RESUMO
Nutrients in the lumen of the small intestine are sensed by special cells in the epithelial lining. The ensuing neurohumoral reflexes affect gastrointestinal absorption/secretion, motility, and vascular perfusion. To study in vivo the effect of a monosaccharide (glucose) or polysaccharide (starch) present in the jejunum on glucose absorption from an adjacent part of the intestine and investigate the possible underlying mechanisms. Using the single pass intraluminal perfusion technique, a segment of jejunum (perfusion segment) was continuously perfused with 20 mM glucose to determine glucose absorption. One hour later, a bolus of a saccharide was instilled in an isolated adjacent jejunal segment and the change in glucose absorption was monitored for a further 2 h. The contribution of neural mechanisms in this process was investigated. Instillation of glucose (20 mM or 40 mM) in either distal or proximal jejunal pouch elicited immediate and sustained inhibition of glucose absorption (a decrease by 25%; P < 0.01) from the perfused jejunal segment. Comparable inhibition was obtained with instillation of other monosaccharides or starch in the jejunal pouch. This inhibition was abolished by adding tetrodotoxin to the pouch or to the perfused jejunal segment and also by pretreatment with sympathetic blockers (guanethidine or hexamethonium) and by chemical ablation of capsaicin-sensitive primary afferent fibers. Glucose absorption within the jejunum is auto-regulated through backward and forward mechanisms. This regulation is mediated by neural reflexes involving capsaicin-sensitive afferent and sympathetic efferent fibers. These reflexes might serve to protect against hyperglycemia.
Assuntos
Glucose/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Polissacarídeos/farmacologia , Reflexo/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Capsaicina/farmacologia , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Ratos , Ratos Sprague-Dawley , Tetrodotoxina/farmacologiaRESUMO
BACKGROUND: Colitis is associated with functional abnormalities in proximal non-inflamed gut areas, but animal models to study small bowel dysfunction in colitis have limitations. This study aims to determine small intestinal alanine absorption and cytokine expression in a novel model of colonic ulceration induced by electro-cautery. METHODS: A descending colon ulcer was induced in rats by a bipolar electro-cautery probe. Ulcer score was determined using Satoh's criteria. Jejunal alanine absorption was measured immediately and at different time intervals post ulcer induction. Levels of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) protein and m-RNA were determined in mucosal scrapings obtained from the colon, duodenum, jejunum and ileum at various time intervals after colonic ulcer induction. RESULTS: The mean ulcer score was 3 up to 48h, followed by healing by 96h post ulcer induction. Small bowel histology was normal throughout. Jejunal alanine absorption was reduced by 12-34% immediately and up to 72h after cautery and returned to normal at 96h. IL-1 and TNF-α mRNA increased significantly in the colon, duodenum, jejunum and ileum 3h post electro-cautery and returned to normal at 48h, while that of IL-6 increased significantly at 48h post ulcer induction. Similarly, IL-1, IL-6 and TNF-α protein levels increased in the duodenum, jejunum, ileum and colon up to 48h post ulcer induction. CONCLUSIONS: Electrically induced localized colonic injury increased production of pro-inflammatory cytokines in non-inflamed segments of the small intestine and was associated with derangements of jejunal absorptive function.
Assuntos
Alanina/metabolismo , Colite/fisiopatologia , Citocinas/metabolismo , Absorção Intestinal , Intestino Delgado/imunologia , Jejuno/metabolismo , Animais , Colite/imunologia , Colo/imunologia , Colo/lesões , Modelos Animais de Doenças , Duodeno/imunologia , Duodeno/metabolismo , Eletrocoagulação , Íleo/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Intestino Delgado/metabolismo , Jejuno/imunologia , Masculino , Ratos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Úlcera/imunologia , Úlcera/fisiopatologiaRESUMO
Adult hippocampal neurogenesis is prone to modulation by several intrinsic and extrinsic factors. The anterior nucleus (AN) of the thalamus has extensive connections with the hippocampus, and stimulation of this region may play a role in altering neurogenesis. We have previously shown that electrical stimulation of the AN can substantially boost hippocampal neurogenesis in adult rats. Here, we performed selective unilateral chemical excitation of the cell bodies of the AN as it offers a more specific and sustained stimulation when compared to electrical stimulation. Our aim is to investigate the long-term effects of KA stimulation of the AN on baseline hippocampal proliferation of neural stem cells and neurogenesis. Continuous micro-perfusion of very low doses of kainic acid (KA) was administered into the right AN for seven days. Afterwards, adult male rats received 5'-bromo-2'-deoxyuridine (BrdU) injections (200 mg/kg, i.p) and were euthanized at either one week or four weeks post micro-perfusion. Open field and Y-maze tests were performed before euthanasia. The KA stimulation of the AN evoked sustained hippocampal neurogenesis that was associated with improved spatial memory in the Y-maze test. Administering dexamethasone prior to and simultaneously with the KA stimulation decreased both the hippocampal neurogenesis and the improved spatial recognition memory previously seen in the Y-maze test. These results suggest that hippocampal neurogenesis may be a downstream effect of stimulation in general, and of excitation of the cell bodies of the AN in particular, and that stimulation of that area improves spatial memory in rats.
