and 90.4+/-38.1% increase in AUC to the 2nd CRD compared with the 1st CRD (performed 30 min before) in female Fisher and Sprague-Dawley (SD) rats, respectively. CRF had no effect while the CRF1 antagonist, antalarmin (20 mg/kg, s.c.), alone or with sauvagine, blocked the enhanced response to the 2nd CRD, performed 60 min after the 1st CRD, and reduced further the AUC by 33.5+/-23.3% and 63.5+/-7.2%, respectively in Fisher rats. These data suggest that peripheral CRF2 receptor activation exerts antinociceptive effects on CRD-induced visceral pain, whereas CRF1 contributes to visceral sensitization.
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Affiliation(s)
- Mulugeta Million
- Center for Neurovisceral Sciences and Women's Health, Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
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Abstract
To examine processes underlying generational and developmental influences on anxiety, this laboratory produced two lines of (N:NIH strain) rats, selectively bred on the basis extreme rates of ultrasonic vocalization in 2 minutes of isolation at Postnatal Day 10. The research reviewed in this article focuses on: (1) establishment of the selectively bred lines; (2) defining infant behavioral and physiological phenotypes and (3) determining whether infantile USV phenotypes endure over development. The High and Low lines have diverged widely in their USV rates from each other and from the Random control line, which has maintained N:NIH strain rates overall from generation to generation. Beginning in the 11th generation, High USV pups have shown significantly higher frequencies of defecation and urination during isolation screening than the Low USV and random control line. Both lines show altered autonomic regulation of heart rates (HR) in response to stressors as juveniles and adults. These differences in HR responses in High and Low lines appear to be mediated by changes in the balance of sympathetic versus parasympathetic mechanisms. Other behavioral characteristics of the High line are consistent with an "anxious"/ "depressive" phenotype, such as vocalizations to touch in a novel environment, and performance in the Porsolt Swim, whereas Low line shows few differences in anxiety behavior. Future work will resolve the similarities and differences in the High and Low phenotypes and provide a developmental perspective to the growing body of information about affective regulation in humans and animals provided by selectively bred animal models.
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Affiliation(s)
- Susan A Brunelli
- Developmental Psychobiology, New York State Psychiatric Institute and Columbia College of Physicians and Surgeons, New York, NY 10032, USA.
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Taché Y, Martinez V, Wang L, Million M. CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome. Br J Pharmacol 2004; 141:1321-30. [PMID: 15100165 PMCID: PMC1574904 DOI: 10.1038/sj.bjp.0705760] [Citation(s) in RCA: 174] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2004] [Accepted: 02/25/2004] [Indexed: 12/11/2022] Open
Abstract
1. The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF(1)) and 2 (CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF(1) receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors. 2. Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. 3. Nonselective CRF(1)/CRF(2) antagonists and selective CRF(1) antagonists inhibit exogenous (central or peripheral) CRF- and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF(2) antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals. 4. These findings implicate CRF(1) receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF(1)-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.
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Affiliation(s)
- Y Taché
- CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, University of California-Los Angeles, 1130 Wilshire Boulevard, Los Angeles, CA 90073, U.S.A.
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Wei R, Sternberg EM. IL-1β-mediated neuropeptide and immediate early gene mRNA induction is defective in Lewis hypothalamic cell cultures. J Neuroimmunol 2004; 146:114-25. [PMID: 14698853 DOI: 10.1016/j.jneuroim.2003.10.050] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
We previously found that Lewis (LEW/N) hypothalamic cells respond to interleukin-1beta (IL-1beta) with reduced corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) peptide synthesis and secretion compared to Fischer (F344/N) cells. To investigate whether this peptide hyporesponsiveness in LEW/N cells is secondary to their deficient mRNA expression, temporal mRNA expression patterns of CRH, AVP, and several hypothalamic neuropeptides induced by IL-1beta in LEW/N and F344/N hypothalamic dissociated cell cultures were delineated by quantitative real-time polymerase chain reaction (RT-PCR). To investigate the molecular mechanisms underlying neuropeptide mRNA induction in cells of both strains, temporal mRNA expression patterns of immediate early genes (IEGs) and several signal transduction-associated molecules were also examined. We found that LEW/N hypothalamic cells were hyporesponsive to IL-1beta induction of neuropeptide and IEG mRNA, while LEW/N cells transcribed more IL-1 receptor and inducible nitric oxide synthase (iNOS) compared to F344N/N cells, suggesting that LEW/N and F344/N hypothalamic cells are differentially activated by IL-1beta.
