RESUMEN
Early-life stress (ELS) is a high-risk factor for the development of chronic visceral pain in adulthood. Emerging evidence suggests that mast cells play a key role in the development of visceral hypersensitivity through interaction with neurons. The sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of visceral pain. However, the precise mechanism by which mast cells and CRF neurons interact in the PVN in the pathogenesis of visceral hypersensitivity remains elusive. In the present study, we used neonatal maternal separation (MS), an ELS model, and observed that neonatal MS induced visceral hypersensitivity and triggered PVN mast cell activation in adult rats, which was repressed by intra-PVN infusion of the mast cell stabilizer disodium cromoglycate (cromolyn). Wild-type (WT) mice but not mast cell-deficient KitW-sh/W-sh mice that had experienced neonatal MS exhibited chronic visceral hypersensitivity. MS was associated with an increase in the expression of proinflammatory mediators, the number of CRF+ cells and CRF protein in the PVN, which was prevented by intra-PVN infusion of cromolyn. Furthermore, we demonstrated that intra-PVN infusion of the mast degranulator compound 48/80 significantly induced mast cell activation, resulting in proinflammatory mediator release, CRF neuronal sensitization, and visceral hypersensitivity, which was suppressed by cromolyn. Overall, our findings demonstrated that neonatal MS induces the activation of PVN mast cells, which secrete numerous proinflammatory mediators that may participate in neighboring CRF neuronal activity, ultimately directly inducing visceral hypersensitivity in adulthood.
Asunto(s)
Hiperalgesia , Mastocitos , Privación Materna , Núcleo Hipotalámico Paraventricular , Estrés Psicológico , Dolor Visceral , Animales , Masculino , Ratones , Ratas , Animales Recién Nacidos , Modelos Animales de Enfermedad , Hiperalgesia/etiología , Hiperalgesia/inmunología , Hiperalgesia/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Transgénicos , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/inmunología , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas Sprague-Dawley , Dolor Visceral/inmunología , Dolor Visceral/metabolismoRESUMEN
BACKGROUND & AIMS: Psychological stress is a trigger for the development of irritable bowel syndrome and associated symptoms including abdominal pain. Although irritable bowel syndrome patients show increased activation in the limbic brain, including the amygdala, the underlying molecular and cellular mechanisms regulating visceral nociception in the central nervous system are incompletely understood. In a rodent model of chronic stress, we explored the role of microglia in the central nucleus of the amygdala (CeA) in controlling visceral sensitivity. Microglia are activated by environmental challenges such as stress, and are able to modify neuronal activity via synaptic remodeling and inflammatory cytokine release. Inflammatory gene expression and microglial activity are regulated negatively by nuclear glucocorticoid receptors (GR), which are suppressed by the stress-activated pain mediator p38 mitogen-activated protein kinases (MAPK). METHODS: Fisher-344 male rats were exposed to water avoidance stress (WAS) for 1 hour per day for 7 days. Microglia morphology and the expression of phospho-p38 MAPK and GR were analyzed via immunofluorescence. Microglia-mediated synaptic remodeling was investigated by quantifying the number of postsynaptic density protein 95-positive puncta. Cytokine expression levels in the CeA were assessed via quantitative polymerase chain reaction and a Luminex assay (Bio-Rad, Hercules, CA). Stereotaxic infusion into the CeA of minocycline to inhibit, or fractalkine to activate, microglia was followed by colonic sensitivity measurement via a visceromotor behavioral response to isobaric graded pressures of tonic colorectal distension. RESULTS: WAS induced microglial deramification in the CeA. Moreover, WAS induced a 3-fold increase in the expression of phospho-p38 and decreased the ratio of nuclear GR in the microglia. The number of microglia-engulfed postsynaptic density protein 95-positive puncta in the CeA was increased 3-fold by WAS, while cytokine levels were unchanged. WAS-induced changes in microglial morphology, microglia-mediated synaptic engulfment in the CeA, and visceral hypersensitivity were reversed by minocycline whereas in stress-naïve rats, fractalkine induced microglial deramification and visceral hypersensitivity. CONCLUSIONS: Our data show that chronic stress induces visceral hypersensitivity in male rats and is associated with microglial p38 MAPK activation, GR dysfunction, and neuronal remodeling in the CeA.