Assuntos
Ácido Caínico , Neurogênese , Masculino , Ratos , Animais , Ácido Caínico/farmacologia , Hipocampo , Neurônios , Memória Espacial , Bromodesoxiuridina/farmacologiaRESUMO
Previous studies have suggested a link between urinary tract infections (UTIs) and cognitive impairment. One possible contributing factor for UTI-induced cognitive changes that has not yet been investigated is a potential alteration in hippocampal neurogenesis. In this study, we aim to investigate the effect of UTI on brain plasticity by specifically examining alterations in neurogenesis. Adult male Sprague Dawley rats received an intra-urethral injection of an Escherichia coli (E. coli) clinical isolate (108 CFU/mL). We found that rats with a UTI (CFU/mL ≥ 105) had reduced proliferation of neural stem cells (NSCs) at an early time point post infection (day 4) and neurogenesis at a later time point (day 34). This was associated with the decreased expression in mRNA of BDNF, NGF, and FGF2, and elevated expression of IL-1ß in the hippocampus at 6 h post infection, but with no changes in optical intensity of the microglia and astrocytes. In addition, infected rats spent less time exploring a novel arm in the Y-maze test. Treatment with an anti-inflammatory drug did not revert the effect on NSCs, while treatment with antibiotics further decreased the basal level of their proliferation. This study presents novel findings on the impact of urinary tract infections on hippocampal neurogenesis that could be correlated with cognitive impairment.
RESUMO
Deep brain stimulation (DBS) has shown positive clinical results in neurodegenerative diseases. Previous work from our group showed that a single session of DBS to the anteromedial thalamic nucleus (AMN) in awake rats, increased proliferation of stem/progenitor cells in the dentate gyrus (DG) of the hippocampus. We thought to examine the effect of single versus multiple sessions of DBS to the AMN in modulating adult hippocampal neurogenesis. Rats received unilateral single session, multiple sessions or no electrical stimulation (sham) in the right AMN. Rats received 5'-bromo-2'-deoxyuridine (BrdU) injections and were followed over a period of 1 week or 4 weeks. Single session of electrical stimulation induced a 1.9-fold increase in the number of proliferating BrdU positive cells after one week from stimulation and a 1.8-fold increase at four weeks post stimulation, both in the ipsilateral DG. As for multiple sessions of stimulation, they induced a 3- fold increase that extended to the contralateral DG after 4 weeks from stimulation. Spatial reference memory was tested in the Y-maze test by examining novel arm exploration. Both single and multiple sessions of stimulation prompted an increase in novel arm exploration at week 4, while only the multiple sessions of stimulation had this effect starting from week 1. This study demonstrates that sustained activation of the AMN boosts neurogenesis and improves spatial reference memory.
Assuntos
Núcleos Anteriores do Tálamo/fisiologia , Estimulação Encefálica Profunda , Hipocampo/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Memória Espacial/fisiologia , Animais , Giro Denteado/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Since the initial description by Wall [Wall, P.D., 1967. The laminar organization of dorsal horn and effects of descending impulses. J. Neurophysiol. 188, 403-423] of tonic descending inhibitory control of dorsal horn neurons, several studies have aimed to characterize the role of various brain centers in the control of nociceptive input to the spinal cord. The role of brainstem centers in pain inhibition has been well documented over the past four decades. Lesion to peripheral nerves results in hypersensitivity to mild tactile or cold stimuli (allodynia) and exaggerated response to nociceptive stimuli (hyperalgesia), both considered as cardinal signs of neuropathic pain. The increased interest in animal models for peripheral neuropathy has raised several questions concerning the rostral conduction of the neuropathic manifestations and the role of supraspinal centers, especially brainstem, in the inhibitory control or in the abnormal contribution to the maintenance and facilitation of neuropathic-like behavior. This review aims to summarize the data on the ascending and descending modulation of neuropathic manifestations and discusses the recent experimental data on the role of supraspinal centers in the control of neuropathic pain. In particular, the review emphasizes the importance of the reciprocal interconnections between the analgesic areas of the brainstem and the pain-related areas of the forebrain. The latter includes the cerebral limbic areas, the prefrontal cortex, the intralaminar thalamus and the hypothalamus and play a critical role in the control of pain considered as part of an integrated behavior related to emotions and various homeostatic regulations. We finally speculate that neuropathic pain, like extrapyramidal motor syndromes, reflects a disorder in the processing of somatosensory information.
