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Noor-Mohammadi E, Yuan T, Ligon CO, Ammar RM, Rabini S, Johnson AC, Greenwood-Van Meerveld B. Anti-nociceptive effect of STW 5-II in rodent models of stress and post-inflammatory visceral hypersensitivity. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156167. [PMID: 39454377 DOI: 10.1016/j.phymed.2024.156167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 08/06/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024]
Abstract
AIMS Visceral hypersensitivity is a therapy-resistant hallmark of irritable bowel syndrome (IBS). Many IBS patients' symptoms develop following an acute colitis, and most report that stress worsens symptoms. STW 5-II, a combination of six herbal extracts, is a clinically proven treatment for IBS, but the mechanism is uncertain. Here, we employ two well-characterized rodent models to test the hypothesis that STW 5-II attenuates chronic colonic hypersensitivity. MAIN METHODS Separate cohorts of male rats were used for each model of colonic hypersensitivity. The first model used repeated water avoidance stress (1hr/day for 10 days), while the second model used intracolonic trinitrobenzene sulfonic acid to induce a short-lived colitis followed by post-inflammatory visceral hypersensitivity. Both models used sham treatment controls. Colonic sensitivity was quantified as the number of abdominal contractions to graded pressures (20-60 mmHg) of isobaric colorectal distension (CRD). Phosphorylation of extracellular signal-regulated kinase (pERK) was assessed via immunohistochemistry in the brain, spinal cord, and dorsal root ganglion (DRG). STW 5-II (10 ml/kg, p.o.) or vehicle (p.o.) was administered for 7 days, prior to CRD and pERK expression. KEY FINDINGS Rats exposed to either model developed significant colonic hypersensitivity. Both models enhanced CRD-evoked pERK in DRGs, spinal cord, and brain. STW 5-II decreased colonic hypersensitivity and reduced CRD-evoked brain, spinal, and DRG pERK. SIGNIFICANCE Both models induced colonic hypersensitivity and enhanced pERK expression. STW 5-II inhibited colonic hypersensitivity and decreased noxious neuronal activation in both models, which could explain its clinically proven efficacy in relieving visceral hypersensitivity-related symptoms in IBS.
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Affiliation(s)
- Ehsan Noor-Mohammadi
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
| | - Tian Yuan
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Casey O Ligon
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Ramy M Ammar
- Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Havelstraße 5, 64295 Darmstadt, Germany; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafr-El Sheikh 33516, Egypt
| | - Sabine Rabini
- Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Havelstraße 5, 64295 Darmstadt, Germany
| | - Anthony C Johnson
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Murray GM, Sessle BJ. Pain-sensorimotor interactions: New perspectives and a new model. NEUROBIOLOGY OF PAIN (CAMBRIDGE, MASS.) 2024; 15:100150. [PMID: 38327725 PMCID: PMC10847382 DOI: 10.1016/j.ynpai.2024.100150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 11/25/2023] [Accepted: 01/19/2024] [Indexed: 02/09/2024]
Abstract
How pain and sensorimotor behavior interact has been the subject of research and debate for many decades. This article reviews theories bearing on pain-sensorimotor interactions and considers their strengths and limitations in the light of findings from experimental and clinical studies of pain-sensorimotor interactions in the spinal and craniofacial sensorimotor systems. A strength of recent theories is that they have incorporated concepts and features missing from earlier theories to account for the role of the sensory-discriminative, motivational-affective, and cognitive-evaluative dimensions of pain in pain-sensorimotor interactions. Findings acquired since the formulation of these recent theories indicate that additional features need to be considered to provide a more comprehensive conceptualization of pain-sensorimotor interactions. These features include biopsychosocial influences that range from biological factors such as genetics and epigenetics to psychological factors and social factors encompassing environmental and cultural influences. Also needing consideration is a mechanistic framework that includes other biological factors reflecting nociceptive processes and glioplastic and neuroplastic changes in sensorimotor and related brain and spinal cord circuits in acute or chronic pain conditions. The literature reviewed and the limitations of previous theories bearing on pain-sensorimotor interactions have led us to provide new perspectives on these interactions, and this has prompted our development of a new concept, the Theory of Pain-Sensorimotor Interactions (TOPSMI) that we suggest gives a more comprehensive framework to consider the interactions and their complexity. This theory states that pain is associated with plastic changes in the central nervous system (CNS) that lead to an activation pattern of motor units that contributes to the individual's adaptive sensorimotor behavior. This activation pattern takes account of the biological, psychological, and social influences on the musculoskeletal tissues involved in sensorimotor behavior and on the plastic changes and the experience of pain in that individual. The pattern is normally optimized in terms of biomechanical advantage and metabolic cost related to the features of the individual's musculoskeletal tissues and aims to minimize pain and any associated sensorimotor changes, and thereby maintain homeostasis. However, adverse biopsychosocial factors and their interactions may result in plastic CNS changes leading to less optimal, even maladaptive, sensorimotor changes producing motor unit activation patterns associated with the development of further pain. This more comprehensive theory points towards customized treatment strategies, in line with the management approaches to pain proposed in the biopsychosocial model of pain.
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Affiliation(s)
- Greg M. Murray
- Discipline of Restorative and Reconstructive Dentistry, Sydney School of Dentistry, Faculty of Medicine and Health, The University of Sydney, Darcy Road, Westmead, NSW 2145, Australia
| | - Barry J. Sessle
- Faculty of Dentistry and Temerty Faculty of Medicine Department of Physiology, and Centre for the Study of Pain, University of Toronto, 124 Edward St, Toronto, ON M5G 1G6, Canada
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Fujikawa Y, Tominaga K. Enhanced neuron-glia network in the submucosa and increased neuron outgrowth into the mucosa are associated with distinctive expressions of neuronal factors in the colon of rat IBS model. Neurogastroenterol Motil 2023; 35:e14595. [PMID: 37170695 DOI: 10.1111/nmo.14595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 01/16/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023]
Abstract
BACKGROUND Neuronal attraction and repulsion factors regulate neuron network formation. In the colon of irritable bowel syndrome (IBS), neuron network and enteric glial cells (EGCs) in the submucosa, neuronal outgrowth in the mucosa, and expressions of neuronal factors remain unknown. METHODS IBS models were prepared by intracolonic injections of acetic acid to Wistar Kyoto (WKY) rats. Using whole-mount submucosal plexus tissue stripped from the distal colon, we examined neuron network, EGC morphology, and localization of both attraction factor (nerve growth factor: NGF) and repulsion factor (semaphorin3A: Sema3A). We evaluated mRNA expressions of NGF and Sema3A in the mucosa and submucosa and neuron outgrowth into the mucosa. KEY RESULTS In IBS models, nerve fibers were thickened and densely increased in the submucosa remarkably from the outer toward the inner plexus. Submucosal EGCs exhibited process hyperplasia and bulbous swelling of terminals. NGF was predominantly expressed in EGCs than neurons in the submucosa. NGF mRNA expressions were increased in the submucosa in WKY, and their expressions were increased in the mucosa after the injection. Sema3A mRNA expressions were increased in both layers of WKY but tended to be decreased in the mucosa alone after the injection. Neuron outgrowth was increased into the mucosa. NGF was localized at EGCs in the lamina propria mucosae but not mucosal mast cells. CONCLUSIONS & INFERENCES Neuron network enhancement in the submucosa and neuron outgrowth into the mucosa may be associated with axon guidance factors expressed in hyperplastic EGCs in the colonic submucosa of IBS models.
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Redei EE, Udell ME, Solberg Woods LC, Chen H. The Wistar Kyoto Rat: A Model of Depression Traits. Curr Neuropharmacol 2023; 21:1884-1905. [PMID: 36453495 PMCID: PMC10514523 DOI: 10.2174/1570159x21666221129120902] [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: 08/04/2022] [Revised: 09/19/2022] [Accepted: 10/21/2022] [Indexed: 12/05/2022] Open
Abstract
There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair- like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may share characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.
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Affiliation(s)
- Eva E. Redei
- Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Mallory E. Udell
- Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Leah C. Solberg Woods
- Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Hao Chen
- Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center, Memphis, TN, USA
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Jiang Y, Wang Y, Wang M, Lin L, Tang Y. Clinical significance and related factors of rectal hyposensitivity in patients with functional defecation disorder. Front Med (Lausanne) 2023; 10:1119617. [PMID: 36895717 PMCID: PMC9988933 DOI: 10.3389/fmed.2023.1119617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/26/2023] [Indexed: 02/23/2023] Open
Abstract
Background Rectal hyposensitivity (RH) is not uncommon in patients with functional defecation disorder (FDD). FDD patients with RH are usually unsatisfied with their treatment. Aims The aim of this study was to find the significance of RH in patients with FDD and the related factors of RH. Methods Patients with FDD first completed clinical questionnaires regarding constipation symptoms, mental state, and quality of life. Then anorectal physiologic tests (anorectal manometry and balloon expulsion test) were performed. Rectal sensory testing (assessing rectal response to balloon distension using anorectal manometry) was applied to obtain three sensory thresholds. Patients were separated into three groups (non-RH, borderline RH, and RH) based on the London Classification. The associations between RH and clinical symptoms, mental state, quality of life, and rectal/anal motility were investigated. Results Of 331 included patients with FDD, 87 patients (26.3%) had at least one abnormally elevated rectal sensory threshold and 50 patients (15.1%) were diagnosed with RH. Patients with RH were older and mostly men. Defecation symptoms were more severe (p = 0.013), and hard stool (p < 0.001) and manual maneuver (p = 0.003) were more frequently seen in the RH group. No difference in rectal/anal pressure was found among the three groups. Elevated defecatory desire volume (DDV) existed in all patients with RH. With the number of elevated sensory thresholds increasing, defecation symptoms got more severe (r = 0.35, p = 0.001). Gender (male) (6.78 [3.07-15.00], p < 0.001) and hard stool (5.92 [2.28-15.33], p < 0.001) were main related factors of RH. Conclusion Rectal hyposensitivity plays an important role in the occurrence of FDD and is associated with defecation symptom severity. Older male FDD patients with hard stool are prone to suffer from RH and need more care.
