RESUMEN
Neurogastroenterology refers to the study of the extrinsic and intrinsic nervous system circuits controlling the gastrointestinal (GI) tract. Over the past 5-10 yr there has been an explosion in novel methodologies, technologies and approaches that offer great promise to advance our understanding of the basic mechanisms underlying GI function in health and disease. This review focuses on the use of optogenetics combined with electrophysiology in the field of neurogastroenterology. We discuss how these technologies and tools are currently being used to explore the brain-gut axis and debate the future research potential and limitations of these techniques. Taken together, we consider that the use of these technologies will enable researchers to answer important questions in neurogastroenterology through fundamental research. The answers to those questions will shorten the path from basic discovery to new treatments for patient populations with disorders of the brain-gut axis affecting the GI tract such as irritable bowel syndrome (IBS), functional dyspepsia, achalasia, and delayed gastric emptying.
Asunto(s)
Gastroenterología/métodos , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/fisiología , Neurología/métodos , Optogenética/métodos , Animales , Sistema Nervioso Entérico , Gastroenterología/tendencias , Humanos , Síndrome del Colon Irritable/fisiopatología , Vías Nerviosas/fisiología , Neurología/tendenciasRESUMEN
Symptoms of functional gastrointestinal disorders (FGIDs), including fullness, bloating, abdominal pain, and altered gastrointestinal (GI) motility, present a significant clinical problem, with a reported prevalence of 25%-40% within the general population. More than 60% of those affected seek and require healthcare, and affected individuals report a significantly decreased quality of life. FGIDs are highly correlated with episodes of acute and chronic stress and are increased in prevalence and reported severity in women compared with men. Although there is evidence that sex and stress interact to exacerbate FGID symptoms, the physiological mechanisms that mediate these sex-dependent disparities are incompletely understood, although hormonal-related differences in GI motility and visceral sensitivity have been purported to play a significant role in the etiology. In this mini review, we will discuss brain-gut axis control of GI motility and sensitivity, the influence of estrogen on GI motility and sensitivity, and stress modulation of the brain-gut axis.
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Encéfalo/metabolismo , Estrógenos/metabolismo , Enfermedades Gastrointestinales , Tracto Gastrointestinal , Estrés Psicológico/fisiopatología , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/psicología , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/fisiopatología , HumanosRESUMEN
Abdominal pain represents a significant complaint in patients with irritable bowel syndrome (IBS). While the etiology of IBS is incompletely understood, prior exposure to gastrointestinal inflammation or psychologic stress is frequently associated with the development of symptoms. Inflammation or stress-induced expression of growth factors or cytokines may contribute to the pathophysiology of IBS. Here, we aimed to investigate the therapeutic potential of inhibiting the receptor of glial cell line-derived neurotrophic factor, rearranged during transfection (RET), in experimental models of inflammation and stress-induced visceral hypersensitivity resembling IBS sequelae. In RET-cyan fluorescent protein [(CFP) RetCFP/+] mice, thoracic and lumbosacral dorsal root ganglia were shown to express RET, which colocalized with calcitonin gene-related peptide. To understand the role of RET in visceral nociception, we employed GSK3179106 as a potent, selective, and gut-restricted RET kinase inhibitor. Colonic hyperalgesia, quantified as exaggerated visceromotor response to graded pressures (0-60 mm Hg) of isobaric colorectal distension (CRD), was produced in multiple rat models induced 1) by colonic irritation, 2) following acute colonic inflammation, 3) by adulthood stress, and 4) by early life stress. In all the rat models, RET inhibition with GSK3179106 attenuated the number of abdominal contractions induced by CRD. Our findings identify a role for RET in visceral nociception. Inhibition of RET kinase with a potent, selective, and gut-restricted small molecule may represent a novel therapeutic strategy for the treatment of IBS through the attenuation of post-inflammatory and stress-induced visceral hypersensitivity.