Assuntos
Encéfalo/fisiopatologia , Limiar da Dor/fisiologia , Dor/etiologia , Dor/patologia , Doenças do Sistema Nervoso Periférico/complicações , Medula Espinal/fisiopatologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Modelos Biológicos , Vias Neurais/patologia , Vias Neurais/fisiopatologia , Doenças do Sistema Nervoso Periférico/patologia , Medula Espinal/patologiaRESUMO
Intestinal nutrient transport is altered in response to changes in dietary conditions and luminal substrate level. It is not clear, however, whether an amino acid in the intestinal lumen can acutely affect its own absorption from a distant site. Our aim is to study the effect of an amino acid present in rat small intestinal segment on its own absorption from a proximal or distal site and elucidate the underlying mechanisms. The effect of instillation of alanine (Ala) in either jejunum or ileum on its own absorption at ileal or jejunal level was examined in vivo. The modulation of this intestinal regulatory loop by the following interventions was studied: tetrodotoxin (TTX) added to Ala, subdiaphragmatic vagotomy, chemical ablation of capsaicin-sensitive primary afferent (CSPA) fibers, and IV administration of calcitonin gene-related peptide (CGRP) antagonist. In addition, the kinetics of jejunal Ala absorption and the importance of Na+-dependent transport were studied in vitro after instilling Ala in the ileum. Basal jejunal Ala absorption [0.198 +/- 0.018 micromol x cm(-1) x 20 min(-1) (means +/- SD)] was significantly decreased with the instillation of 20 mM Ala in the ileum or in an adjacent distal jejunal segment (0.12 +/- 0.015; P < 0.0001 and 0.138 +/- 0.014; P < 0.002, respectively). Comparable inhibition was observed in the presence of proline in the ileum. Moreover, basal Ala absorption from the ileum (0.169 +/- 0.025) was significantly decreased by the presence of 20 mM Ala in the jejunum (0.103 +/- 0.027; P < 0.01). The inhibitory effect on jejunal Ala absorption was abolished by TTX, subdiaphragmatic vagotomy, neonatal capsaicin treatment, and CGRP antagonism. In vitro studies showed that Ala in the ileum affects Na+-mediated transport and increases K(m) without affecting Vmax. Intraluminal amino acids control their own absorption from a distant part of the intestine, by affecting the affinity of the Na+-mediated Ala transporter, through a neuronal mechanism that involves CSPA and CGRP.