Asunto(s)
Núcleo Amigdalino Central/inmunología , Síndrome del Colon Irritable/inmunología , Microglía/inmunología , Estrés Psicológico/complicaciones , Dolor Visceral/inmunología , Animales , Núcleo Amigdalino Central/citología , Núcleo Amigdalino Central/efectos de los fármacos , Núcleo Amigdalino Central/patología , Quimiocina CX3CL1/administración & dosificación , Modelos Animales de Enfermedad , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Minociclina/administración & dosificación , Plasticidad Neuronal/inmunología , Ratas , Receptores de Glucocorticoides/metabolismo , Técnicas Estereotáxicas , Estrés Psicológico/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND & AIMS: Despite achieving endoscopic remission, more than 20% of inflammatory bowel disease patients experience chronic abdominal pain. These patients have increased rectal transient receptor potential vanilloid-1 receptor (TRPV1) expression, a key transducer of inflammatory pain. Because inflammatory bowel disease patients in remission exhibit dysbiosis and microbial manipulation alters TRPV1 function, our goal was to examine whether microbial perturbation modulated transient receptor potential function in a mouse model. METHODS: Mice were given dextran sodium sulfate (DSS) to induce colitis and were allowed to recover. The microbiome was perturbed by using antibiotics as well as fecal microbial transplant (FMT). Visceral and somatic sensitivity were assessed by recording visceromotor responses to colorectal distention and using hot plate/automated Von Frey tests, respectively. Calcium imaging of isolated dorsal root ganglia neurons was used as an in vitro correlate of nociception. The microbiome composition was evaluated via 16S rRNA gene variable region V4 amplicon sequencing, whereas fecal short-chain fatty acids (SCFAs) were assessed by using targeted mass spectrometry. RESULTS: Postinflammatory DSS mice developed visceral and somatic hyperalgesia. Antibiotic administration during DSS recovery induced visceral, but not somatic, hyperalgesia independent of inflammation. FMT of postinflammatory DSS stool into antibiotic-treated mice increased visceral hypersensitivity, whereas FMT of control stool reversed antibiotics' sensitizing effects. Postinflammatory mice exhibited both increased SCFA-producing species and fecal acetate/butyrate content compared with controls. Capsaicin-evoked calcium responses were increased in naive dorsal root ganglion neurons incubated with both sodium butyrate/propionate alone and with colonic supernatants derived from postinflammatory mice. CONCLUSIONS: The microbiome plays a central role in postinflammatory visceral hypersensitivity. Microbial-derived SCFAs can sensitize nociceptive neurons and may contribute to the pathogenesis of postinflammatory visceral pain.
Asunto(s)
Colitis Ulcerosa/complicaciones , Disbiosis/inmunología , Microbioma Gastrointestinal/inmunología , Dolor Visceral/inmunología , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/microbiología , Colon/efectos de los fármacos , Colon/inmunología , Colon/microbiología , Colon/patología , Sulfato de Dextran/administración & dosificación , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Disbiosis/microbiología , Ácidos Grasos Volátiles/análisis , Ácidos Grasos Volátiles/metabolismo , Heces/química , Heces/microbiología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Nocicepción , Nociceptores/inmunología , Nociceptores/metabolismo , Canales Catiónicos TRPV/metabolismo , Dolor Visceral/microbiologíaRESUMEN
Visceral pain, characterized by abdominal discomfort, originates from organs in the abdominal cavity and is a characteristic symptom in patients suffering from irritable bowel syndrome, vulvodynia or interstitial cystitis. Most organs in which visceral pain originates are in contact with the external milieu and continuously exposed to microbes. In order to maintain homeostasis and prevent infections, the immune- and nervous system in these organs cooperate to sense and eliminate (harmful) microbes. Recognition of microbial components or products by receptors expressed on cells from the immune and nervous system can activate immune responses but may also cause pain. We review the microbial compounds and their receptors that could be involved in visceral pain development.
Asunto(s)
Microbiota/inmunología , Dolor Visceral/inmunología , Dolor Visceral/microbiología , Animales , Humanos , Inmunidad/inmunología , Sistema Nervioso/microbiología , Dolor Visceral/etiologíaRESUMEN
Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.