Asunto(s)
Colon/enzimología , Modelos Animales de Enfermedad , Síndrome del Colon Irritable/enzimología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ret/metabolismo , Células A549 , Animales , Línea Celular Tumoral , Colon/efectos de los fármacos , Femenino , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Masculino , Ratones , Ratones Transgénicos , Embarazo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Long-Evans , Ratas Sprague-DawleyRESUMEN
In vivo optogenetics identifies brain circuits controlling behaviors in conscious animals by using light to alter neuronal function and offers a novel tool to study the brain-gut axis. Using adenoviral-mediated expression, we aimed to investigate whether photoactivation with channelrhodopsin (ChR2) or photoinhibition with halorhodopsin (HR3.0) of fibers originating from the central nucleus of the amygdala (CeA) at the bed nucleus of the stria terminalis (BNST) had any effect on colonic sensitivity. We also investigated whether there was any deleterious effect of the adenovirus on the neuronal population or the neuronal phenotype within the CeA-BNST circuitry activated during the optogenetic stimulation. In male rats, the CeA was infected with vectors expressing ChR2 or HR3.0 and fiber optic cannulae were implanted on the BNST. After 8-10 wk, the response to graded, isobaric colonic distension was measured with and without laser stimulation of CeA fibers at the BNST. Immunohistochemistry and histology were used to evaluate vector expression, neuronal integrity, and neurochemical phenotype. Photoactivation of CeA fibers at the BNST with ChR2 induced colonic hypersensitivity, whereas photoinhibition of CeA fibers at the BNST with HR3.0 had no effect on colonic sensitivity. Control groups treated with virus expressing reporter proteins showed no abnormalities in neuronal morphology, neuronal number, or neurochemical phenotype following laser stimulation. Our experimental findings reveal that optogenetic activation of discrete brain nuclei can be used to advance our understanding of complex visceral nociceptive circuitry in a freely moving rat model. NEW & NOTEWORTHY Our findings reveal that optogenetic technology can be employed as a tool to advance understanding of the brain-gut axis. Using adenoviral-mediated expression of opsins, which were activated by laser light and targeted by fiber optic cannulae, we examined central nociceptive circuits mediating visceral pain in a freely moving rat. Photoactivation of amygdala fibers in the stria terminalis with channelrhodopsin induced colonic hypersensitivity, whereas inhibition of the same fibers with halorhodopsin did not alter colonic sensitivity.
Asunto(s)
Dolor Abdominal/etiología , Amígdala del Cerebelo/fisiopatología , Colon/inervación , Optogenética , Dolor Visceral/etiología , Dolor Abdominal/genética , Dolor Abdominal/metabolismo , Dolor Abdominal/fisiopatología , Adenoviridae/genética , Amígdala del Cerebelo/metabolismo , Animales , Channelrhodopsins/biosíntesis , Channelrhodopsins/genética , Estado de Conciencia , Modelos Animales de Enfermedad , Neuronas GABAérgicas/metabolismo , Vectores Genéticos , Halorrodopsinas/biosíntesis , Halorrodopsinas/genética , Láseres de Estado Sólido , Masculino , Mecanotransducción Celular , Inhibición Neural , Vías Nerviosas/fisiopatología , Optogenética/instrumentación , Presión , Ratas Endogámicas F344 , Dolor Visceral/genética , Dolor Visceral/metabolismo , Dolor Visceral/fisiopatologíaRESUMEN
Preclinical research remains an important tool for discovery and validation of novel therapeutics for gastrointestinal disorders. While in vitro assays can be used to verify receptor-ligand interactions and test for structural activity of new compounds, only whole-animal studies can demonstrate drug efficacy within the gastrointestinal system. Most major gastrointestinal disorders have been modeled in animals; however the translational relevance of each model is not equal. The purpose of this chapter is to provide a critical evaluation of common animal models that are being used to develop pharmaceuticals for gastrointestinal disorders. For brevity, the models are presented for upper gastrointestinal disorders involving the esophagus, stomach, and small intestine and lower gastrointestinal disorders that focus on the colon. Particular emphasis is used to explain the face and construct validity of each model, and the limitations of each model, including data interpretation, are highlighted. This chapter does not evaluate models that rely on surgical or other non-pharmacological interventions for treatment.