Assuntos
Alanina/metabolismo , Íleo/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Jejuno/metabolismo , Alanina/administração & dosagem , Animais , Transporte Biológico , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Capsaicina/farmacologia , Sistema Nervoso Entérico/metabolismo , Retroalimentação Fisiológica , Feminino , Íleo/efeitos dos fármacos , Íleo/inervação , Infusões Intravenosas , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/inervação , Jejuno/efeitos dos fármacos , Jejuno/inervação , Cinética , Neurônios Aferentes/metabolismo , Prolina/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo , Sódio/metabolismo , Tetrodotoxina/farmacologia , Vagotomia , Nervo Vago/metabolismoRESUMO
The exchange of fluids and chemicals between the tooth pulp and the periphery, through the dentinal tubules has been well documented. Application of irritants on the open tubules produces aversion in awake rats that can be prevented by prior occlusion of these tubules. This study aims at characterizing the secretion of inflammatory mediators in tooth perfusates and assessing the effects of systemic pretreatment with anti-inflammatory drugs on the levels of these mediators. Several groups of rats (n=5-6 each) were used for intradental application of either saline, capsaicin (100 microg in 100 microl), or endotoxin (20 microg in 100 microl) for a period of 40 min followed by filling the perfusion chamber with sterile saline and collecting the perfusate every 30 min for 6h. The perfusates were used for the determination of the concentrations of cytokines by ELISA. Application of irritants produced a highly significant increase in PGE2 (peak at 2h) and NGF (peak at 4-6h). Dexamethasone antagonized the effects of endotoxin and capsaicin, while NSAID affected mainly the endotoxin-induced inflammation. Our results confirm the validity of the tooth perfusion technique and demonstrate that the efficacy of treatment with anti-inflammatory drugs depends on the type of inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Incisivo , Mediadores da Inflamação/metabolismo , Irritantes/farmacologia , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios/imunologia , Capsaicina/farmacologia , Celecoxib , Dexametasona/farmacologia , Dinoprostona/metabolismo , Endotoxinas/farmacologia , Incisivo/efeitos dos fármacos , Incisivo/lesões , Indometacina/farmacologia , Morfina/farmacologia , Fator de Crescimento Neural/metabolismo , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Fármacos do Sistema Sensorial/farmacologia , Sulfonamidas/farmacologiaRESUMO
Neuropathic pain is considered to be pathological in nature and has been shown to involve, at least partially, dysregulated inflammatory processes. It is a severe chronic disease that can develop following lesions to the central nervous system or to peripheral nerves. The peripheral nerve damage can be caused by either diseases such as diabetes, or by trauma. A common underlying mechanism of neuropathic pain is the presence of inflammation at the site of the damaged or affected nerve(s). This inflammatory response, especially when unresolved, initiates and maintains a cascade of events resulting in the activation of innate immune cells at the site of tissue injury. The release of inflammatory mediators such as cytokines, neurotrophic factors, and chemokines initiates local actions and can result in a more generalized immune response. The resultant neuroinflammatory environment can cause activation of glial cells, which can release, in an uncontrolled manner, more of these mediators and exasperate the situation, thus having a prominent role in nociception. The neuropathic pain pathophysiology is complex and includes peripheral and central neuronal alterations as well as neuro-immune interactions, which become more prominent during inflammatory reactions. This report focuses on how targeting inflammatory mediators may result in novel therapeutic approaches to neuropathic pain management.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Fator Tímico Circulante/fisiologia , Analgésicos/química , Animais , Anti-Inflamatórios/química , Citocinas/metabolismo , Humanos , Fatores Imunológicos/química , Inflamação/imunologia , Inflamação/patologia , Microglia/fisiologia , Neuralgia/imunologia , Neuralgia/patologia , Neuroimunomodulação , Oligopeptídeos/química , Fator Tímico Circulante/químicaRESUMO
Brain inflammation can result in functional disorders observed in several neurodegenerative diseases and that can be also associated with reduced neurogenesis. In this study, we investigate the effect of mild inflammation, induced by unilateral injection of Endotoxin (ET) in the substantia nigra (SN)/Ventral Tegmental Area, on the proliferation and survival of stem/progenitor cells in the dentate gyrus (DG) of the hippocampus. Adult female rats received unilateral injection of ET (2 µg/2 µl saline) or sterile saline (2 µl) in the right SN followed by 5'-Bromo-2'-deoxyuridine (BrdU) injections (66 mg/kg/injection). Intranigral ET injection induced bilateral decrease in the number of newly born BrdU positive cells in the DG. This effect was paralleled by a significant decrease in the exploratory behavior of rats, as assessed by the Y-maze novel arm exploration task. ET also induced a transient decrease in the number of tyrosine hydroxylase-positive cells in the injected SN, impaired motor behavior, and caused microglial activation in the SN. This study provides an experimental simulation of the remote effects of moderate and reversible neuroinflammation resulting in impaired communication between midbrain dopaminergic neurons and the hippocampus.