Asunto(s)
Trastorno del Espectro Autista , Dolor Crónico , Cistitis Intersticial , Disbiosis , Microbioma Gastrointestinal/fisiología , Enfermedades Inflamatorias del Intestino , Síndrome del Colon Irritable , Neuronas Aferentes , Nocicepción/fisiología , Dolor Visceral , Trastorno del Espectro Autista/etiología , Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Dolor Crónico/etiología , Dolor Crónico/inmunología , Dolor Crónico/metabolismo , Dolor Crónico/fisiopatología , Cistitis Intersticial/etiología , Cistitis Intersticial/inmunología , Cistitis Intersticial/metabolismo , Cistitis Intersticial/fisiopatología , Disbiosis/complicaciones , Disbiosis/inmunología , Disbiosis/metabolismo , Disbiosis/fisiopatología , Humanos , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/fisiopatología , Síndrome del Colon Irritable/etiología , Síndrome del Colon Irritable/inmunología , Síndrome del Colon Irritable/metabolismo , Síndrome del Colon Irritable/fisiopatología , Neuronas Aferentes/inmunología , Neuronas Aferentes/metabolismo , Neuronas Aferentes/microbiología , Dolor Visceral/etiología , Dolor Visceral/inmunología , Dolor Visceral/metabolismo , Dolor Visceral/fisiopatologíaRESUMEN
BACKGROUND: The opioid-mediated analgesic activity of mucosal CD4+ T lymphocytes in colitis has been reported in immunocompetent mice so far. Here, we investigated whether CD4+ T lymphocytes alleviate from inflammation-induced abdominal pain in mice with defective immune regulation. METHODS: Endogenous control of visceral pain by opioids locally produced in inflamed mucosa was assessed in IL-10-deficient mice. KEY RESULTS: CD4+ T lymphocytes but not F4/80+ macrophages isolated from the lamina propria of IL-10-deficient mice with colitis express enkephalin-containing opioid peptides as assessed by cytofluorometry. Colitis in IL-10-/- mice was not associated with abdominal pain. Intraperitoneal injection of naloxone-methiodide, a peripheral opioid receptor antagonist, induced abdominal hypersensitivity in IL-10-/- mice with colitis. CONCLUSION AND INFERENCES: Opioid-mediated analgesic activity of mucosal T lymphocytes remains operating in IL-10-/- mice with impaired immune regulation. The data suggest that endogenous T cell-derived opioids might reduce inflammation-induced abdominal pain in inflammatory bowel diseases associated with homozygous "loss of function mutations" in interleukin-10.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-10/deficiencia , Mucosa Intestinal/inmunología , Péptidos Opioides/inmunología , Dolor Visceral/inmunología , Animales , Colitis/complicaciones , Colitis/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor Visceral/etiologíaRESUMEN
BACKGROUND: Visceral hypersensitivity is one of the main pathogenesis of irritable bowel syndrome (IBS) and mast cell activation is closely related to visceral hypersensitivity. As a critical molecule of the innate immune system, toll-like receptor 4 (TLR4) may modulate the activation of mast cell. Alleviating effect of electroacupuncture (EA) on visceral hypersensitivity has been proved, whereas, whether the TLR4 and mast cell is involved in this process remains unclear. METHODS: Forty Sprague-Dawley rats were randomly divided into five groups: control group, model group, EA group, sham EA group, and mast cell stabilizer (MCS) group. Visceral sensitivity during colorectal distension was assessed by the measurement of visceral motor reflex (VMR). TLR4 mRNA and protein expression were assessed by real-time PCR and immunohistochemistry, respectively. Mast cell number and mast cell tryptase (MCT) expression were detected. The level of inflammatory cytokine in serum was detected with ELISA. KEY RESULTS: Visceral sensitivity was significantly higher in the model group than in the control group. EA and MCS significantly reduced VMR score at 0.8 mL and 1.2 mL distention pressures. Compared with model group, TLR4 mRNA expression, the protein expression of TLR4 and MCT, and the number of mast cells with degranulation in the colonic tissue, serum concentration of IL-1ß and IL-8 were all significantly decreased in EA and MCS group. CONCLUSIONS & INFERENCES: Electroacupuncture ameliorated visceral hypersensitivity in colon-sensitized model probably via decreasing the level of pro-inflammatory cytokines released by mast cell which were decreased when the TLR4 expression in the colonic tissue was downregulated by EA.