Asunto(s)
Sistema Nervioso Entérico/fisiopatología , Enfermedades Gastrointestinales/fisiopatología , Motilidad Gastrointestinal , Tracto Gastrointestinal/inervación , Animales , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Enfermedades Gastrointestinales/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , HumanosRESUMEN
The gastrointestinal (GI) system is responsible for the digestion and absorption of ingested food and liquids. Due to the complexity of the GI tract and the substantial volume of material that could be covered under the scope of GI physiology, this chapter briefly reviews the overall function of the GI tract, and discusses the major factors affecting GI physiology and function, including the intestinal microbiota, chronic stress, inflammation, and aging with a focus on the neural regulation of the GI tract and an emphasis on basic brain-gut interactions that serve to modulate the GI tract. GI diseases refer to diseases of the esophagus, stomach, small intestine, colon, and rectum. The major symptoms of common GI disorders include recurrent abdominal pain and bloating, heartburn, indigestion/dyspepsia, nausea and vomiting, diarrhea, and constipation. GI disorders rank among the most prevalent disorders, with the most common including esophageal and swallowing disorders, gastric and peptic ulcer disease, gastroparesis or delayed gastric emptying, irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). Many GI disorders are difficult to diagnose and their symptoms are not effectively managed. Thus, basic research is required to drive the development of novel therapeutics which are urgently needed. One approach is to enhance our understanding of gut physiology and pathophysiology especially as it relates to gut-brain communications since they have clinical relevance to a number of GI complaints and represent a therapeutic target for the treatment of conditions including inflammatory diseases of the GI tract such as IBD and functional gut disorders such as IBS.
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Sistema Nervioso Entérico/fisiopatología , Enfermedades Gastrointestinales/fisiopatología , Animales , Jugo Gástrico/metabolismo , Absorción Gastrointestinal , Enfermedades Gastrointestinales/inmunología , Motilidad Gastrointestinal , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/inervación , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/fisiopatología , Humanos , Secreciones Intestinales/metabolismoRESUMEN
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.
Asunto(s)
Enfermedades Gastrointestinales , Hepatopatías , Nocicepción , Dolor Visceral , Animales , Enfermedades Gastrointestinales/metabolismo , Enfermedades Gastrointestinales/fisiopatología , Hepatopatías/metabolismo , Hepatopatías/fisiopatología , Modelos Animales , Nocicepción/efectos de los fármacos , Nocicepción/fisiología , Terapias en Investigación/métodos , Investigación Biomédica Traslacional , Dolor Visceral/etiología , Dolor Visceral/metabolismo , Dolor Visceral/fisiopatología , Dolor Visceral/psicología , Dolor Visceral/terapiaRESUMEN
Although current therapeutics provide relief from acute pain, drugs used for treatment of chronic pain are typically less efficacious and limited by adverse side effects, including tolerance, addiction, and gastrointestinal upset. Thus, there is a significant need for novel therapies for the treatment of chronic pain. In concert with chronic pain, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic pain disorders. Stress exacerbation of chronic pain suggests that centrally acting drugs targeting the pain- and stress-responsive brain regions represent a valid target for the development of novel therapeutics. This review provides an overview of how stress modulates spinal and central pain pathways, identifies key neurotransmitters and receptors within these pathways, and highlights their potential as novel targets for therapeutics to treat chronic pain.
Asunto(s)
Dolor Crónico/fisiopatología , Estrés Psicológico/fisiopatología , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/metabolismo , Humanos , Neurotransmisores/metabolismo , Nociceptores/metabolismoRESUMEN
BACKGROUND & AIMS: 5-hydroxytryptamine receptor (5-HT(4)R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4)R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity. METHODS: Mucosal expression of the 5-HT(4)R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl(-) secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT(4)R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808. RESULTS: Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5-HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT(4)Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)R agonists accelerated propulsive motility; a 5-HT(4)R antagonist blocked this effect. Bath application of 5-HT(4)R agonists did not affect motility. Oral or intracolonic administration of 5-HT(4)R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4)R antagonist. CONCLUSIONS: Mucosal 5-HT(4) receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4)R agonists. Colon-targeted, intraluminal delivery of 5-HT(4)R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.