RESUMO
A major component of tooth innervation is made of capsaicin-sensitive primary afferents (CSPA). These fibers play a key role in tooth pain and inflammation; little is known, however, about the role of CSPA in tooth eruption. The aim of this study was to examine the role of the capsaicin-sensitive afferents in the process of eruption of intact rat incisors. CSPA fibers in several rat groups, were subjected to one of the following experimental procedures: systemic chemical ablation, systemic ablation followed by chemical sympathectomy and localized activation. The observed effects on incisor eruption were compared to those made on controls. The total amount of eruption in control/naïve rats, measured over a total period of 144 h, was 3.18 ± 0.07 mm and decreased to 2.43 ± 0.08 mm (n = 7; p < 0.001) following systemic ablation of CSPA. Further decrease to 2.24 ± 0.08 mm (n = 7; p < 0.001) was noticed when chemical sympathectomy was added to CSPA ablation. The average rate of eruption was 1.7 ± 0.25 mm following CSPA activation, compared to an average of 0.8 ± 0.07 mm for controls (n = 7; p < 0.001). Capsaicin sensitive fibers play an important role in tooth homeostasis, and intact neural supply is required for tooth growth under normal conditions.
Assuntos
Processo Alveolar/inervação , Capsaicina/metabolismo , Incisivo/inervação , Mandíbula/inervação , Erupção Dentária/fisiologia , Vias Aferentes/fisiologia , Animais , Masculino , Modelos Animais , Ratos , Ratos Sprague-DawleyRESUMO
Exposure to mid range ultrat violet radiations (UVBs) has been shown to produce systemic inflammation and hyperalgesia in mice [Saadé, N.E., Nasr, I.W., Massaad, C.A., Safieh-Garabedian, B., Jabbur, S.J., Kanaan, S.A., 2000. Modulation of ultraviolet-induced hyperalgesia and cytokine upregulation by interleukins 10 and 13. Br. J. Pharmacol. 131, 1317-1324]. Our aim was to characterize a new rat model of localized exposure to UVB and to determine the role of skin innervation in the observed hyperalgesia and cytokine upregulation. In several groups of rats one hindpaw was exposed to UVB (250-350 mJ/cm(2)) and this was followed by the application, to the plantar area of the paw, of either Von Frey hairs or a few acetone drops to measure tactile and cold allodynia, respectively. Thermal hyperalgesia was assessed by the paw withdrawal latency and duration. Cytokine levels were determined, by ELISA, in processed samples of skin tissue isolated from the exposed and non-exposed paws. UVB induced a biphasic thermal hyperalgesia and cold and tactile allodynia with an early phase that peaked at 3-6h and disappeared at 24h and a late phase with a peak at 48 h and recovery at 72-h post-exposure. Tumor necrosis factor, interleukins 1 beta, 6, 8, 10 and NGF levels were significantly increased following the same biphasic temporal pattern. Chemical ablation of capsaicin sensitive afferents and guanethidine injection produced significant alteration of the hyperalgesia and allodynia. The increase in cytokine levels by UVB was also altered by both treatments. The present study describes a new animal model for localized UVB-induced inflammatory hyperalgesia and provides evidence about the involvement of neurogenic mechanisms in the observed hyperalgesia and upregulation of proinflammatory mediators.
Assuntos
Dermatite/imunologia , Modelos Animais de Doenças , Hiperalgesia/imunologia , Ratos Sprague-Dawley , Pele/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Citocinas/metabolismo , Dermatite/tratamento farmacológico , Guanetidina/farmacologia , Hiperalgesia/tratamento farmacológico , Fator de Crescimento Neural/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Neuroimunomodulação/efeitos da radiação , Neurônios Aferentes/fisiologia , Nociceptores/fisiologia , Nociceptores/efeitos da radiação , Ratos , Pele/inervação , Pele/efeitos da radiação , Simpatectomia Química , Simpatolíticos/farmacologia , Raios Ultravioleta/efeitos adversos , VigíliaRESUMO
Although motor cortex stimulation (MCS) is being increasingly used to treat chronic refractory neuropathic pain in humans, its mechanisms of action remain elusive. Studies in animals have suggested the involvement of subcortical structures, in particular, the thalamus. Most of these studies have been performed in rats, a species presenting significant differences in thalamic anatomy and function relative to primates, in particular, a very limited number of thalamic GABA interneurons. The aim of this study was to investigate the effects of MCS on single-unit activities of the thalamic ventral posterior lateral (VPL) nucleus in cats, which contains substantial numbers of GABA interneurons. Spontaneous and evoked activities of VPL units were studied before and after MCS. Motor cortex stimulation induced significant depression of the wide-dynamic-range (WDR) cells' firing rate, concomitant with activity enhancement of nonnociceptive (NN) units. More than half of WDR cells showed a significant decrease in the firing rate, while a similar proportion of NN units exhibited the opposite after-effect. Maximal firing attenuation of WDR cells occurred when the MCS location matched somatotopically their receptive field. Repetition of MCS runs led to an accentuation of WDR depression. After peripheral stimulation, evoked activity in each cell showed MCS effects similar to those observed in spontaneous activity. These data demonstrate a selective top-down inhibition by MCS of nonspecific nociceptive (WDR) cells, enhanced by somatotopic concordance and stimulation repetition, in parallel to facilitation of NN cells. These 2 outcomes may play a role in the complex analgesic effect of MCS observed in neuropathic pain conditions.