Asunto(s)
Electroacupuntura , Hiperalgesia/inmunología , Mastocitos/inmunología , Receptor Toll-Like 4/inmunología , Dolor Visceral/inmunología , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15-45 mg of TNBS) in 30 rats, whereas the control rats (n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity (P = 0.03), 2) an increased colon weight-to-length ratio (P = 0.01), 3) higher inflammatory and fibrosis scores (P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production (P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae. NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.
Asunto(s)
Ansiedad , Colon , Motilidad Gastrointestinal , Enfermedades Inflamatorias del Intestino , Dolor Visceral , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Conducta Animal/fisiología , Colitis/inmunología , Colitis/fisiopatología , Colitis/psicología , Colon/inervación , Colon/metabolismo , Colon/fisiopatología , Citocinas/análisis , Modelos Animales de Enfermedad , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/fisiopatología , Enfermedades Inflamatorias del Intestino/psicología , Masculino , Permeabilidad , Peroxidasa/análisis , Ratas , Proteínas de Uniones Estrechas/análisis , Dolor Visceral/etiología , Dolor Visceral/inmunología , Dolor Visceral/fisiopatología , Dolor Visceral/psicologíaRESUMEN
T lymphocytes play a pivotal role in endogenous regulation of inflammatory visceral pain. The analgesic activity of T lymphocytes is dependent on their production of opioids, a property acquired on antigen activation. Accordingly, we investigated whether an active recruitment of T lymphocytes within inflamed colon mucosa via a local vaccinal strategy may counteract inflammation-induced visceral pain in mice. Mice were immunized against ovalbumin (OVA). One month after immunization, colitis was induced by adding 3% (wt/vol) dextran sulfate sodium into drinking water containing either cognate antigen OVA or control antigen bovine serum albumin for 5 days. Noncolitis OVA-primed mice were used as controls. Visceral sensitivity was then determined by colorectal distension. Oral administration of OVA but not bovine serum albumin significantly reduced dextran sulfate sodium-induced abdominal pain without increasing colitis severity in OVA-primed mice. Analgesia was dependent on local release of enkephalins by effector anti-OVA T lymphocytes infiltrating the inflamed mucosa. The experiments were reproduced with the bacillus Calmette-Guerin vaccine as antigen. Similarly, inflammatory visceral pain was dramatically alleviated in mice vaccinated against bacillus Calmette-Guerin and then locally administered with live Mycobacterium bovis. Together, these results show that the induction of a secondary adaptive immune response against vaccine antigens in inflamed mucosa may constitute a safe noninvasive strategy to relieve from visceral inflammatory pain.
Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Colitis/complicaciones , Colitis/etiología , Inmunización/efectos adversos , Membrana Mucosa/patología , Dolor Visceral , Animales , Antígenos CD11/genética , Antígenos CD11/metabolismo , Colitis/patología , Modelos Animales de Enfermedad , Encefalinas/deficiencia , Encefalinas/genética , Encefalinas/farmacología , Adyuvante de Freund/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovalbúmina/efectos adversos , Precursores de Proteínas/deficiencia , Precursores de Proteínas/genética , Estadísticas no Paramétricas , Dolor Visceral/etiología , Dolor Visceral/inmunología , Dolor Visceral/patologíaRESUMEN
BACKGROUND: Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal Th1/Th17-associated inflammation, enkephalins released by colitogenic CD4+ T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in Th1/Th17-associated colitis. METHODS: The anti-inflammatory effects of endogenous opioids were investigated in both Th1/Th17-associated (transfer of CD4+CD45RBhigh T lymphocytes) and Th2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4+ T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4+CD45RBhigh T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred. RESULTS: Peripheral opioid receptor blockade increases the severity of Th1/Th17-induced colitis and attenuates Th2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a Th2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4+CD45RBhigh T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury. CONCLUSIONS: Endogenous opioids, including T-cell-derived enkephalins, promote a Th2-type immune response, which, depending on the context, may either attenuate (Th1/Th17-associated) or aggravate (Th2-associated) intestinal inflammation.