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Affiliation(s)
- Ya Jiang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Wang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Meifeng Wang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lin Lin
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yurong Tang
- Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
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Wang T, Li J, Jia Y, Zhao J, He M, Bai G. Tandem Mass Tag Analysis of the Effect of the Anterior Cingulate Cortex in Nonerosive Reflux Disease Rats with Shugan Jiangni Hewei Granules Treatment. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8104337. [PMID: 35941898 PMCID: PMC9356813 DOI: 10.1155/2022/8104337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022]
Abstract
Objective The current study aims to analyze the improvement mechanism of visceral hypersensitivity (VH) and targets of Shugan Jiangni Hewei granules (SJHG) for nonerosive reflux disease (NERD) treatment as well as to offer an experimental foundation for its clinical use. Methods Healthy male Sprague-Dawley rats (n = 36) were acquired in the current study that was further split into three groups: blank, model, and drug (SJHG). Subsequently, differentially expressed proteins and bioinformatics analysis were performed on the collected tissue samples acquired from the anterior cingulate cortex of the model and SJHG rat groups using a tandem mass tag- (TMT-) based proteomics. Eventually, the obtained data from the bioinformatic analysis was further verified through western blotting. Results From the bioinformatics analysis, only 64 proteins were differentially expressed between the NC and SJHG groups. These molecules were found to be highly expressed in immunological response and neural signal transmission. Finally, we confirmed three therapeutic targets of SJHG, namely, kininogen 1 (Kng1), junctional adhesion molecule A (JAM-A), and the PI3K/Akt signaling pathway. Conclusions SJHG is effective in treating VH, Kng1 and JAM-A may be therapeutic targets of SJHG, and the therapeutic mechanism of SJHG may be realized by influencing immune response or transmission of neural signals.
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Affiliation(s)
- Tianzuo Wang
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Jing Li
- Department of Gastroenterology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110033, China
| | - Yuebo Jia
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Jiaqi Zhao
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Meijun He
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110847, China
| | - Guang Bai
- Department of Gastroenterology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110033, China
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Ameliorative Effects of Humulus japonicus Extract and Polysaccharide-Rich Extract of Phragmites rhizoma in Rats with Gastrointestinal Dysfunctions Induced by Water Avoidance Stress. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:9993743. [PMID: 35096122 PMCID: PMC8799342 DOI: 10.1155/2022/9993743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/10/2021] [Accepted: 12/15/2021] [Indexed: 12/16/2022]
Abstract
Chronic stress can cause the gastrointestinal disorders characterized by an altered bowel movement and abdominal pain. Studies have shown that Humulus japonicus extract (HJE) has anti-inflammatory and antidiarrheal effects, and Phragmites rhizoma extract (PEP) has antioxidative and antistress effects. The present study aimed to investigate the possible effects of HJE and PEP in rat models with stress-induced gastrointestinal dysfunctions. The rats were exposed to water avoidance stress (WAS, 1 h/day) for 10 days to induce gastrointestinal disorders. We found that WAS significantly increased fecal pellet output during 1 h stress, gastric emptying, colonic contractility, and permeability compared to the normal rats. Pretreatment with HJE and PEP (0.25 and 0.5 mL/kg, both administered separately) improved the increased gastric emptying and colonic contractility induced by electrical field stimulation, acetylcholine, and serotonin and also alleviated the increased colonic permeability. HJE and PEP also increased the claudin-1 and occludin expressions, reduced by WAS. WAS increased the concentration of TNF-α and TBARS and reduced FRAP. HJE and PEP recovered these effects. HJE and PEP improved the gastrointestinal disorders induced by WAS by upregulating the tight junction protein, possibly acting on cholinergic and serotonergic receptors to abolish the colonic hypercontractility and hyperpermeability and degradation of inflammatory cytokines via an antioxidant effect.
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8
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Lv Y, Wen J, Fang Y, Zhang H, Zhang J. Corticotropin-releasing factor receptor 1 (CRF-R1) antagonists: Promising agents to prevent visceral hypersensitivity in irritable bowel syndrome. Peptides 2022; 147:170705. [PMID: 34822913 DOI: 10.1016/j.peptides.2021.170705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022]
Abstract
Corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that coordinates the endocrine system, autonomic nervous system, immune system, and physiological behavior. CRF is a signaling regulator in the neuro-endocrine-immune (NEI) network that mediates visceral hypersensitivity. Rodent models to simulate changes in intestinal motility similar to those reported in the irritable bowel syndrome (IBS), demonstrate that the CRF receptor 1 (CRF-R1) mediates intestinal hypersensitivity under many conditions. However, the translation of preclinical studies into clinical trials has not been successful possibly due to the lack of sufficient understanding of the multiple variants of CRF-R1 and CRF-R1 antagonists. Investigating the sites of action of central and peripheral CRF is critical for accelerating the translation from preclinical to clinical studies.
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Affiliation(s)
- Yuanxia Lv
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Jing Wen
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Yingying Fang
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
| | - Haoyuan Zhang
- Department of Clinical Medicine, North Sichuan Medical College, Nanchong City, China.
| | - Jianwu Zhang
- School of Pharmacy, North Sichuan Medical College, Nanchong City, China.
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9
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Wu PY, Menta B, Visk A, Ryals JM, Christianson JA, Wright DE, Chadwick AL. The impact of foot shock-induced stress on pain-related behavior associated with burn injury. Burns 2021; 47:1896-1907. [PMID: 33958242 PMCID: PMC8526636 DOI: 10.1016/j.burns.2021.04.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 04/05/2021] [Accepted: 04/12/2021] [Indexed: 11/21/2022]
Abstract
Acute pain is prevalent following burn injury and can often transition to chronic pain. Prolonged acute pain is an important risk factor for chronic pain and there is little preclinical research to address this problem. Using a mouse model of second-degree burn, we investigated whether pre-existing stress influences pain(sensitivity) after a burn injury. We introduced a contribution of stress in two different ways: (1) the use of foot-shock as a pre-injury stressor or (2) the use of A/J mice to represent higher pre-existing stress compared to C57Bl/6 mice. C57Bl/6 and A/J mice were exposed to repeated mild foot shock to induce stress for 10 continuous days and mice underwent either burn injury or sham burn injury of the plantar surface of the right hind paw. Assessments of mechanical and thermal sensitivities of the injured and uninjured paw were conducted during the shock protocol and at intervals up to 82-day post-burn injury. In both strains of mice that underwent burn injury, thermal hypersensitivity and mechanical allodynia appeared rapidly in the ipsilateral paw. Mice that were stressed took much longer to recover their hind paw mechanical thresholds to baseline compared to non-stressed mice in both burn and non-burn groups. Analysis of the two mouse strains revealed that the recovery of mechanical thresholds in A/J mice which display higher levels of baseline anxiety was shorter than C57Bl/6 mice. No differences were observed regarding thermal sensitivities between strains. Our results support the view that stress exposure prior to burn injury affects mechanical and thermal thresholds and may be relevant to as a risk factor for the transition from acute to chronic pain. Finally, genetic differences may play a key role in modality-specific recovery following burn injury.
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Affiliation(s)
- Pau Yen Wu
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Blaise Menta
- Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Alexander Visk
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Janelle M Ryals
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Julie A Christianson
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Douglas E Wright
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA; Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
| | - Andrea L Chadwick
- Department of Anesthesiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Hyporesponsivity to mu-opioid receptor agonism in the Wistar-Kyoto rat model of altered nociceptive responding associated with negative affective state. Pain 2021; 162:405-420. [PMID: 32826755 DOI: 10.1097/j.pain.0000000000002039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 08/03/2020] [Indexed: 11/25/2022]
Abstract
ABSTRACT Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon are poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared with Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared with SD counterparts. Equivalent plasma morphine levels in the 2 rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal gray (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of the vlPAG, namely, the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in the MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.