Assuntos
Potenciais de Ação/fisiologia , Córtex Motor/fisiologia , Neurônios/fisiologia , Núcleos Ventrais do Tálamo/fisiologia , Animais , Gatos , Estimulação ElétricaRESUMO
Physio-pathological conditions such as neuroinflammation can modulate neurogenesis in the hippocampus. The aim of this study is to follow the time course of inflammation-induced effects on the neurogenic niche and the counter-effects of an anti-inflammatory drug. Rats received intracerebroventricular injections of lipopolysaccharide/endotoxin (ET) and intraperitoneal injections of 5'-bromo-2'-deoxyuridine, then perfused at different time intervals. At day 3, ET injection resulted in thermal hyperalgesia accompanied by a significant decrease in neurogenesis. A rebound of neurogenesis was detected at day 6 and levels were back to basal at day 9. Daily treatment with Piroxicam alleviated the ET-induced effects.
Assuntos
Endotoxinas/toxicidade , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Neurogênese/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Endotoxinas/administração & dosagem , Hiperalgesia/induzido quimicamente , Injeções Intraventriculares , Masculino , Piroxicam/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Intact neural supply is necessary for tooth eruption. Sympathetic denervation accelerates or decelerates the eruption rate depending on the tooth condition (intact or injured). The aim of this study is to reexamine the role of the sympathetic innervation, through the observation of the effects of pre or post ganglionic chemical sympathectomy on the eruption of intact rat incisors. MATERIALS AND METHODS: Different groups of rats were subjected to either ganglionic or peripheral chemical sympathectomy and the observed effects on incisor eruption were compared to those made on intact/sham groups or on rats subjected to inferior alveolar nerve (IAN) lesion. RESULTS: The total amount of eruption in control/naïve rats, measured over a total period of 144â¯h, was 3⯱â¯0.15â¯mm and decreased to 2.57⯱â¯0.06â¯mm (nâ¯=â¯8; pâ¯<â¯0.01) or 2.8⯱â¯0.10â¯mm (nâ¯=â¯8; pâ¯<â¯0.05) following treatment with guanethidine and hexamethonium, respectively. This amount decreased to 1.8⯱â¯0.14â¯mm (pâ¯<â¯0.001 vs. control, nâ¯=â¯7; or pâ¯<â¯0.01 vs. sham, nâ¯=â¯5) in rats subjected to IAN lesion. CONCLUSION: Sympathectomy delayed tooth eruption. Blocking the sympathetic effectors with guanethidine exerted more potent effects than ganglionic block with hexamethonium. Intact sympathetic supply is required for tooth growth under normal conditions.
Assuntos
Incisivo/inervação , Mandíbula/inervação , Nervo Mandibular , Sistema Nervoso Simpático/fisiologia , Erupção Dentária/fisiologia , Animais , Denervação , Feminino , Bloqueadores Ganglionares/farmacologia , Hexametônio/farmacologia , Incisivo/crescimento & desenvolvimento , Mandíbula/efeitos dos fármacos , Mandíbula/patologia , Nervo Mandibular/anatomia & histologia , Nervo Mandibular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Simpatectomia/métodos , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/patologiaRESUMO
Small intestinal dysfunction has been described in patients with ulcerative colitis and in experimental animal models of colitis. This is demonstrated by a decrease in fluid, electrolyte, amino acid, fat and carbohydrate absorption as well as by deranged intestinal motility. Histopathological changes in the small intestines in colitis have not been consistently demonstrated, but there is evidence of structural and biochemical alterations as shown by increased intestinal permeability and a decrease in the expression of multiple brush border membrane enzymes such as disaccharidases and aminopetidases, in both humans and experimental animals. The pathophysiology of this dysfunction has not been elucidated, but it is thought to include alterations in neural circuitry such as increased neuronal excitability, neuronal damage and changes of neuropeptidergic innervation and receptors as well as an increase in local production of pro-inflammatory cytokines and alterations in the production of some neurohumoral mediators. In the following, we provide an update on the advancement of clinical and scientific contributions to elucidate the underlying mechanisms of the alteration of the functions of apparently intact small intestinal segments, induced by ulcerative colitis.