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Affiliation(s)
- Rongtai Wei
- Integrative Neural Immune Program, NIMH, NIH, 36 Convent Drive, Building 36, Room 1A23, Bethesda, MD 20892-4020, USA
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Contoreggi C, Rice KC, Chrousos G. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders. Neuroendocrinology 2004; 80:111-23. [PMID: 15523186 DOI: 10.1159/000081785] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2003] [Accepted: 07/23/2004] [Indexed: 11/19/2022]
Abstract
Overproduction of corticotropin-releasing hormone (CRH) and stress system abnormalities are seen in psychiatric diseases such as depression, anxiety, eating disorders, and addiction. Investigations of CRH type 1 receptor (CRHR1) nonpeptide antagonists suggest therapeutic potential for treatment of these and other neuropsychiatric diseases. However, overproduction of CRH in the brain and on its periphery and disruption of the hypothalamic-pituitary-adrenal axis are also found in 'somatic' disorders. Some rare forms of Cushing's disease and related pituitary/adrenal disorders are obvious applications for CRHR1 antagonists. In addition, however, these antagonists may also be effective in treating more common somatic diseases. Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists. Hormonal, autonomic, and immune aberrations are also present in chronic inflammatory, autoimmune, and allergic diseases, with considerable evidence linking CRH with the observed abnormalities. Furthermore, autonomic dysregulation is a prominent feature of common gastrointestinal disorders, such as irritable bowel syndrome and peptic ulcer disease. Patients with irritable bowel syndrome and other gastrointestinal disorders frequently develop altered pain perception and affective symptoms. CRH acts peripherally to modulate bowel activity both directly through the autonomic system and centrally by processing viscerosensory and visceromotor neural signals. This review presents clinical and preclinical evidence for the role of CRH in the pathophysiology of these disorders and for potential diagnostic and therapeutic applications of CRHR1 antagonists. Recognition of a dysfunctional stress system in these and other diseases will alter the understanding and treatment of 'psychosomatic' disorders.
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Affiliation(s)
- Carlo Contoreggi
- National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.
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Million M, Grigoriadis DE, Sullivan S, Crowe PD, McRoberts JA, Zhou H, Saunders PR, Maillot C, Mayer EA, Taché Y. A novel water-soluble selective CRF1 receptor antagonist, NBI 35965, blunts stress-induced visceral hyperalgesia and colonic motor function in rats. Brain Res 2003; 985:32-42. [PMID: 12957366 DOI: 10.1016/s0006-8993(03)03027-0] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The stress response involves the activation of two corticotropin-releasing factor (CRF) receptor subtypes. We investigated the role of CRF1 in stress-related visceral responses. A novel water-soluble tricyclic CRF1 antagonist, NBI 35965 was developed that displayed a high affinity for CRF1 (Ki approximately 4 nM) while having no binding affinity to CRF2. This antagonist also inhibited the stimulation of cAMP induced by sauvagine in CRF1 transfected cells. NBI 35965 administered per orally (p.o.) in rats (1, 3, 10 or 30 mg/kg) inhibited dose-dependently [125I]sauvagine binding selectively at brain sites of CRF1 distribution as shown by ex vivo receptor autoradiography. At the highest doses, NBI 35965 completely prevented [125I]sauvagine labeling in the cortex. NBI 35965 (10 mg/kg) administered p.o. or subcutaneously (s.c.) 1 h before intravenous CRF completely blocked the 81% shortening of distal colonic transit time induced by CRF. NBI 35965 (20 mg/kg s.c.) significantly reduced the defecation in response to water avoidance stress but not that induced by s.c. carbachol. In adult male Long-Evans rats that had undergone maternal separation, acute water avoidance stress significantly increased the visceromotor response to colorectal distention (20-80 mmHg) by 42+/-19% compared with the response before stress. Stress-induced visceral hyperalgesia was abolished by NBI 35965 (20 mg/kg, s.c.). The data show that NBI 35965 is a novel water-soluble selective CRF1 antagonist with bioavailability to the brain upon peripheral administration and that CRF1 receptor signaling pathways are involved in water avoidance stress-induced hyperalgesia to colorectal distention and stimulation of colonic transit.