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11
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Okumura T, Ishioh M, Nozu T. Central regulatory mechanisms of visceral sensation in response to colonic distension with special reference to brain orexin. Neuropeptides 2021; 86:102129. [PMID: 33636498 DOI: 10.1016/j.npep.2021.102129] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/08/2021] [Accepted: 02/09/2021] [Indexed: 01/22/2023]
Abstract
Visceral hypersensitivity is a major pathophysiology in irritable bowel syndrome (IBS). Although brain-gut interaction is considered to be involved in the regulation of visceral sensation, little had been known how brain controls visceral sensation. To improve therapeutic strategy in IBS, we should develop a novel approach to control visceral hypersensitivity. Here, we summarized recent data on central control of visceral sensation by neuropeptides in rats. Orexin, ghrelin or oxytocin in the brain is capable of inducing visceral antinociception. Dopamine, cannabinoid, adenosine, serotonin or opioid in the central nervous system (CNS) plays a role in the visceral hyposensitivity. Central ghrelin, levodopa or morphine could induce visceral antinociception via the orexinergic signaling. Orexin induces visceral antinociception through dopamine, cannabinoid, adenosine or oxytocin. Orexin nerve fibers are identified widely throughout the CNS and orexins are implicated in a number of functions. With regard to gastrointestinal functions, in addition to its visceral antinociception, orexin acts centrally to stimulate gastrointestinal motility and improve intestinal barrier function. Brain orexin is also involved in regulation of sleep/awake cycle and anti-depressive action. From these evidence, we would like to make a hypothesis that decreased orexin signaling in the brain may play a role in the pathophysiology in a part of patients with IBS who are frequently accompanied with sleep disturbance, depressive state and disturbed gut functions such as gut motility disturbance, leaky gut and visceral hypersensitivity.
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Affiliation(s)
- Toshikatsu Okumura
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan.
| | - Masatomo Ishioh
- Division of Metabolism, Biosystemic Science, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
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12
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Bravo L, Llorca-Torralba M, Suárez-Pereira I, Berrocoso E. Pain in neuropsychiatry: Insights from animal models. Neurosci Biobehav Rev 2020; 115:96-115. [PMID: 32437745 DOI: 10.1016/j.neubiorev.2020.04.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 04/11/2020] [Accepted: 04/23/2020] [Indexed: 02/08/2023]
Abstract
Pain is the most common symptom reported in clinical practice, meaning that it is associated with many pathologies as either the origin or a consequence of other illnesses. Furthermore, pain is a complex emotional and sensorial experience, as the correspondence between pain and body damage varies considerably. While these issues are widely acknowledged in clinical pain research, until recently they have not been extensively considered when exploring animal models, important tools for understanding pain pathophysiology. Interestingly, chronic pain is currently considered a risk factor to suffer psychiatric disorders, mainly stress-related disorders like anxiety and depression. Conversely, pain appears to be altered in many psychiatric disorders, such as depression, anxiety and schizophrenia. Thus, pain and psychiatric disorders have been linked in epidemiological and clinical terms, although the neurobiological mechanisms involved in this pathological bidirectional relationship remain unclear. Here we review the evidence obtained from animal models about the co-morbidity of pain and psychiatric disorders, placing special emphasis on the different dimensions of pain.
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Affiliation(s)
- Lidia Bravo
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Meritxell Llorca-Torralba
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Suárez-Pereira
- Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003 Cádiz, Spain; Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Esther Berrocoso
- Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya 21, 11009 Cádiz, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; Neuropsychopharmacology and Psychobiology Research Group, Department of Psychology, University of Cádiz, 11510 Puerto Real, Cádiz, Spain.
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13
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Gondré-Lewis MC, Bassey R, Blum K. Pre-clinical models of reward deficiency syndrome: A behavioral octopus. Neurosci Biobehav Rev 2020; 115:164-188. [PMID: 32360413 DOI: 10.1016/j.neubiorev.2020.04.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/08/2020] [Accepted: 04/20/2020] [Indexed: 12/15/2022]
Abstract
Individuals with mood disorders or with addiction, impulsivity and some personality disorders can share in common a dysfunction in how the brain perceives reward, where processing of natural endorphins or the response to exogenous dopamine stimulants is impaired. Reward Deficiency Syndrome (RDS) is a polygenic trait with implications that suggest cross-talk between different neurological systems that include the known reward pathway, neuroendocrine systems, and motivational systems. In this review we evaluate well-characterized animal models for their construct validity and as potential models for RDS. Animal models used to study substance use disorder, major depressive disorder (MDD), early life stress, immune dysregulation, attention deficit hyperactivity disorder (ADHD), post traumatic stress disorder (PTSD), compulsive gambling and compulsive eating disorders are discussed. These disorders recruit underlying reward deficiency mechanisms in multiple brain centers. Because of the widespread and remarkable array of associated/overlapping behavioral manifestations with a common root of hypodopaminergia, the basic endophenotype recognized as RDS is indeed likened to a behavioral octopus. We conclude this review with a look ahead on how these models can be used to investigate potential therapeutics that target the underlying common deficiency.
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Affiliation(s)
- Marjorie C Gondré-Lewis
- Department of Anatomy, Howard University College of Medicine, 520 W Street, NW, Washington D.C., 20059, United States; Developmental Neuropsychopharmacology Laboratory, Howard University College of Medicine, 520 W Street, NW, Washington D.C., 20059, United States.
| | - Rosemary Bassey
- Developmental Neuropsychopharmacology Laboratory, Howard University College of Medicine, 520 W Street, NW, Washington D.C., 20059, United States; Department of Science Education, Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, 500 Hofstra University, Hempstead, NY 11549, United States
| | - Kenneth Blum
- Western University Health Sciences, Graduate College of Biomedical Sciences, Pomona, California, United States
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14
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O'Brien R, O'Malley D. The Glucagon-like peptide-1 receptor agonist, exendin-4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome. Neurogastroenterol Motil 2020; 32:e13738. [PMID: 31602785 DOI: 10.1111/nmo.13738] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/15/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) is beneficial in relieving pain-related symptoms of Irritable bowel syndrome (IBS), a prevalent, multi-factorial functional bowel disorder characterized by diarrhea and/or constipation, abdominal bloating, and pain. Activation of myenteric neurons has been implicated in the inhibitory effects of GLP-1 on gastrointestinal motility; however, the mechanisms of action underlying this are not clear. METHODS A rat model of IBS was used to examine physiological changes evoked by intraperitoneal administration of a GLP-1 receptor agonist, exendin-4. Behavioral and physiological analysis of stress-sensitive Wister Kyoto (WKY) rats was used to determine if administration of exendin-4, in the presence or absence of neutralizing interleukin-6 receptor monoclonal antibodies, modified IBS-like symptoms. Immunofluorescence, calcium imaging, and Western blotting techniques were used to investigate the potential role of enteric neural plexi and tight junction protein expression in this effect. KEY RESULTS Consistent with the expression of GLP-1 and interleukin-6 receptors in both submucosal and myenteric ganglia, exendin-4 and interleukin-6 stimulated calcium responses in these neurons. In vivo administration of exendin-4 normalized stress-induced defecation and visceral pain sensitivity in WKY rats. No additional changes were noted in rats co-treated with exendin-4 and anti-interleukin-6 receptor antibodies. Mucosal expression of occludin, a tight junction protein, was decreased by exendin-4. Centrally regulated anxiety-like behaviors were not modified. CONCLUSIONS AND INFERENCES These data suggest that intraperitoneal injection of exendin-4 improves bowel dysfunction in WKY rats without impacting on centrally regulated anxiety-like behaviors. Modulation of enteric neuronal function and tight junction expression appear to underlie the functional benefits of this intervention.
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Affiliation(s)
- Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
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15
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Accarie A, Vanuytsel T. Animal Models for Functional Gastrointestinal Disorders. Front Psychiatry 2020; 11:509681. [PMID: 33262709 PMCID: PMC7685985 DOI: 10.3389/fpsyt.2020.509681] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 10/22/2020] [Indexed: 12/12/2022] Open
Abstract
Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.
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Affiliation(s)
- Alison Accarie
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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16
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Hestehave S, Abelson KSP, Brønnum Pedersen T, Munro G. Stress sensitivity and cutaneous sensory thresholds before and after neuropathic injury in various inbred and outbred rat strains. Behav Brain Res 2019; 375:112149. [DOI: 10.1016/j.bbr.2019.112149] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/21/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022]
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17
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Bassett SA, Young W, Fraser K, Dalziel JE, Webster J, Ryan L, Fitzgerald P, Stanton C, Dinan TG, Cryan JF, Clarke G, Hyland N, Roy NC. Metabolome and microbiome profiling of a stress-sensitive rat model of gut-brain axis dysfunction. Sci Rep 2019; 9:14026. [PMID: 31575902 PMCID: PMC6773725 DOI: 10.1038/s41598-019-50593-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 09/09/2019] [Indexed: 12/16/2022] Open
Abstract
Stress negatively impacts gut and brain health. Individual differences in response to stress have been linked to genetic and environmental factors and more recently, a role for the gut microbiota in the regulation of stress-related changes has been demonstrated. However, the mechanisms by which these factors influence each other are poorly understood, and there are currently no established robust biomarkers of stress susceptibility. To determine the metabolic and microbial signatures underpinning physiological stress responses, we compared stress-sensitive Wistar Kyoto (WKY) rats to the normo-anxious Sprague Dawley (SD) strain. Here we report that acute stress-induced strain-specific changes in brain lipid metabolites were a prominent feature in WKY rats. The relative abundance of Lactococcus correlated with the relative proportions of many brain lipids. In contrast, plasma lipids were significantly elevated in response to stress in SD rats, but not in WKY rats. Supporting these findings, we found that the greatest difference between the SD and WKY microbiomes were the predicted relative abundance of microbial genes involved in lipid and energy metabolism. Our results provide potential insights for developing novel biomarkers of stress vulnerability, some of which appear genotype specific.