Assuntos
Colite Ulcerativa/fisiopatologia , Sistema Nervoso Entérico/fisiopatologia , Motilidade Gastrointestinal , Intestino Delgado/inervação , Intestino Delgado/metabolismo , Síndromes de Malabsorção/etiologia , Animais , Colite Ulcerativa/complicações , Citocinas/metabolismo , Humanos , Intestino Delgado/patologia , Intestino Delgado/fisiopatologia , Síndromes de Malabsorção/fisiopatologia , Óxido Nítrico/metabolismo , Permeabilidade , Serotonina/metabolismo , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
The thymic peptide thymulin is known for its immunomodulatory role. However, several recent reports have indicated that thymulin is capable of interacting directly and/or indirectly with the nervous system. One of the first lines of evidence of this interaction was obtained in a series of experiments showing the hyperalgesic actions of this peptide. We demonstrated that, at low doses (ng), local (intraplantar) or systemic (intraperitoneal) injections of thymulin resulted in hyperalgesia with an increase in proinflammatory mediators, and that this peptide could act directly on the afferent nerve terminals through prostaglandin-E2 (PGE2)-dependent mechanisms, thus forming a neuroimmune loop involving capsaicin-sensitive primary afferent fibers. In further experiments, systemic injections of relatively high doses (1-25 microg) of thymulin or of an analogue peptide (PAT) deprived of hyperalgesic effect, have been shown to reduce the inflammatory pain and the upregulated levels of cytokines induced by endotoxin (ET) injection. In addition, PAT treatment appeared to alleviate the sickness behavior (motor behavior and fever) induced by systemic inflammation. These effects could be attributed, at least partly, to the downregulation of proinflammatory mediators. Furthermore, when compared with the effects of other anti-inflammatory drugs, PAT exerted equal or even stronger analgesic effects, and at much lower concentrations. Subsequent experiments were designed to examine the effects of intracerebroventricular (i.c.v.) injections of thymulin on cerebral inflammation induced by i.c.v. injection of ET. Pretreatment with thymulin reduced, in a dose-dependent manner, the ET-induced hyperalgesia, and exerted differential effects on the upregulated levels of cytokines in different areas of the brain, suggesting a neuroprotective role for thymulin in the central nervous system (CNS). Preliminary results demonstrate that thymulin inhibits in the hippocampus the ET-induced nuclear activation of NF-kappaB, the transcription factor required for the expression of proinflammatory cytokines genes. Although the mechanism of action of these molecules is not totally elucidated, our results indicate a possible therapeutic use of thymulin or PAT as analgesic and anti-inflammatory drugs.
Assuntos
Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Fatores Imunológicos/farmacologia , Dor/tratamento farmacológico , Fator Tímico Circulante/análogos & derivados , Analgésicos/imunologia , Animais , Humanos , Hiperalgesia/imunologia , Fatores Imunológicos/imunologia , Dor/imunologia , Fator Tímico Circulante/imunologiaRESUMO
Local inflammation in the colon has been associated with nutrient malabsorption and altered motility in the small bowel. These remote effects suggest the release of mediators which can act (or alter) the function of intestinal segments located far from the primary area of inflammation. This study describes the changes in the expression of pro-inflammatory cytokines in the colon and in various segments of the small intestine in two rat models of experimental colitis. Colitis was induced by the intracolonic administration of 100 microL of 6% iodoacetamide or 250 microL of 2, 4, 6-trinitrobenzene sulfonic acid. Levels of interleukin one beta, interleukin 6, and tumor necrosis factor alpha were measured by ELISA in tissue homogenate sampled from duodenum, jejunum, ileum and colon at different time intervals. In homogenates of strips isolated from duodenum, jejunum and ileum, tumor necrosis alpha and interleukin-6, increased significantly 3-6 h after iodoacetamide or TNBS administration and remained elevated until the colonic inflammation subsided. Interleukin one beta showed comparable but delayed increase. Similar, but more pronounced increase of the three cytokines was noticed in areas of the colon adjacent to the ulcer. Histologic examinations revealed important inflammatory changes in the colon; however, examination of sections from the small intestines did not reveal significant differences between controls and rats with colitis. In conclusion, expression of pro-inflammatory cytokines is increased in remote segments of the small intestines during colitis. The findings may provide a partial explanation or a molecular substrate for the associated small bowel dysfunction.