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Affiliation(s)
- Mulugeta Million
- CURE/Digestive Diseases Research Center and Center for Neurovisceral Sciences and Women's Health (CNS), West Los Angeles VA Medical Center, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90073, USA.
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Kreis ME, Mueller MH, Reber D, Glatzle J, Enck P, Grundy D. Stress-induced attenuation of brain stem activation following intestinal anaphylaxis in the rat. Neurosci Lett 2003; 345:187-91. [PMID: 12842287 DOI: 10.1016/s0304-3940(03)00519-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Intestinal anaphylaxis triggers neuronal activation in the nucleus tractus solitarius (nTS) of the rat brain stem. Stress may modulate reflex circuitry in the brain stem and facilitate intestinal inflammatory responses. We hypothesized that stress would modulate central neuronal activation during intestinal anaphylaxis. NTS neurons were activated following intestinal antigen challenge in sensitized Hooded Lister rats but not in negative controls (P < 0.05). The number of Fos-positive neurons following intestinal anaphylaxis decreased in animals exposed to water-avoidance stress (P < 0.05), although serum levels of rat mast cell protease II were not different in stressed and unstressed animals, indicating a similar degree of mast cell degranulation. Stress seems to inhibit neuronal activation in the rat brain stem during intestinal inflammation without modulation of the inflammatory response itself. This may have implications for a potential efferent neuronal modulation of inflammatory responses in the gut.
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Affiliation(s)
- M E Kreis
- Universität Tübingen, Klinik für Allgemeine Chirurgie, Waldhörnlestrasse 22, D-72072 Tübingen, Germany.
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Maillot C, Wang L, Million M, Taché Y. Intraperitoneal corticotropin-releasing factor and urocortin induce Fos expression in brain and spinal autonomic nuclei and long lasting stimulation of colonic motility in rats. Brain Res 2003; 974:70-81. [PMID: 12742625 DOI: 10.1016/s0006-8993(03)02553-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
CRF injected intraperitoneally (i.p.) stimulates colonic motor function and induces Fos expression in colonic myenteric neurons. We investigated central and spinal Fos expression and changes in colonic motility in response to i.p. injection of CRF and urocortin. Ovine CRF(9-33) that is devoid of intrinsic activity at the CRF receptors, was used as control peptide. Myoelectrical activity was monitored for 1 h before and after peptide injection (10 microg/kg, i.p.) in conscious non fasted rats with chronically implanted intraparietal electrodes in the cecum and proximal colon. Brain and lumbosacral spinal cord were processed for Fos immunohistochemistry at 1 h postinjection. CRF and urocortin elicited defecation and a new pattern of ceco-colonic clustered spike bursts that peaked within 15 min and lasted for the 1 h experimental period while CRF(9-33) did not modify baseline myoelectrical activity and defecation. CRF increased significantly Fos expression in the central nucleus of the amygdala (lateral part), parabrachial nucleus (external lateral subnucleus), area postrema, nucleus tractus solitarius, locus coeruleus, paraventricular nucleus of the hypothalamus, the intermediolateral column and area I-VII, X at the L6-S1 level of the spinal cord by 11-, 6.5-, 5.3-, 5.0-, 4.7-, 2.7- and 1.4-fold, respectively compared with i.p. CRF(9-33) injected rats that had little Fos expression. Urocortin induced a similar pattern of Fos response in the brain and the spinal cord. These results indicate that i.p. CRF and urocortin induce a peptide specific activation of brain nuclei receiving viscerosensory inputs and involved in autonomic circuitries whose effector limbs may impact on visceral function.
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Affiliation(s)
- Céline Maillot
- Digestive Diseases Research Center, Department of Medicine, Digestive Diseases Division, Los Angeles, CA, USA
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Frankel PS, Cunningham KA. The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain. Brain Res 2002; 958:251-60. [PMID: 12470860 DOI: 10.1016/s0006-8993(02)03548-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (P<0.05) in the number of c-Fos-positive cells detected in the anterior cingulate cortex at 1 h, the shell of the nucleus accumbens at 1 and 2 h, the bed nucleus of stria terminalis lateral at 2 h and the paraventricular hypothalamic nucleus at 1, 2 and 4 h following systemic d-LSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD.
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Affiliation(s)
- Paul S Frankel
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-1031, USA.
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