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Affiliation(s)
- Shalome A Bassett
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand
| | - Wayne Young
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Karl Fraser
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Julie E Dalziel
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand. .,Riddet Institute, Massey University, Palmerston North, New Zealand.
| | - Jim Webster
- Farm Systems North, AgResearch Ltd., Ruakura Research Centre, Hamilton, New Zealand
| | - Leigh Ryan
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand
| | - Patrick Fitzgerald
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Catherine Stanton
- Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Gerard Clarke
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - Niall Hyland
- Laboratory of Neurogastroenterology, APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Physiology, University College Cork, Cork, Ireland
| | - Nicole C Roy
- Food Nutrition & Health, AgResearch Ltd., Grasslands Research Centre, Tennent Drive, Palmerston North, 4442, New Zealand.,Riddet Institute, Massey University, Palmerston North, New Zealand.,High-Value Nutrition National Science Challenge, Auckland, New Zealand
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18
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Buckley MM, O'Brien R, Buckley JM, O'Malley D. GHSR-1 agonist sensitizes rat colonic intrinsic and extrinsic neurons to exendin-4: A role in the manifestation of postprandial gastrointestinal symptoms in irritable bowel syndrome? Neurogastroenterol Motil 2019; 31:e13684. [PMID: 31311066 DOI: 10.1111/nmo.13684] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/19/2019] [Accepted: 07/08/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS. METHODS Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains. KEY RESULTS Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist. CONCLUSIONS & INFERENCES These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.
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Affiliation(s)
- Maria M Buckley
- Department of Physiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, Biosciences Institute, University College Cork, Cork, Ireland
| | - Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Julliette M Buckley
- Department of Surgery, University College Cork, Cork, and Mater Private Hospital, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland
- APC Microbiome Ireland, Biosciences Institute, University College Cork, Cork, Ireland
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Higher odds of irritable bowel syndrome among hospitalized patients using cannabis: a propensity-matched analysis. Eur J Gastroenterol Hepatol 2019; 31:756-765. [PMID: 30807448 DOI: 10.1097/meg.0000000000001382] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The endogenous cannabinoid system modulates many brain-gut and gut-brain physiologic pathways, which are postulated to be dysfunctional in irritable bowel syndrome (IBS). Herein, we examine the relationship between cannabis use disorder (CUD) and having IBS. PATIENTS AND METHODS After selecting patients aged 18 years and above from the 2014 Nationwide Inpatient Survey, we used the International Classification of Diseases, 9th ed. codes to identify individuals with CUD, IBS, and the established risk factors for IBS. We then estimated the crude and adjusted odds ratios of having a diagnosis of IBS with CUD and assessed for the interactions of CUD with other risk factors (SAS 9.4). We confirmed our findings in two ways: conducting a similar analysis on a previous Nationwide Inpatient Survey data (2012); and using a greedy algorithm to design a propensity-scored case-control (1 : 10) study, approximating a pseudorandomized clinical trial. RESULTS Out of 4 709 043 patients evaluated, 0.03% had a primary admission for IBS and 1.32% had CUD. CUD was associated with increased odds of IBS [adjusted odds ratio: 2.03; 95% confidence interval (CI): 1.53-2.71]. CUD was related to higher odds for IBS among males compared with females (3.48; 1.98-6.12 vs. 1.48; 0.88-2.50), and Hispanics and Caucasians compared with Blacks (5.28; 1.77-15.76, 1.80; 1.02-3.18 vs. 1.80; 0.65-5.03). On propensity-matching, CUD was associated with 80% increased odds for IBS (1.82; 1.27-2.60). CONCLUSION Our findings suggest that CUD is significantly associated with IBS among the general population. Males, Caucasians, and Hispanics might be more impacted by CUD associated IBS. Additional biomedical studies are required to elucidate this relationship.
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20
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Meleine M, Accarie A, Wauters L, Toth J, Gourcerol G, Tack J, Farré R, Vanuytsel T. Colonic hypersensitivity and low-grade inflammation in a spontaneous animal model for functional gastrointestinal disorders. Neurogastroenterol Motil 2019; 31:e13614. [PMID: 31069897 DOI: 10.1111/nmo.13614] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 04/03/2019] [Accepted: 04/16/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND A complex interplay between a failing intestinal barrier and low-grade inflammation leading to sensorimotor disturbances is an often-cited mechanism in the pathogenesis of functional gastrointestinal disorders (FGID). However, the cause-consequence relationship between these features has not been clearly established. We previously described jejunal alterations in the normoglycemic BB-rat (BBDP-N) model proposing this model as a suitable animal model to study FGID pathophysiology. The current study explores colonic permeability, inflammation, and sensitivity of the BB-rat. METHODS Colonic tissue of BBDP-N and control (BBDR) rats at 50, 90, 110, 160, and 220 days (n ≥ 7 per group) was used to assess intestinal permeability in Ussing chambers and inflammation, including infiltration by eosinophils, mast cells, and eosinophil peroxidase (EPO) activity. Anxiety-like symptoms were evaluated at 50, 90, and 220 days and colonic sensitivity at 160 and 220 days by measuring the visceromotor response (VMR) to isobaric colorectal distensions. KEYS RESULTS Lamina propria eosinophil and mast cell infiltration and increased EPO activity were demonstrated from 90 days onward. Increased permeability and myenteric ganglionitis were observed in the oldest BBDP-N rats. At 220 days, the VMR was significantly increased suggesting colonic hypersensitivity. At the same age, increased anxiety-like behavior was observed. CONCLUSION AND INFERENCES We demonstrated a lamina propria eosinophil and mast cell infiltration preceding visceral hypersensitivity in the colon of the BBDP-N rat, reminiscent of patients with FGID. These findings help elucidating pathogenetic pathways in FGID and further validate the BBDP-N rat as an attractive model to study pathophysiology and therapy of FGID.
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Affiliation(s)
- Mathieu Meleine
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium.,Inserm UMR 1073, Institute for Innovation and Biomedical Research, Rouen University, Rouen, France
| | - Alison Accarie
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
| | - Lucas Wauters
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
| | - Joran Toth
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
| | - Guillaume Gourcerol
- Inserm UMR 1073, Institute for Innovation and Biomedical Research, Rouen University, Rouen, France
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
| | - Ricard Farré
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism, and Ageing (ChroMetA), KU Leuven, Leuven, Belgium
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21
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Distinct effects of early-life experience and trait aggression on cardiovascular reactivity and recovery. Physiol Behav 2019; 199:375-385. [PMID: 30529343 DOI: 10.1016/j.physbeh.2018.12.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 11/12/2018] [Accepted: 12/03/2018] [Indexed: 12/19/2022]
Abstract
We previously demonstrated independent effects of early-life experience (ELE) and trait aggression (TA) on resting heart rate (HR) and mean arterial pressure (MAP) in rats. The present study examined the effects of TA and ELE on stress-evoked cardiovascular reactivity and recovery. Pups born to Wistar-Kyoto dams were exposed to daily 180-min periods of maternal separation (MS) during the first two weeks of life, and aggression was assessed in adult offspring using the resident-intruder test. Radiotelemetry was then used to record stress-evoked HR and MAP responses in response to: strobe light, novel environment, intruder rat, or restraint. Maximal HR and MAP responses were quantified as indices of reactivity, and exponential decay curves were fitted to determine decay constants as a measure of recovery. Strobe light was the weakest stressor, evoking the lowest increases in MAP and HR, which were significantly greater in MS-exposed rats irrespective of TA. In contrast, reactivity to and recovery from exposure to a novel environment or an intruder were significantly influenced by TA, but not ELE. TA animals exhibited greater reactivity in both of these paradigms, with either decreased (novel environment) or increased (intruder) recovery. Restraint stress induced the largest changes in HR and MAP with the slowest recovery, and these responses were shaped by a significant ELE x TA interaction. These data indicate that cardiovascular reactivity and recovery are influenced by ELE, TA, or ELE x TA interaction depending on stressor aversiveness as well as its physical and psychological dimensions.