Assuntos
Colite/imunologia , Interleucina-1/imunologia , Interleucina-6/imunologia , Intestino Delgado/imunologia , Fator de Necrose Tumoral alfa/imunologia , Doença Aguda , Animais , Doença Crônica , Colite/patologia , Modelos Animais de Doenças , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Deep brain stimulation (DBS) provides clinical benefits for a variety of movement disorders and lately emerged as a potential treatment for cognitive and mood disorders. Modulation of adult hippocampal neurogenesis may play a role in mediating its effects. OBJECTIVE: To investigate the effects of unilateral anteromedial thalamic nucleus (AMN) stimulation on adult hippocampal neurogenesis in awake and unrestrained rats. METHODS: Four groups of adult Sprague-Dawley male and female rats received unilateral stimulation (n = 6 each) or sham surgery (n = 4 each) in the right AMN; another group of males (n = 4) was stimulated in the right ventral posterolateral thalamic nucleus (VPL). A naive group of males and females (n = 4 each) was also included. Rats received 4 injections (50 mg/kg/injection) of 5'-bromo-2'-deoxyuridine (BrdU) 3 days post-surgery and were euthanized 24 h later. The fractionator method was used together with confocal microscopy to count BrdU, GFAP and NeuN positive cells in the dentate gyrus (DG) and hilar zone of the hippocampus. RESULTS: Focal neurogenesis was induced in the ipsilateral DG after AMN but not VPL stimulation. Stimulation-induced effects were sex-independent and translated into a 76% increase in proliferation of neural stem/progenitor cells. Increased neurogenesis was most prominent at the caudal region of the DG, while no effect was detected in the hilar and the subventricular zones. CONCLUSIONS: The exclusive hippocampal neurogenic response to AMN stimulation suggests an involvement of the Papez circuitry in mediating DBS effects and in the treatment of cognitive and behavioral disorders.
Assuntos
Estimulação Encefálica Profunda , Hipocampo/fisiologia , Neurogênese , Tálamo/fisiologia , Animais , Feminino , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Masculino , Ratos , Ratos Sprague-Dawley , VigíliaRESUMO
Increased levels of pro- and anti-inflammatory cytokines were observed in various segments of histologically-intact small intestine in animal models of acute and chronic colitis. Whether these cytokines are produced locally or spread from the inflamed colon is not known. In addition, the role of gut innervation in this upregulation is not fully understood. To examine whether cytokines are produced de novo in the small intestine in two rat models of colitis; and to investigate the role of capsaicin-sensitive primary afferents in the synthesis of these inflammatory cytokines. Colitis was induced by rectal instillation of iodoacetamide (IA) or trinitrobenzene sulphonic acid (TNBS) in adult Sprague-Dawley rats. Using reverse transcriptase (RT) and real-time PCR, TNF-α, and IL-10 mRNA expression was measured in mucosal scrapings of the duodenum, jejunum, ileum and colon at different time intervals after induction of colitis. Capsaicin-sensitive primary afferents (CSPA) were ablated using subcutaneous injections of capsaicin at time 0, 8 and 32 h, and the experiment was repeated at specific time intervals to detect any effect on cytokines expression. TNF-α mRNA expression increased by 3-40 times in the different intestinal segments (p<0.05 to p<0.001), 48h after IA-induced colitis. CSPA ablation completely inhibited this upregulation in the small intestine, but not in the colon. Similar results were obtained in TNBS-induced colitis at 24 h. Intestinal IL-10 mRNA expression significantly decreased at 12 h and then increased by 6-43 times (p<0.05 to p<0.001) 48h after IA administration. This increase was abolished in rats subjected to CSPA ablation except in the colon, where IL-10 further increased by twice (p<0.05). In the TNBS group, there was 4-12- and 4-7-fold increases in small intestinal IL-10 mRNA expression at 1 and 21 days after colitis induction, respectively (both p<0.01). This increase was not observed in rats pretreated with capsaicin. Capsaicin-treated and untreated rats had comparable visual ulcer scores after colitis induction. Inflammatory cytokines are produced de novo in distant intestinal segments in colitis. CSPA fibers play a key role in the upregulation of this synthesis.