Asunto(s)
Colitis/inmunología , Encefalinas/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Linfocitos T CD4-Positivos/trasplante , Colitis/tratamiento farmacológico , Inmunidad Mucosa , Transfusión de Linfocitos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Naloxona/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Dolor Visceral/inmunologíaRESUMEN
BACKGROUND AND PURPOSE (AIMS): Psychoneuroimmunology is both a theoretical and practical field of medicine in which human biology and psychology are considered an interconnected unity. Through such a framework it is possible to elucidate complex syndromes in gastrointestinal related pain, particularly chronic non-malignant. The aim is to provide insight into pathophysiological mechanisms and suggest treatment modalities according to a comprehensive paradigm. The article also presents novel findings that may guide clinicians to recognize new targets or scientists to find new research topics. METHODS: A literature search of 'PubMed' and 'Google Scholar' databases was performed. Search terms included: 'Visceral pain', 'Psychoneuroimmunology', 'Psychoneuroimmunology and pain', 'Pain in GI system', 'GI related pain', 'Pain and microbiota', 'Enteric nervous system', 'Enteric nervous system and inflammation', 'CNS and pain', 'Inflammation and pain in GI tract', 'Neurogastroenterology', 'Neuroendocrinology', 'Immune system in GI pain'. After searching and reading sources deemed recent and relevant, a narrative review was written with a tendency to discriminate the peripheral, intermediate, and central pathophysiological mechanisms or treatment targets. RESULTS: Recent evidence point out the importance of considering the brain-gut axis as the main connector of the central and peripheral phenomena encountered in patients suffering from chronic non-malignant gastrointestinal related pain. This axis is also a prime clinical target with multiple components to be addressed in order for therapy to be more effective. Patients suffering from inflammatory bowel disease or functional gastrointestinal disorders represent groups that could benefit most from the proposed approach. CONCLUSIONS (BASED ON OUR FINDINGS): Rather than proceeding with established allopathic single-target central or peripheral treatments, by non-invasively modulating the brain-gut axis components such as the psychological and neuroendocrinological status, microbiota, enteric nervous system, or immune cells (e.g. glial or mast cells), a favourable clinical outcome in various chronic gastrointestinal related pain syndromes may be achieved. Clinical tools are readily available in forms of psychotherapy, prebiotics, probiotics, nutritional advice, and off-label drugs. An example of the latter is low-dose naltrexone, a compound which opens the perspective of targeting glial cells to reduce neuroinflammation and ultimately pain. IMPLICATIONS (OUR OPINION ON WHAT OUR FINDINGS MEAN): Current findings from basic science provide sound mechanistic evidence and once entering clinical practice should yield more effective outcomes for patients. In addition to well-established pharmacotherapy comprised notably of anti-inflammatories, antibiotics, and proton-pump inhibitors, valid treatment strategies may contain other options. These disease modulating add-ons include probiotics, prebiotics, food supplements with anti-inflammatory properties, various forms of psychotherapy, and low-dose naltrexone as a glial modulator that attenuates neuroinflammation. Clearly, a broader and still under exploited set of evidence-based tools is available for clinical use.
Asunto(s)
Dolor Abdominal , Encéfalo , Dolor Crónico , Microbioma Gastrointestinal/fisiología , Enfermedades Inflamatorias del Intestino , Psiconeuroinmunología/métodos , Dolor Visceral , Dolor Abdominal/inmunología , Dolor Abdominal/metabolismo , Dolor Abdominal/fisiopatología , Encéfalo/inmunología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Dolor Crónico/inmunología , Dolor Crónico/metabolismo , Dolor Crónico/fisiopatología , Microbioma Gastrointestinal/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/fisiopatología , Dolor Visceral/inmunología , Dolor Visceral/metabolismo , Dolor Visceral/fisiopatologíaRESUMEN
In the central nervous system, bidirectional signaling between glial cells and neurons ('neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions.