Asunto(s)
Analgésicos/farmacología , Colon/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Motilidad Gastrointestinal/efectos de los fármacos , Hiperalgesia/prevención & control , Mucosa Intestinal/efectos de los fármacos , Dolor/prevención & control , Receptores de Serotonina 5-HT4/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Administración Oral , Analgésicos/administración & dosificación , Animales , Cloruros/metabolismo , Cromosomas Artificiales Bacterianos , Colon/inervación , Colon/metabolismo , Modelos Animales de Enfermedad , Células Enterocromafines/efectos de los fármacos , Células Enterocromafines/metabolismo , Fármacos Gastrointestinales/administración & dosificación , Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Cobayas , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inmunohistoquímica , Mucosa Intestinal/inervación , Mucosa Intestinal/metabolismo , Masculino , Potenciales de la Membrana , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Moco/metabolismo , Dolor/metabolismo , Dolor/fisiopatología , Umbral del Dolor/efectos de los fármacos , Presión , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT4/genética , Receptores de Serotonina 5-HT4/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/administración & dosificaciónRESUMEN
BACKGROUND: Irritable bowel syndrome patients have abnormal visceral perception. Probiotic organisms may produce beneficial effects in these patients by reducing visceral hypersensitivity. AIM: To investigate the effects of the probiotic organism, Bifidobacterium infantis 35624, on post-inflammatory visceral hypersensitivity in rats. METHODS: Colitis was induced using intracolonic administration of trinitrobenzenesulfonic acid; control rats received saline (day 0). Myeloperoxidase (MPO) levels and colonic damage scores were determined. From days 15-29, rats (n = 10/group) rats were orally dosed with 2 ml of B. infantis ≥ 10(8) colony-forming units/ml or vehicle (MRS broth). A second series of rats (n = 10/group) was dosed in the same manner from days 15-59. The level of colonic stimulation during colorectal distension (CRD) was determined by recording a visceromotor response (VMR) to CRD at 30 mmHg pre- and post-treatment. Post-treatment samples of colonic tissue were weighed, graded for morphologic damage, and assayed for MPO levels. RESULTS: All rats were hypersensitive at day 15. On day 30, hypersensitivity to colorectal distension remained in the vehicle group, but was significantly reduced in the B. infantis group (mean VMR/10 min: vehicle = 15.4 ± 1.0 vs. B. infantis = 7.6 ± 1.0, p < 0.001). A similar, significant effect was observed at day 60. On both day 30 and day 60, tissue weight, colonic damage scores, and MPO levels resembled those of control animals. CONCLUSIONS: Oral administration of Bifidobacterium infantis 35624 normalized sensitivity to colorectal distension in a rat model of post-inflammatory colonic hypersensitivity.
Asunto(s)
Bifidobacterium , Síndrome del Colon Irritable/terapia , Nocicepción , Probióticos , Dolor Visceral , Animales , Mucosa Intestinal/patología , Síndrome del Colon Irritable/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.
Asunto(s)
Modelos Animales de Enfermedad , Síndrome del Colon Irritable , Dolor Visceral , Animales , HumanosRESUMEN
BACKGROUND: Chronic visceral pain is persistent pain emanating from thoracic, pelvic, or abdominal origin that is poorly localized with regard to the specific organ affected. The prevalence can range up to 25% in the adult population as chronic visceral pain is a common feature of many visceral disorders, which may or may not be accompanied by distinct structural or histological abnormalities within the visceral organs. Mounting evidence suggests that changes in epigenetic mechanisms are involved in the top-down or bottom-up sensitization of pain pathways and the development of chronic pain. Epigenetic changes can lead to long-term alterations in gene expression profiles of neurons and consequently alter functionality of peripheral neurons, dorsal root ganglia, spinal cord, and brain neurons. However, epigenetic modifications are dynamic, and thus, detrimental changes may be reversible. Hence, external factors/therapeutic interventions may be capable of modulating the epigenome and restore normal gene expression for extended periods of time. PURPOSE: The goal of this review is to highlight the latest discoveries made toward understanding the epigenetic mechanisms that are involved in the development or maintenance of chronic visceral pain. Furthermore, this review will provide evidence supporting that targeting these epigenetic mechanisms may represent a novel approach to treat chronic visceral pain.