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Lefter R, Ciobica A, Guenné S, Compaoré M, Kiendrebéogo M, Stanciu C, Trifan A. Complex Neurobehavioral Testing of a Rat Model of the Irritable Bowel Syndrome. NEUROPHYSIOLOGY+ 2018; 50:266-277. [DOI: 10.1007/s11062-018-9748-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Indexed: 02/05/2023]
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Greenwood-Van Meerveld B, Johnson AC. Mechanisms of Stress-induced Visceral Pain. J Neurogastroenterol Motil 2018; 24:7-18. [PMID: 29291604 PMCID: PMC5753899 DOI: 10.5056/jnm17137] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022] Open
Abstract
Evidence suggests that long-term stress facilitates visceral pain through sensitization of pain pathways and promotes chronic visceral pain disorders such as the irritable bowel syndrome (IBS). This review will describe the importance of stress in exacerbating IBS-induced abdominal pain. Additionally, we will briefly review our understanding of the activation of the hypothalamic-pituitary-adrenal axis by both chronic adult stress and following early life stress in the pathogenesis of IBS. The review will focus on the glucocorticoid receptor and corticotropin-releasing hormone-mediated mechanisms in the amygdala involved in stress-induced visceral hypersensitivity. One potential mechanism underlying persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in stress-induced visceral nociception, alterations in DNA methylation and histone acetylation patterns within the brain, have been linked to alterations in nociceptive signaling via increased expression of pro-nociceptive neurotransmitters. This review will discuss the latest studies investigating the long-term effects of stress on visceral sensitivity. Additionally, we will critically review the importance of experimental models of adult stress and early life stress in enhancing our understanding of the basic molecular mechanisms of nociceptive processing.
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Affiliation(s)
- Beverley Greenwood-Van Meerveld
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK,
USA
- Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK,
USA
- VA Medical Center, University of Oklahoma Health Science Center, Oklahoma City, OK,
USA
| | - Anthony C Johnson
- VA Medical Center, University of Oklahoma Health Science Center, Oklahoma City, OK,
USA
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24
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Dalziel JE, Fraser K, Young W, McKenzie CM, Bassett SA, Roy NC. Gastroparesis and lipid metabolism-associated dysbiosis in Wistar-Kyoto rats. Am J Physiol Gastrointest Liver Physiol 2017; 313:G62-G72. [PMID: 28408641 PMCID: PMC5538835 DOI: 10.1152/ajpgi.00008.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/23/2017] [Accepted: 04/05/2017] [Indexed: 02/07/2023]
Abstract
Altered gastric accommodation and intestinal morphology suggest impaired gastrointestinal (GI) transit may occur in the Wistar-Kyoto (WKY) rat strain, as common in stress-associated functional GI disorders. Because changes in GI transit can alter microbiota composition, we investigated whether these are altered in WKY rats compared with the resilient Sprague-Dawley (SD) rats under basal conditions and characterized plasma lipid and metabolite differences. Bead transit was tracked by X-ray imaging to monitor gastric emptying (4 h), small intestine (SI) transit (9 h), and large intestine transit (12 h). Plasma extracts were analyzed by lipid and hydrophilic interaction liquid chromatography (HILIC) and liquid chromatography-mass spectrometry (LC-MS). Cecal microbial composition was determined by Illumina MiSeq 16S rRNA amplicon sequencing and analysis using the QIIME pipeline. Stomach retention of beads was 77% for WKY compared with 35% for SD rats. GI transit was decreased by 34% (9 h) and 21% (12 h) in WKY compared with SD rats. Excluding stomach retention, transiting beads moved 29% further along the SI over 4-9 h for WKY compared with SD rats. Cecal Ruminococcus, Roseburia, and unclassified Lachnospiraceae genera were less abundant in WKY rats, whereas the minor taxa Dorea, Turicibacter, and Lactobacillus were higher. Diglycerides, triglycerides, phosphatidyl-ethanolamines, and phosphatidylserine were lower in WKY rats, whereas cholesterol esters and taurocholic acids were higher. The unexpected WKY rat phenotype of delayed gastric emptying, yet rapid SI transit, was associated with altered lipid and metabolite profiles. The delayed gastric emptying of the WKY phenotype suggests this rat strain may be useful as a model for gastroparesis.NEW & NOTEWORTHY This study reveals that the stress-prone Wistar-Kyoto rat strain has a baseline physiology of gastroparesis and rapid small intestine transit, together with metabolic changes consistent with lipid metabolism-associated dysbiosis, compared with nonstress-prone rats. This suggests that the Wistar-Kyoto rat strain may be an appropriate animal model for gastroparesis.
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Affiliation(s)
- J. E. Dalziel
- 1Food Nutrition and Health Team, Food and Bio-Based Products Group, AgResearch Grasslands Research Centre, Palmerston North, New Zealand;
| | - Karl Fraser
- 1Food Nutrition and Health Team, Food and Bio-Based Products Group, AgResearch Grasslands Research Centre, Palmerston North, New Zealand;
| | - Wayne Young
- 1Food Nutrition and Health Team, Food and Bio-Based Products Group, AgResearch Grasslands Research Centre, Palmerston North, New Zealand;
| | - Catherine M. McKenzie
- 2Bioinformatics Mathematics and Statistics, AgResearch, Palmerston North, New Zealand; and
| | - Shalome A. Bassett
- 1Food Nutrition and Health Team, Food and Bio-Based Products Group, AgResearch Grasslands Research Centre, Palmerston North, New Zealand;
| | - Nicole C. Roy
- 1Food Nutrition and Health Team, Food and Bio-Based Products Group, AgResearch Grasslands Research Centre, Palmerston North, New Zealand; ,3Riddet Institute, Massey University, Palmerston North, New Zealand
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Lin WT, Liao YJ, Peng YC, Chang CH, Lin CH, Yeh HZ, Chang CS. Relationship between use of selective serotonin reuptake inhibitors and irritable bowel syndrome: A population-based cohort study. World J Gastroenterol 2017; 23:3513-3521. [PMID: 28596687 PMCID: PMC5442087 DOI: 10.3748/wjg.v23.i19.3513] [Citation(s) in RCA: 9] [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: 12/14/2016] [Revised: 02/12/2017] [Accepted: 03/31/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the relationship between selective serotonin reuptake inhibitor (SSRI) use and the subsequent development of irritable bowel syndrome (IBS). METHODS This retrospective, observational, population-based cohort study collected data from Taiwan's National Health Insurance Research Database. A total of 19653 patients newly using SSRIs and 78612 patients not using SSRIs, matched by age and sex at a ratio of 1:4, were enrolled in the study from January 1, 2000 to December 31, 2010. The patients were followed until IBS diagnosis, withdrawal from the National Health Insurance system, or the end of 2011. We analyzed the effects of SSRIs on the risk of subsequent IBS using Cox proportional hazards regression models. RESULTS A total of 236 patients in the SSRI cohort (incidence, 2.17/1000 person-years) and 478 patients in the comparison cohort (incidence, 1.04/1000 person-years) received a new diagnosis of IBS. The mean follow-up period from SSRI exposure to IBS diagnosis was 2.05 years. The incidence of IBS increased with advancing age. Patients with anxiety disorders had a significantly increased adjusted hazard ratio (aHR) of IBS (aHR = 1.33, 95%CI: 1.11-1.59, P = 0.002). After adjusting for sex, age, urbanization, family income, area of residence, occupation, the use of anti-psychotics and other comorbidities, the overall aHR in the SSRI cohort compared with that in the comparison cohort was 1.74 (95%CI: 1.44-2.10; P < 0.001). The cumulative incidence of IBS was higher in the SSRI cohort than in the non-SSRI cohort (log-rank test, P < 0.001). CONCLUSION SSRI users show an increased risk of subsequent diagnosis of IBS in Taiwan.
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Tsang SW, Auyeung KKW, Bian ZX, Ko JKS. Pathogenesis, Experimental Models and Contemporary Pharmacotherapy of Irritable Bowel Syndrome: Story About the Brain-Gut Axis. Curr Neuropharmacol 2017; 14:842-856. [PMID: 27009115 PMCID: PMC5333584 DOI: 10.2174/1570159x14666160324144154] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 02/07/2016] [Accepted: 03/22/2016] [Indexed: 11/22/2022] Open
Abstract
Background Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease. Methods Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed. Results When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation. Conclusion Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients.