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Dolor Crónico/fisiopatología , Inflamación Neurogénica/fisiopatología , Neuroglía/fisiología , Neuronas/fisiología , Médula Espinal/fisiopatología , Dolor Visceral/fisiopatología , Animales , Dolor Crónico/inmunología , Femenino , Humanos , Masculino , Inflamación Neurogénica/inmunología , Neuroinmunomodulación/inmunología , Neuroinmunomodulación/fisiología , Factores Sexuales , Médula Espinal/inmunología , Dolor Visceral/inmunologíaRESUMEN
BACKGROUND: Infectious gastroenteritis is a major risk factor to develop postinfectious irritable bowel syndrome (PI-IBS). It remains unknown why only a subgroup of infected individuals develops PI-IBS. We hypothesize that immunogenetic predisposition is an important risk factor. Hence, we studied the effect of Citrobacter rodentium infection on visceral sensitivity in Th1-predominant C57BL/6 and Th2-predominant Balb/c mice. METHODS: Eight-week-old mice were gavaged with C. rodentium, followed by 1 h of water avoidance stress (WAS) at 5 weeks PI. At 10, 14 days, and 5 weeks PI, samples were assessed for histology and inflammatory gene expression by RT-qPCR. Visceral sensitivity was evaluated by visceromotor response recordings (VMR) to colorectal distension. KEY RESULTS: Citrobacter rodentium evoked a comparable colonic inflammatory response at 14 days PI characterized by increased crypt length and upregulation of Th1/Th17 cytokine mRNA levels (puncorrected < 0.05) in both C57BL/6 and Balb/c mice. At 5 weeks PI, inflammatory gene mRNA levels returned to baseline in both strains. The VMR was maximal at 14 days PI in C57BL/6 (150 ± 47%; p = 0.02) and Balb/c mice (243 ± 52%; p = 0.03). At 3 weeks PI, the VMR remained increased in Balb/c (176 ± 23%; p = 0.02), but returned to baseline in C57BL/6 mice. At 5 weeks PI, WAS could not re-introduce visceral hypersensitivity (VHS). CONCLUSIONS & INFERENCES: Citrobacter rodentium infection induces transient VHS in C57BL/6 and Balb/c mice, which persisted 1 week longer in Balb/c mice. Although other strain-related differences may contribute, a Th2 background may represent a risk factor for prolonged PI-VHS. As PI-VHS is transient, other factors are crucial for persistent VHS development as observed in PI-IBS.
Asunto(s)
Citrobacter rodentium , Infecciones por Enterobacteriaceae/genética , Antecedentes Genéticos , Mediadores de Inflamación , Estrés Fisiológico/fisiología , Dolor Visceral/genética , Animales , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Fenómenos Inmunogenéticos/fisiología , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Especificidad de la Especie , Células Th2/fisiología , Dolor Visceral/inmunología , Dolor Visceral/metabolismoRESUMEN
BACKGROUND: Chronic visceral pain is a defining feature of irritable bowel syndrome (IBS). IBS patients often show alterations in innate and adaptive immune function which may contribute to symptoms. Immune mediators are known to modulate the activity of viscero-sensory afferent nerves, but the focus has been on the innate immune system. Interleukin-2 (IL-2) is primarily associated with adaptive immune responses but its effects on colo-rectal afferent function in health or disease are unknown. METHODS: Myeloperoxidase (MPO) activity determined the extent of inflammation in health, acute trinitrobenzene-sulfonic acid (TNBS) colitis, and in our post-TNBS colitis model of chronic visceral hypersensitivity (CVH). The functional effects of IL-2 on high-threshold colo-rectal afferents and the expression of IL-2R and NaV 1.7 mRNA in colo-rectal dorsal root ganglia (DRG) neurons were compared between healthy and CVH mice. KEY RESULTS: MPO activity was increased during acute colitis, but subsided to levels comparable to health in CVH mice. IL-2 caused direct excitation of colo-rectal afferents that was blocked by tetrodotoxin. IL-2 did not affect afferent mechanosensitivity in health or CVH. However, an increased proportion of afferents responded directly to IL-2 in CVH mice compared with controls (73% vs 33%; p < 0.05), and the abundance of IL-2R and NaV 1.7 mRNA was increased 3.5- and 2-fold (p < 0.001 for both) in colo-rectal DRG neurons. CONCLUSIONS & INFERENCES: IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.