Asunto(s)
Epigénesis Genética/efectos de los fármacos , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/genética , Animales , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/genética , Dolor Crónico/fisiopatología , Sistemas de Liberación de Medicamentos , Humanos , Dolor Visceral/fisiopatologíaRESUMEN
BACKGROUND: The expression of RET in the developing enteric nervous system (ENS) suggests that RET may contribute to adult intestinal function. ENS cholinergic nerves play a critical role in the control of colonic function through the release of acetylcholine (ACh). In the current study, we hypothesized that a RET-mediated mechanism may regulate colonic ion transport and motility through modulation of cholinergic nerves. METHODS: The effect of RET inhibition on active ion transport was assessed electrophysiologically in rat colonic tissue mounted in Ussing chambers via measurements of short circuit current (Isc) upon electrical field stimulation (EFS) or pharmacologically with cholinergic agonists utilizing a gastrointestinal (GI)-restricted RET inhibitor. We assessed the effect of the RET inhibitor on propulsive motility via quantification of fecal pellet output (FPO) induced by the acetylcholinesterase inhibitor neostigmine. KEY RESULTS: We found that enteric ganglia co-expressed RET and choline acetyltransferase (ChAT) transcripts. In vitro, the RET kinase inhibitor GSK3179106 attenuated the mean increase in Isc induced by either EFS or carbachol but not bethanechol. In vivo, GSK3179106 significantly reduced the prokinetic effect of neostigmine. CONCLUSION AND INFERENCES: Our findings provide evidence that RET-mediated mechanisms regulate colonic function by maintaining cholinergic neuronal function and enabling ACh-evoked chloride secretion and motility. We suggest that modulating the cholinergic control of the colon via a RET inhibitor may represent a novel target for the treatment of intestinal disorders associated with increased secretion and accelerated GI transit such as irritable bowel syndrome with diarrhea (IBS-D).
Asunto(s)
Neuronas Colinérgicas/efectos de los fármacos , Colon/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Transporte Iónico/efectos de los fármacos , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Animales , Colina O-Acetiltransferasa/metabolismo , Agonistas Colinérgicos/farmacología , Neuronas Colinérgicas/metabolismo , Colon/metabolismo , Defecación/efectos de los fármacos , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/metabolismo , Tránsito Gastrointestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-ret/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
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.
RESUMEN
Background: Irritable bowel syndrome (IBS) is characterized by visceral pain and abnormal bowel habits that are worsened during stress. Evidence also suggests altered intestinal barrier function in IBS. Previously, we demonstrated that stereotaxic application of the stress hormone corticosterone (CORT) onto the central nucleus of the amygdala (CeA) induces colonic hyperalgesia and anxiety-like behavior in a rat model, however the effect on intestinal permeability and mucosal function remain to be evaluated. Methods: Male Fischer 344 rats underwent bilateral stereotaxic implantation of CORT or inert cholesterol (CHOL)-containing micropellets (30 µg) onto the dorsal margin of the CeA. Seven days later, colonic tissue was isolated to assess tissue permeability in modified Ussing chambers via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). Secretory responses to electrical field stimulation (EFS) of submucosal enteric nerves as well as activation with forskolin were used to assess movements of ions across the isolated colonic tissues. In a separate cohort, colonic histology, and mast cell infiltration was assessed. Key Results: Compared to CHOL-implanted controls, we determined that exposing the CeA to elevated levels of CORT significantly increased macromolecular flux across the colonic epithelial layer without changing TEER. Nerve-mediated but not cAMP-mediated active transport was inhibited in response to elevated amygdala CORT. There were no histological changes or increases in mast cell infiltration within colonic tissue from CORT treated animals. Conclusion and Inferences: These observations support a novel role for the CeA as a modulator of nerve-mediated colonic epithelial function.
RESUMEN
Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the 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 visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing.
RESUMEN
This study examined the long-term effects of an acute colitis on central corticotropin-releasing factor (CRF) expression. An increase in CRF mRNA in the paraventricular nucleus of the hypothalamus (PVN) and the central nucleus of the amygdala (CeA) was observed during active colitis, and the effect in the PVN was maintained following recovery. In summary, hypothalamic gene expression of CRF persists in the PVN despite resolution of an acute colitis.