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Affiliation(s)
| | | | | | - J K S Ko
- Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, China
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Lee JY, Kim N, Kim YS, Nam RH, Ham MH, Lee HS, Jo W, Shim Y, Choi YJ, Yoon H, Shin CM, Lee DH. Repeated Water Avoidance Stress Alters Mucosal Mast Cell Counts, Interleukin-1β Levels with Sex Differences in the Distal Colon of Wistar Rats. J Neurogastroenterol Motil 2016; 22:694-704. [PMID: 27466288 PMCID: PMC5056580 DOI: 10.5056/jnm16007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2016] [Revised: 05/23/2016] [Accepted: 06/14/2016] [Indexed: 12/13/2022] Open
Abstract
Background/Aims This study was aimed at evaluating differences in the effects of repeated water avoidance stress (rWAS) on colonic movement, mucosal mast cell counts, cytokine levels, and visceromotor response (VMR) to colorectal distension (CRD) in rats of both sexes. Methods Wistar rats were divided into stress and no-stress groups. Rats in the stress group were exposed to rWAS (1 hr/day) for 10 days. Mucosal mast cells were immunohistochemically stained with anti-mast cell tryptase antibody and counted. The colonic mucosal cytokine levels were measured with enzyme-linked immunosorbent assay. The VMR to CRD (visceral analgesia) was assessed by using a barostat and noninvasive manometry. Results The mean number of fecal pellets in the rWAS group increased significantly as compared with that in the no-stress group in both sexes. After adjustment for body weight, the female rats had a significantly higher pellet output than the male rats. The mucosal mast cell count of the female rWAS group was higher than that of the male rWAS group (13.0 ± 0.9 vs 8.8 ± 0.6; P < 0.001). The colonic mucosal interleukin-1β level was also higher only in the female rats of the rWAS group than in those of the no-stress group. On days 10 and 11, a decrease in VMR to CRD was observed at 40 and 60 mmHg in both sexes of the rWAS group, without a sex-based difference. Conclusions The colonic response to stress appeared to be more sensitive in the female rats than in the male rats. However, stress-induced visceral analgesia had no sex-related difference and the underlying mechanism needs to be further evaluated.
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Affiliation(s)
- Ju Yup Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea.,Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Yong Sung Kim
- Department of Gastroenterology and Digestive Disease Research Institute, Wonkwang University School of Medicine, Iksan, Jeollabuk-do, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Min Hee Ham
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Wonjun Jo
- Department of BioNano Technology and Gachon BioNano Research Institute, Gachon University, Seongnam, Gyeonggi-do, Korea
| | - Youngkwang Shim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
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Fuentes IM, Walker NK, Pierce AN, Holt BR, Di Silvestro ER, Christianson JA. Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice. IBRO Rep 2016; 1:10-18. [PMID: 28164167 PMCID: PMC5289700 DOI: 10.1016/j.ibror.2016.07.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Experiencing early life stress can result in maladjusted stress response via dysregulation of the hypothalamic-pituitary-adrenal axis and serves as a risk factor for developing chronic pelvic pain disorders. We investigated whether neonatal maternal separation (NMS) would increase susceptibility to experimental colitis or exposure to acute or chronic stress. Male mice underwent NMS from postnatal day 1-21 and as adults were assessed for open field behavior, hindpaw sensitivity, and visceromotor response (VMR) to colorectal distension (CRD). VMR was also measured before and after treatment with intracolonic trinitrobenzene sulfonic acid (TNBS) or exposure to acute or chronic water avoidance stress (WAS). Myeloperoxidase (MPO) activity, proinflammatory gene and corticotropin-releasing factor (CRF) receptor expression were measured in distal colon. Baseline VMR was not affected by NMS, but undergoing CRD increased anxiety-like behaviors and mechanical hindpaw sensitivity of NMS mice. Treatment with TNBS dose-dependently decreased body weight and survival only in NMS mice. Following TNBS treatment, IL-6 and artemin mRNA levels were decreased in the distal colon of NMS mice, despite increased MPO activity. A single WAS exposure increased VMR during CRD in NMS mice and increased IL-6 mRNA and CRF2 protein levels in the distal colon of naïve mice, whereas CRF2 protein levels were heightened in NMS colon both at baseline and post-WAS exposure. Taken together, these results suggest that NMS in mice disrupts inflammatory- and stress-induced gene expression in the colon, potentially contributing towards an exaggerated response to specific stressors later in life.
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Affiliation(s)
- Isabella M Fuentes
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Natalie K Walker
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Angela N Pierce
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Briana R Holt
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Elizabeth R Di Silvestro
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
| | - Julie A Christianson
- Department of Anatomy and Cell Biology, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160
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Abstract
OBJECTIVES We evaluated the stability of the comorbidity between vulvodynia and orofacial pain (OFP) and its associated clinical characteristics over a 2-year follow-up period. MATERIALS AND METHODS In an earlier study of vestibulodynia patients, we administered questionnaires assessing demographic data, self-reported pain, anxiety, somatic awareness, and presence of signs and symptoms suggestive of clinical and subclinical OFP. The present study readministered the same surveys to a subset of the original cohort after a 2-year follow-up period. RESULTS Of the 138 women in the previous study, 71 (51%) agreed to participate in the present study. We confirmed our earlier findings that (1) OFP is a highly prevalent (66%) condition among women with vestibulodynia, and (2) compared with women with no OFP symptoms, those with OFP symptoms experience higher levels of anxiety (P=0.005) and somatic awareness (P<0.001). Although OFP symptoms showed improvement in many of the vestibulodynia patients (33%) with OFP symptoms at baseline, 13% had either developed new symptoms or transitioned from subclinical to clinical OFP classification. Intercourse-related pain decreased in 69% of patients and increased in 24% of patients. Consistent with our earlier report, we did not observe significant differences with respect to demographics or severity of pain during intercourse among the subgroups. DISCUSSION OFP is a common comorbidity among women with vestibulodynia, although the presence of OFP can vary over time. The comorbidity between vestibulodynia and OFP suggests that common underlying mechanisms may mediate both conditions.
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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: 359] [Impact Index Per Article: 35.9] [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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Greenwood-Van Meerveld B, Prusator DK, Johnson AC. Animal models of gastrointestinal and liver diseases. Animal models of visceral pain: pathophysiology, translational relevance, and challenges. Am J Physiol Gastrointest Liver Physiol 2015; 308:G885-903. [PMID: 25767262 DOI: 10.1152/ajpgi.00463.2014] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/11/2015] [Indexed: 02/08/2023]
Abstract
Visceral pain describes pain emanating from the thoracic, pelvic, or abdominal organs. In contrast to somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. Animal models have played a pivotal role in our understanding of the mechanisms underlying the pathophysiology of visceral pain. This review focuses on animal models of visceral pain and their translational relevance. In addition, the challenges of using animal models to develop novel therapeutic approaches to treat visceral pain will be discussed.
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Affiliation(s)
- Beverley Greenwood-Van Meerveld
- Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Dawn K Prusator
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anthony C Johnson
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
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Moloney RD, Golubeva AV, O'Connor RM, Kalinichev M, Dinan TG, Cryan JF. Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain. Neurobiol Stress 2015; 2:28-33. [PMID: 26844237 PMCID: PMC4721404 DOI: 10.1016/j.ynstr.2015.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 03/15/2015] [Accepted: 04/03/2015] [Indexed: 11/19/2022] Open
Abstract
Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need.
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Affiliation(s)
- Rachel D. Moloney
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland
- Department of Psychiatry, University College Cork, Ireland
| | - Anna V. Golubeva
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland
| | | | | | - Timothy G. Dinan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland
- Department of Psychiatry, University College Cork, Ireland
| | - John F. Cryan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Ireland
- Corresponding author. Dept Anatomy & Neuroscience, Room 386, Western Gateway Building, University College Cork, Western Rd., Cork, Ireland.
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Hyland NP, O'Mahony SM, O'Malley D, O'Mahony CM, Dinan TG, Cryan JF. Early-life stress selectively affects gastrointestinal but not behavioral responses in a genetic model of brain-gut axis dysfunction. Neurogastroenterol Motil 2015; 27:105-113. [PMID: 25443141 DOI: 10.1111/nmo.12486] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 11/15/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Early-life stress and a genetic predisposition to display an anxiety- and depressive-like phenotype are associated with behavioral and gastrointestinal (GI) dysfunction. Animals exposed to early-life stress, and those genetically predisposed to display anxiety or depressive behaviors, have proven useful tools in which to study stress-related GI disorders, such as irritable bowel syndrome (IBS). IBS is a heterogeneous disorder, and likely a consequence of both genetic and environmental factors. However, the combined effects of early-life stress and a genetic predisposition to display anxiety- and depression-like behaviors on GI function have not been investigated. METHODS We assessed the effect of maternal separation (MS) on behavioral and GI responses in WKY animals relative to a normo-anxious reference strain. KEY RESULTS Both non-separated (NS) WKY and WKY-MS animals displayed anxiety-like responses in the open-field test and depressive-like behaviors in the forced swim test relative to Sprague-Dawley rats. However, MS had no further influence on anxiety- and depressive-like behaviors exhibited by this stress-prone rat strain. Similarly, corticosterone levels measured after the OFT were insensitive to MS in WKY animals. However, WKY-MS displayed significantly increased colonic visceral hypersensitivity, fecal output, and altered colonic cholinergic sensitivity. CONCLUSIONS & INFERENCES Our data suggest that early-life stress, on the background of a genetic predisposition to display an anxiety- and depressive-like phenotype, selectively influences GI function rather than stress-related behaviors. Thus, our findings highlight the importance of genetic predisposition on the outcome of early-life adversity on GI function.
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Affiliation(s)
- N P Hyland
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
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Moloney RD, O'Mahony SM, Dinan TG, Cryan JF. Stress-induced visceral pain: toward animal models of irritable-bowel syndrome and associated comorbidities. Front Psychiatry 2015; 6:15. [PMID: 25762939 PMCID: PMC4329736 DOI: 10.3389/fpsyt.2015.00015] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 01/28/2015] [Indexed: 12/12/2022] Open
Abstract
Visceral pain is a global term used to describe pain originating from the internal organs, which is distinct from somatic pain. It is a hallmark of functional gastrointestinal disorders such as irritable-bowel syndrome (IBS). Currently, the treatment strategies targeting visceral pain are unsatisfactory, with development of novel therapeutics hindered by a lack of detailed knowledge of the underlying mechanisms. Stress has long been implicated in the pathophysiology of visceral pain in both preclinical and clinical studies. Here, we discuss the complex etiology of visceral pain reviewing our current understanding in the context of the role of stress, gender, gut microbiota alterations, and immune functioning. Furthermore, we review the role of glutamate, GABA, and epigenetic mechanisms as possible therapeutic strategies for the treatment of visceral pain for which there is an unmet medical need. Moreover, we discuss the most widely described rodent models used to model visceral pain in the preclinical setting. The theory behind, and application of, animal models is key for both the understanding of underlying mechanisms and design of future therapeutic interventions. Taken together, it is apparent that stress-induced visceral pain and its psychiatric comorbidities, as typified by IBS, has a multifaceted etiology. Moreover, treatment strategies still lag far behind when compared to other pain modalities. The development of novel, effective, and specific therapeutics for the treatment of visceral pain has never been more pertinent.
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Affiliation(s)
- Rachel D Moloney
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland
| | - Siobhain M O'Mahony
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Anatomy and Neuroscience, University College Cork , Cork , Ireland
| | - Timothy G Dinan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Psychiatry, University College Cork , Cork , Ireland
| | - John F Cryan
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, Biosciences Institute, University College Cork , Cork , Ireland ; Department of Anatomy and Neuroscience, University College Cork , Cork , Ireland
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Buckley MM, O'Halloran KD, Rae MG, Dinan TG, O'Malley D. Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome. J Physiol 2014; 592:5235-5250. [PMID: 25260633 PMCID: PMC4262336 DOI: 10.1113/jphysiol.2014.279968] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 09/19/2014] [Indexed: 12/14/2022] Open
Abstract
The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.
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Affiliation(s)
- Maria M Buckley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Physiology, University College Cork, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, University College Cork, Cork, Ireland
| | - Mark G Rae
- Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Psychiatry, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Physiology, University College Cork, Cork, Ireland
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Buckley MM, O'Halloran KD, Rae MG, Dinan TG, O'Malley D. Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome. J Physiol 2014; 592:5235-5250. [PMID: 25260633 DOI: 10.1113/jphysiol] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.
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Affiliation(s)
- Maria M Buckley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Physiology, University College Cork, Cork, Ireland
| | - Ken D O'Halloran
- Department of Physiology, University College Cork, Cork, Ireland
| | - Mark G Rae
- Department of Physiology, University College Cork, Cork, Ireland
| | - Timothy G Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Psychiatry, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland Department of Physiology, University College Cork, Cork, Ireland
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39
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Nam H, Clinton SM, Jackson NL, Kerman IA. Learned helplessness and social avoidance in the Wistar-Kyoto rat. Front Behav Neurosci 2014; 8:109. [PMID: 24744709 PMCID: PMC3978372 DOI: 10.3389/fnbeh.2014.00109] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 03/14/2014] [Indexed: 12/31/2022] Open
Abstract
The Wistar-Kyoto (WKY) rat is an established depression model characterized by elevated anxiety- and depression-like behavior across a variety of tests. Here we further characterized specific behavioral and functional domains relevant to depression that are altered in WKY rats. Moreover, since early-life experience potently shapes emotional behavior, we also determined whether aspects of WKYs' phenotype were modifiable by early-life factors using neonatal handling or maternal separation. We first compared WKYs' behavior to that of Sprague–Dawley (SD), Wistar, and Spontaneously Hypertensive (SHR) rats in: the open field test, elevated plus maze, novelty-suppressed feeding test, a social interaction test, and the forced swim test (FST). WKYs exhibited high baseline immobility in the FST and were the only strain to show increased immobility on FST Day 2 vs. Day 1 (an indicator of learned helplessness). WKYs also showed greater social avoidance, along with enlarged adrenal glands and hearts relative to other strains. We next tested whether neonatal handling or early-life maternal separation stress influenced WKYs' behavior. Neither manipulation affected their anxiety- and depressive-like behaviors, likely due to a strong genetic underpinning of their phenotype. Our findings indicate that WKY rats are a useful model that captures specific functional domains relevant to clinical depression including: psychomotor retardation, behavioral inhibition, learned helplessness, social withdrawal, and physiological dysfunction. WKY rats appear to be resistant to early-life manipulations (i.e., neonatal handling) that are therapeutic in other strains, and may be a useful model for the development of personalized anti-depressant therapies for treatment resistant depression.
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Affiliation(s)
- Hyungwoo Nam
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA ; Cell, Molecular, and Developmental Biology, Graduate Biomedical Sciences Program, University of Alabama at Birmingham Birmingham, AL, USA
| | - Sarah M Clinton
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA
| | - Nateka L Jackson
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA
| | - Ilan A Kerman
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA
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40
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Rea K, Olango WM, Okine BN, Madasu MK, McGuire IC, Coyle K, Harhen B, Roche M, Finn DP. Impaired endocannabinoid signalling in the rostral ventromedial medulla underpins genotype-dependent hyper-responsivity to noxious stimuli. Pain 2014; 155:69-79. [DOI: 10.1016/j.pain.2013.09.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 08/18/2013] [Accepted: 09/09/2013] [Indexed: 12/20/2022]
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Abstract
The intensity and severity of perceived pain does not correlate consistently with the degree of peripheral or central nervous system tissue damage or with the intensity of primary afferent or spinal nociceptive neurone activity. In this respect, the modulation of pain by emotion and context is now widely recognized. In particular, stress, fear and anxiety exert potent, but complex, modulatory influences on pain. Stress can either suppress pain (stress-induced analgesia) or exacerbate it (stress-induced hyperalgesia; SIH) depending on the nature, duration and intensity of the stressor. Herein, we review the methods and models used to study the phenomenon of SIH in rodents and humans and then present a detailed discussion of our current understanding of neural substrates and neurobiological mechanisms. The review provides perspectives and challenges for the current and future treatment of pain and the co-morbidity of pain with stress-related psychiatric disorders including anxiety and depression.
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Affiliation(s)
- Weredeselam M Olango
- Pharmacology and Therapeutics, School of Medicine, NCBES Galway Neuroscience Centre and Centre for Pain Research, National University of Ireland, University Road, Galway, Ireland
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42
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Carroll SY, O’Mahony SM, Grenham S, Cryan JF, Hyland NP. Disodium cromoglycate reverses colonic visceral hypersensitivity and influences colonic ion transport in a stress-sensitive rat strain. PLoS One 2013; 8:e84718. [PMID: 24367692 PMCID: PMC3867510 DOI: 10.1371/journal.pone.0084718] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 11/18/2013] [Indexed: 01/05/2023] Open
Abstract
The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.
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Affiliation(s)
- Siobhan Yvonne Carroll
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
| | - Siobhain Mary O’Mahony
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Susan Grenham
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - John Francis Cryan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
| | - Niall Patrick Hyland
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland
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Foreman RD, Linderoth B. Neural mechanisms of spinal cord stimulation. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2013. [PMID: 23206679 DOI: 10.1016/b978-0-12-404706-8.00006-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Neuromodulation, specifically spinal cord stimulation (SCS), relieves pain and improves organ function. This chapter discusses the limited information presently available about the underlying mechanisms that explain the beneficial effects of treating patients with SCS. Where applicable, information is presented about translational research that illustrates the importance of collaboration between clinicians, basic scientists, and engineers. This chapter presents the infant stage of studies that attempt to explain the mechanisms which come into play for treating neuropathic pain, ischemic pain in peripheral vascular disease, and diseases of the visceral organs, specifically the gastrointestinal tract and the heart. The basic science studies will demonstrate how SCS acts on various pain syndromes and diseases via multiple pathways in the central nervous system as well as in somatic structures and visceral organs.
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Affiliation(s)
- Robert D Foreman
- Department of Physiology, Health Sciences Center, University of Oklahoma, Oklahoma City, Oklahoma, USA
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Neural Mechanisms That Underlie Angina-Induced Referred Pain in the Trigeminal Nerve Territory: A c-Fos Study in Rats. ISRN PAIN 2013; 2013:671503. [PMID: 27335881 PMCID: PMC4893399 DOI: 10.1155/2013/671503] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 07/08/2013] [Indexed: 11/17/2022]
Abstract
The present study was designed to determine whether the trigeminal sensory nuclear complex (TSNC) is involved in angina-induced referred pain in the trigeminal nerve territory and to identify the peripheral nerve conducting nociceptive signals that are input into the TSNC. Following application of the pain producing substance (PPS) infusion, the number of Fos-labeled cells increased significantly in the subnucleus caudalis (Sp5C) compared with other nuclei in the TSNC. The Fos-labeled cells in the Sp5C disappeared when the left and right cervical vagus nerves were sectioned. Lesion of the C1-C2 spinal segments did not reduce the number of Fos-labeled cells. These results suggest that the nociceptive signals that conduct vagal afferent fibers from the cardiac region are input into the Sp5C and then projected to the thalamus.