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Colitis/genética , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/genética , Interleucina-2/farmacología , Síndrome del Colon Irritable/genética , Neuronas Aferentes/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Dolor Visceral/genética , Inmunidad Adaptativa , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/citología , Ganglios Espinales/metabolismo , Hiperalgesia/inmunología , Hiperalgesia/fisiopatología , Síndrome del Colon Irritable/inmunología , Síndrome del Colon Irritable/metabolismo , Ratones , Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuronas Aferentes/metabolismo , Peroxidasa/efectos de los fármacos , Peroxidasa/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-2/efectos de los fármacos , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ácido Trinitrobencenosulfónico/toxicidad , Dolor Visceral/inmunología , Dolor Visceral/fisiopatologíaRESUMEN
Intestinal inflammation results in the production of inflammatory pain-inducing mediators that may directly activate colon sensory neurons. Endogenous opioids produced by mucosal effector CD4(+) T lymphocytes identified as colitogenic may paradoxically counterbalance the local pro-algesic effect of inflammatory mediators by acting on opioid receptors expressed on sensory nerve endings. The review will focus on the endogenous immune-mediated regulation of visceral inflammatory pain, current pain treatments in inflammatory bowel diseases and prospectives on new opioid therapeutic opportunities to alleviate pain but avoiding common centrally-mediated side effects.
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Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Péptidos Opioides/uso terapéutico , Manejo del Dolor/métodos , Dolor Visceral/tratamiento farmacológico , Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapéutico , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/fisiopatología , Modelos Inmunológicos , Péptidos Opioides/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Dolor Visceral/complicaciones , Dolor Visceral/inmunología , Dolor Visceral/fisiopatologíaRESUMEN
The high comorbidity existing between visceral pain and psychiatric disorders such as depression and anxiety is well documented and it is gaining increasing interest among scientists. When visceral pain and psychiatric disorders are comorbid, they present a more debilitating condition than each disorder alone, impacting significantly on the quality of life of these patients. Despite several groups having shown that an overlapping pathophysiology exists between visceral pain and stress-related disorders the link between them is not clear yet. Moreover, it still remains to be elucidated if psychiatric conditions predispose the individual to develop visceral hypersensitivity or vice versa. The brain-gut-microbiome axis is the bidirectional communication between the CNS and the gastrointestinal tract. Alterations at different levels of this axis have been implicated in both visceral hypersensitivity and psychiatric disorders. Here we give an overview of what it is known about comorbid visceral pain and psychiatric disorders and provide evidence of potential overlapping pathophysiological mechanisms involved. Preclinical models of comorbid visceral pain and stress-related disorders are also discussed.
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Trastornos Mentales/complicaciones , Trastornos Mentales/fisiopatología , Dolor Visceral/complicaciones , Dolor Visceral/fisiopatología , Animales , Femenino , Humanos , Masculino , Trastornos Mentales/inmunología , Estrés Psicológico/complicaciones , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatología , Dolor Visceral/inmunologíaRESUMEN
BACKGROUND & AIMS: A dysregulated response of CD4(+) T cells against the microbiota contributes to the development of inflammatory bowel disease. Effector CD4(+) T cells, generated in response to microbe-derived antigens, can reduce somatic inflammatory pain through the local release of opioids. We investigated whether colitogenic CD4(+) T cells that accumulate in the inflamed colon also produce opioids and are able to counteract inflammation-induced visceral pain in mice. METHODS: Colitis was induced via transfer of naive CD4(+)CD45RB(high) T cells to immune-deficient mice or by administration of dextran sulfate sodium. Mice without colitis were used as controls. Samples of colon tissue were collected, and production of opioids by immune cells from inflamed intestine was assessed by quantitative polymerase chain reaction and cytofluorometry analyses. The role of intestinal opioid tone in inflammation-induced visceral hypersensitivity was assessed by colorectal distention. RESULTS: In mice with T cell- or dextran sulfate sodium-induced colitis, colitogenic CD4(+) T cells (T-helper 1 and Th17 cells) accumulated in the inflamed intestine and expressed a high level of endogenous opioids. In contrast, macrophages and epithelial cells did not express opioids; opioid synthesis in the myenteric plexus was not altered on induction of inflammation. In mice with colitis, the local release of opioids by colitogenic CD4(+) T cells led to significant reduction of inflammation-associated visceral hypersensitivity. CONCLUSIONS: In mice, colitogenic Th1 and Th17 cells promote intestinal inflammation and colonic tissue damage but have simultaneous opioid-mediated analgesic activity, thereby reducing abdominal pain.