Asunto(s)
Colitis/metabolismo , Colitis/patología , Hormona Liberadora de Corticotropina/metabolismo , Regulación de la Expresión Génica/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Núcleo Hipotalámico Paraventricular/fisiopatología , Animales , Autorradiografía/métodos , Colitis/inducido químicamente , Hormona Liberadora de Corticotropina/genética , Citocinas/genética , Citocinas/metabolismo , Diagnóstico por Imagen/métodos , Ensayo de Cambio de Movilidad Electroforética/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Ácido Trinitrobencenosulfónico/toxicidadRESUMEN
Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. While current therapeutics provides some relief from somatic pain, drugs used for treatment of chronic visceral pain are typically less efficacious and limited by multiple adverse side effects. Thus, the treatment of visceral pain represents a major unmet medical need. Further, more basic research into the physiology and pathophysiology of visceral pain is needed to provide novel targets for future drug development. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. However, persistent stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders. We will focus on stress-induced exacerbation of chronic visceral pain and provide supporting evidence that centrally acting drugs targeting the pain and stress-responsive brain regions may represent a valid target for the development of novel and effective therapeutics.
Asunto(s)
Dolor Visceral/fisiopatología , Animales , Conducta Animal , Modelos Animales de Enfermedad , HumanosRESUMEN
Visceral pain is a global term used to describe pain originating from the internal organs of the body, which affects a significant proportion of the population and is a common feature of functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). While IBS is multifactorial, with no single etiology to completely explain the disorder, many patients also experience comorbid behavioral disorders, such as anxiety or depression; thus, IBS is described as a disorder of the gut-brain axis. Stress is implicated in the development and exacerbation of visceral pain disorders. Chronic stress can modify central pain circuitry, as well as change motility and permeability throughout the gastrointestinal (GI) tract. More recently, the role of the gut microbiota in the bidirectional communication along the gut-brain axis, and subsequent changes in behavior, has emerged. Thus, stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. This review will highlight the evidence by which stress and the gut microbiota interact in the regulation of visceral nociception. We will focus on the influence of stress on the microbiota and the mechanisms by which microbiota can affect the stress response and behavioral outcomes with an emphasis on visceral pain.
Asunto(s)
Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiología , Tracto Gastrointestinal/metabolismo , Síndrome del Colon Irritable/metabolismo , Estrés Psicológico/metabolismo , Dolor Visceral/metabolismo , Animales , Ensayos Clínicos como Asunto/métodos , Humanos , Síndrome del Colon Irritable/psicología , Estrés Psicológico/psicología , Dolor Visceral/psicologíaRESUMEN
Spinal cord stimulation (SCS) has been found to relieve neuropathic and ischemic pain clinically and to attenuate a nociceptive reflex in an animal model of acute colonic hypersensitivity. The goal of the present study was to determine the effect of SCS in a rat model of post-inflammatory colonic hypersensitivity. Acute inflammation was induced in rats by a single enema of trinitrobenzenesulfonic acid (TNBS) (50 mg/kg, 0.5 ml, 25% EtOH). Control rats received a single saline enema. A visceromotor behavioral response (VMR), induced by innocuous colorectal distention (30 mm Hg, 10 min) was used to quantify the level of colonic sensitivity on day 3 and 30 post-enema. Prior to VMR testing, under general anesthesia, an electrode (cathode) was placed epidurally on the dorsal surface of the spinal cord at L1 with a paravertebral anode plate. Three to 7 days after implantation of the SCS electrode, the effect of SCS (50 Hz, 0.2 ms, amplitude 90% of motor threshold for 30 min) on colonic sensitivity was determined. On day 30, rats that had received a single TNBS enema were hypersensitive to innocuous colonic distention when compared to rats that received a saline enema (VMR/10 min: TNBS: 17.2+/-0.8 vs. Saline: 9.6+/-1.1, p<0.01). Spinal cord stimulation significantly reduced the VMR in the TNBS-enema group to a value that resembled the saline-enema group (VMR/10 min: TNBS: 11.2+/-1.2 vs. Saline: 10.0+/-1.0). This study provides the first evidence that SCS might be a potential therapeutic for the treatment of abdominal pain observed in patients with post-inflammatory irritable bowel syndrome.