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O' Mahony SM, Clarke G, McKernan DP, Bravo JA, Dinan TG, Cryan JF. Differential visceral nociceptive, behavioural and neurochemical responses to an immune challenge in the stress-sensitive Wistar Kyoto rat strain. Behav Brain Res 2013; 253:310-7. [PMID: 23872358 DOI: 10.1016/j.bbr.2013.07.023] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Revised: 07/11/2013] [Accepted: 07/14/2013] [Indexed: 01/08/2023]
Abstract
A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.
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O'Malley D, Dinan TG, Cryan JF. Interleukin-6 modulates colonic transepithelial ion transport in the stress-sensitive wistar kyoto rat. Front Pharmacol 2012; 3:190. [PMID: 23162465 PMCID: PMC3491317 DOI: 10.3389/fphar.2012.00190] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 10/11/2012] [Indexed: 01/14/2023] Open
Abstract
Immunological challenge stimulates secretion of the pro-inflammatory cytokine interleukin (IL)-6, resulting in variety of biological responses. In the gastrointestinal tract, IL-6 modulates the excitability of submucosal neurons and stimulates secretion into the colonic lumen. When considered in the context of the functional bowel disorder, irritable bowel syndrome (IBS), where plasma levels of IL-6 are elevated, this may reflect an important molecular mechanism contributing to symptom flares, particularly in the diarrhea-predominant phenotype. In these studies, colonic ion transport, an indicator of absorption and secretion, was assessed in the stress-sensitive Wistar Kyoto (WKY) rat model of IBS. Mucosa-submucosal colonic preparations from WKY and control Sprague Dawley (SD) rats were mounted in Ussing chambers and the basal short circuit current (I(SC)) was electrophysiologically recorded and compared between the strains. Exposure to IL-6 (1 nM) stimulated a secretory current of greater amplitude in WKY as compared to SD samples. Furthermore, the observed IL-6-mediated potentiation of secretory currents evoked by veratridine and capsaicin in SD rats was blunted in WKY rats. Exposure to IL-6 also stimulated an increase in transepithelial resistance in both SD and WKY colonic tissue. These studies demonstrate that the neuroexcitatory effects of IL-6 on submucosal plexi have functional consequences with alterations in both colonic secretory activity and permeability. The IL-6-induced increase in colonic secretory activity appears to neurally mediated. Thus, local increases in IL-6 levels and subsequent activation of enteric neurons may underlie alterations in absorpto-secretory function in the WKY model of IBS.
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Affiliation(s)
- Dervla O'Malley
- Alimentary Pharmabiotic Centre, University College Cork Cork, Ireland ; Department of Physiology, University College Cork Cork, Ireland
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47
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Johnson AC, Tran L, Schulkin J, Greenwood-Van Meerveld B. Importance of stress receptor-mediated mechanisms in the amygdala on visceral pain perception in an intrinsically anxious rat. Neurogastroenterol Motil 2012; 24:479-86, e219. [PMID: 22364507 PMCID: PMC3461498 DOI: 10.1111/j.1365-2982.2012.01899.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Stress worsens abdominal pain experienced by patients with irritable bowel syndrome (IBS), a chronic disorder of unknown origin with comorbid anxiety. Previously, we have demonstrated colonic hypersensitivity in Wistar-Kyoto rats (WKYs), a high-anxiety strain, which models abdominal pain in IBS. In low-anxiety rats, we have demonstrated that the central nucleus of the amygdala (CeA) regulates colonic hypersensitivity and anxiety induced by selective activation of either glucocorticoid receptors (GR) or mineralocorticoid receptors (MR), which is also mediated by the corticotropin releasing factor (CRF) Type-1 receptor. The goal of the present study was to test the hypothesis that the CeA through GR, MR, and/or CRF-1R regulates colonic hypersensitivity in WKYs. METHODS One series of WKYs had micropellets of a GR antagonist, an MR antagonist or cholesterol (control) stereotaxically implanted onto the CeA. Another series were infused in the CeA with CRF-1R antagonist, or vehicle. Colonic sensitivity was measured as a visceromotor response (VMR) to graded colorectal distension (CRD). KEY RESULTS The exaggerated VMR to graded CRD in WKYs was unaffected by GR or MR antagonism in the CeA. In contrast, direct CeA infusion of CRF-1R antagonist significantly inhibited the VMR to CRD at noxious distension pressures. CONCLUSIONS & INFERENCES Stress hormones in the CeA regulate colonic hypersensitivity in the rat through strain-dependent parallel pathways. The colonic hypersensitivity in WKYs is mediated by a CRF-1R mechanism in the CeA, independent of GR and MR. These complementary pathways suggest multiple etiologies whereby stress hormones in the CeA may regulate abdominal pain in IBS patients.
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Affiliation(s)
- Anthony C. Johnson
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Lee Tran
- Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
| | - Jay Schulkin
- Department of Research, American College of Obstetricians and Gynecologists, Washington DC, USA
| | - Beverley Greenwood-Van Meerveld
- V.A. Medical Center and University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA
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48
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Larauche M, Mulak A, Taché Y. Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 2012; 233:49-67. [PMID: 21575632 PMCID: PMC3224675 DOI: 10.1016/j.expneurol.2011.04.020] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Revised: 04/07/2011] [Accepted: 04/28/2011] [Indexed: 02/07/2023]
Abstract
Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain.
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Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90073, USA.
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Larauche M, Mulak A, Taché Y. Stress-related alterations of visceral sensation: animal models for irritable bowel syndrome study. J Neurogastroenterol Motil 2011; 17:213-34. [PMID: 21860814 PMCID: PMC3155058 DOI: 10.5056/jnm.2011.17.3.213] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Accepted: 06/12/2011] [Indexed: 12/11/2022] Open
Abstract
Stressors of different psychological, physical or immune origin play a critical role in the pathophysiology of irritable bowel syndrome participating in symptoms onset, clinical presentation as well as treatment outcome. Experimental stress models applying a variety of acute and chronic exteroceptive or interoceptive stressors have been developed to target different periods throughout the lifespan of animals to assess the vulnerability, the trigger and perpetuating factors determining stress influence on visceral sensitivity and interactions within the brain-gut axis. Recent evidence points towards adequate construct and face validity of experimental models developed with respect to animals' age, sex, strain differences and specific methodological aspects such as non-invasive monitoring of visceromotor response to colorectal distension as being essential in successful identification and evaluation of novel therapeutic targets aimed at reducing stress-related alterations in visceral sensitivity. Underlying mechanisms of stress-induced modulation of visceral pain involve a combination of peripheral, spinal and supraspinal sensitization based on the nature of the stressors and dysregulation of descending pathways that modulate nociceptive transmission or stress-related analgesic response.
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Affiliation(s)
- Muriel Larauche
- CURE/Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Agata Mulak
- CURE/Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Yvette Taché
- CURE/Digestive Diseases Research Center and Center for Neurobiology of Stress, Digestive Diseases Division, Department of Medicine, David Geffen School of Medicine, UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
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50
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O' Mahony SM, Coelho AM, Fitzgerald P, Lee K, Winchester W, Dinan TG, Cryan JF. The effects of gabapentin in two animal models of co-morbid anxiety and visceral hypersensitivity. Eur J Pharmacol 2011; 667:169-74. [PMID: 21645509 DOI: 10.1016/j.ejphar.2011.05.055] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Revised: 05/18/2011] [Accepted: 05/22/2011] [Indexed: 11/18/2022]
Abstract
Visceral hypersensitivity and an increased response to stress are two of the main symptoms of irritable bowel syndrome. Thus efforts to develop animal models of irritable bowel syndrome have centred on both of these parameters. The anticonvulsant gabapentin, which is widely used as an analgesic agent, also reduces anxiety. No data exists to our knowledge of the effects of gabapentin in animal models of co-morbid exaggerated stress response and visceral pain. Our aim was to assess the effect of gabapentin on stress and visceral hypersensitivity in two different animal models of irritable bowel syndrome. The animal models employed were the genetically susceptible Wistar Kyoto rat and the neonatally stressed maternal separation model. These animals were subjected to the open field paradigm to assess stress-induced defecation rates and colorectal distension to assess the level of visceral sensitivity. Gabapentin (30 mg/kg) prevented the stress-induced increase in faecal pellet output in the maternally separated rat, but not the Wistar Kyoto animals. On the other hand gabapentin (30 mg/kg) reduced the number of pain behaviours in response to colorectal distension in both models. These results show that whilst both models have similar responses to gabapentin in terms of visceral pain they differ in terms of their physiological response to stress. This indicates that the origin of anxiety and perhaps then visceral hypersensitivity differs in these models. Overall, these data suggest that gabapentin may be a useful treatment in disorders of co-morbid pain and an overactive stress system such as irritable bowel syndrome.
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Affiliation(s)
- Siobhain M O' Mahony
- Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
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