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Colitis/inmunología , Colon/inmunología , Plexo Mientérico/inmunología , Péptidos Opioides/inmunología , Células TH1/inmunología , Células Th17/inmunología , Dolor Visceral/inmunología , Animales , Colitis/inducido químicamente , Colitis/patología , Colon/inervación , Colon/patología , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Inmunidad Mucosa , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Plexo Mientérico/fisiología , Péptidos Opioides/fisiologíaRESUMEN
Recent advances in brain science have shown that the brain function encoding emotion depends on interoceptive signals such as visceral pain. Visceral pain arose early in our evolutionary history. Bottom-up processing from gut-to-brain and top-down autonomic/neuroendocrine mechanisms in brain-to-gut signaling constitute a circuit. Brain imaging techniques have enabled us to depict the visceral pain pathway as well as the related emotional circuit. Irritable bowel syndrome (IBS) is characterized by chronic recurrent abdominal pain or abdominal discomfort associated with bowel dysfunction. It is also thought to be a disorder of the brain-gut link associated with an exaggerated response to stress. Corticotropin-releasing hormone (CRH), a major mediator of the stress response in the brain-gut axis, is an obvious candidate in the pathophysiology of IBS. Indeed, administration of CRH has been shown to aggravate the visceral sensorimotor response in IBS patients, and the administration of peptidergic CRH antagonists seems to alleviate IBS pathophysiology. Serotonin (5-HT) is another likely candidate associated with brain-gut function in IBS, as 5-HT3 antagonists, 5-HT4 agonists, and antidepressants were demonstrated to regulate 5-HT neurotransmission in IBS patients. Autonomic nervous system function, the neuroimmune axis, and the brain-gut-microbiota axis show specific profiles in IBS patients. Further studies on stress and visceral pain neuropathways in IBS patients are warranted.
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Encéfalo/inmunología , Hormona Liberadora de Corticotropina/inmunología , Síndrome del Colon Irritable/inmunología , Neuroinmunomodulación/inmunología , Serotonina/inmunología , Estrés Psicológico/inmunología , Dolor Visceral/inmunología , Humanos , Modelos Inmunológicos , Modelos NeurológicosRESUMEN
The administration of bacterial endotoxin (i.e., lipopolysaccharide, LPS) constitutes a well-established experimental approach to study the effects of an acute and transient immune activation on physiological, behavioral, and emotional aspects of sickness behavior in animals and healthy humans. However, little is known about possible effects of experimental endotoxemia on pain in humans. This knowledge gap is particularly striking in the context of visceral pain in functional as well as chronic-inflammatory gastrointestinal disorders. Although inflammatory processes have been implicated in the pathophysiology of visceral pain, it remains incompletely understood how inflammatory mediators interact with bottom-up (i.e., increased afferent input) and top-down (i.e., altered central pain processing) mechanisms of visceral hyperalgesia. Considering the recent findings of visceral hyperalgesia after LPS application in humans, in this review, we propose that experimental endotoxemia with its complex peripheral and central effects constitutes an experimental model to study neuroimmune communication in human pain research. We summarize and attempt to integrate relevant animal and human studies concerning neuroimmune communication in visceral and somatic pain, discuss putative mechanisms, and conclude with future research directions.
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Endotoxemia/inmunología , Endotoxemia/fisiopatología , Neuroinmunomodulación , Dolor Visceral/inmunología , Dolor Visceral/fisiopatología , Animales , Modelos Animales de Enfermedad , Endotoxemia/complicaciones , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/fisiopatología , Humanos , Conducta de Enfermedad/fisiología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/fisiopatología , Dolor Visceral/etiologíaRESUMEN
Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders.