Content Validity of the Spanish Adaptation of the Premature Infant Pain Profile Revised.

BACKGROUND: To the best of our knowledge, there are no validated neonatal pain assessment scales in Spanish. Given the need for such a scale, a study was undertaken to adapt and validate the Premature Infant Pain Profile-Revised (PIPP-R) scale. After translation and back-translation, content validity was addressed, a crucial phase in validation studies, in which researchers examine whether the items that make up the scale represent the content that the scale is intended to assess. AIMS: The aim was to provide evidence for the content validity of the Spanish adaptation of the PIPP-R scale. METHOD: The study used the Delphi technique with 10 experts. Data collection was anonymous and was conducted through an online platform. It was an ad hoc survey consisting of four questions, with a five-point Likert scale for each item on the scale and for the instruction table. An item-content validity index (I-CVI) and a scale-content validity index (S-CVI) were calculated for the analysis. RESULTS: After two rounds of the survey, all items exceeded an I-CVI of 0.9. The S-CVI value was 0.98 (±0.03) for the scale, and 1 for its instruction table. The kappa index yielded values indicating an excellent degree of agreement. CONCLUSIONS: The Spanish version of the PIPP-R obtained a high degree of content validity according to the expert group and the Delphi technique.

From the Gut to the Brain: The Role of Enteric Glial Cells and Their Involvement in the Pathogenesis of Parkinson's Disease.

The brain-gut axis has been identified as an important contributor to the physiopathology of Parkinson's disease. In this pathology, inflammation is thought to be driven by the damage caused by aggregation of α-synuclein in the brain. Interestingly, the Braak's theory proposes that α-synuclein misfolding may originate in the gut and spread in a "prion-like" manner through the vagus nerve into the central nervous system. In the enteric nervous system, enteric glial cells are the most abundant cellular component. Several studies have evaluated their role in Parkinson's disease. Using samples obtained from patients, cell cultures, or animal models, the studies with specific antibodies to label enteric glial cells (GFAP, Sox-10, and S100ß) seem to indicate that activation and reactive gliosis are associated to the neurodegeneration produced by Parkinson's disease in the enteric nervous system. Of interest, Toll-like receptors, which are expressed on enteric glial cells, participate in the triggering of immune/inflammatory responses, in the maintenance of intestinal barrier integrity and in the configuration of gut microbiota; thus, these receptors might contribute to Parkinson's disease. External factors like stress also seem to be relevant in its pathogenesis. Some authors have studied ways to reverse changes in EGCs with interventions such as administration of Tryptophan-2,3-dioxygenase inhibitors, nutraceuticals, or physical exercise. Some researchers point out that beyond being activated during the disease, enteric glial cells may contribute to the development of synucleinopathies. Thus, it is still necessary to further study these cells and their role in Parkinson's disease.

Effect of the Cannabinoid Agonist WIN 55,212-2 on Neuropathic and Visceral Pain Induced by a Non-Diarrheagenic Dose of the Antitumoral Drug 5-Fluorouracil in the Rat.

5-fluorouracil (5-FU) is an antineoplastic drug used to treat colorectal cancer, but it causes, among other adverse effects, diarrhea and mucositis, as well as enteric neuropathy, as shown in experimental animals. It might also cause neuropathic pain and alterations in visceral sensitivity, but this has not been studied in either patients or experimental animals. Cannabinoids have antimotility and analgesic effects and may alleviate 5-FU-induced adverse effects. Our aim was to evaluate the effects of the cannabinoid agonist WIN 55,212-2 on neuropathic and visceral pain induced by a non-diarrheagenic dose of 5-FU. Male Wistar rats received a dose of 5-FU (150 mg/kg, ip) and gastrointestinal motility, colonic sensitivity, gut wall structure and tactile sensitivity were evaluated. WIN 55,212-2 (WIN) was administered to evaluate its effect on somatic (50-100 µg ipl; 1 mg/kg, ip) and visceral (1 mg/kg, ip) sensitivity. The cannabinoid tetrad was used to assess the central effects of WIN (1 mg/kg, ip). 5-FU decreased food intake and body weight gain, produced mucositis and thermal hyperalgesia, but these effects were reduced afterwards, and were not accompanied by diarrhea. Tactile mechanical allodynia was also evident and persisted for 15 days. Interestingly, it was alleviated by WIN. 5-FU tended to increase colonic sensitivity whereas WIN reduced the abdominal contractions induced by increasing intracolonic pressure in both control and 5-FU-treated animals. Importantly, the alleviating effects of WIN against those induced by 5-FU were not accompanied by any effect in the cannabinoid tetrad. The activation of the peripheral cannabinoid system may be useful to alleviate neuropathic and visceral pain associated with antitumoral treatment.

Cannabinoid drugs against chemotherapy-induced adverse effects: focus on nausea/vomiting, peripheral neuropathy and chemofog in animal models.

Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.

Molecular Targets to Alleviate Enteric Neuropathy and Gastrointestinal Dysfunction.

Enteric neuropathy underlies long-term gastrointestinal (GI) dysfunction associated with several pathological conditions. Our previous studies have demonstrated that structural and functional changes in the enteric nervous system (ENS) result in persistent alterations of intestinal functions long after the acute insult. These changes lead to aberrant immune response and chronic dysregulation of the epithelial barrier. Damage to the ENS is prognostic of disease progression and plays an important role in the recurrence of clinical manifestations. This suggests that the ENS is a viable therapeutic target to alleviate chronic intestinal dysfunction. Our recent studies in preclinical animal models have progressed into the development of novel therapeutic strategies for the treatment of enteric neuropathy in various chronic GI disorders. We have tested the anti-inflammatory and neuroprotective efficacy of novel compounds targeting specific molecular pathways. Ex vivo studies in human tissues freshly collected after resection surgeries provide an understanding of the molecular mechanisms involved in enteric neuropathy. In vivo treatments in animal models provide data on the efficacy and the mechanisms of actions of the novel compounds and their combinations with clinically used therapies. These novel findings provide avenues for the development of safe, cost-effective, and highly efficacious treatments of GI disorders.

Nutraceuticals and peripheral glial cells: a possible link?

A nutraceutical is a food-derived molecule that provides medical or health benefits beyond its basic nutritional role, including the prevention and treatment of disease and its symptoms. In the peripheral nervous system, satellite glial cells are found in close relationship with neurons, mainly in peripheral sensory ganglia, but, compared with other glial cells, the relationship between these cells and nutraceuticals has received little attention. After describing satellite glial cells and their role and changes in physiology and pathology, we review the studies on the effects of nutraceuticals as modulators of their functions. Maybe due to the difficulties in selectively labeling these cells, only a few studies, performed mainly in rodent models, have analyzed nutraceutical effects, showing that N-acetylcysteine, curcumin, quercetin, osthole and resveratrol may palliate neuropathic pain through satellite glial cells-dependent pathways, namely antioxidant mechanisms and/or interference with purinergic signaling. Neither other conditions in which satellite glial cells are involved (visceral pain, nerve regeneration) nor other nutraceuticals or mechanisms of action have been studied. Although more preclinical and clinical research is needed, the available reports support the general notion that nutraceuticals may become interesting alternatives in the prevention and/or treatment of peripheral gliopathies and their associated conditions, including those affecting the satellite glial cells.

The Enteric Glia and Its Modulation by the Endocannabinoid System, a New Target for Cannabinoid-Based Nutraceuticals?

The enteric nervous system (ENS) is a part of the autonomic nervous system that intrinsically innervates the gastrointestinal (GI) tract. Whereas enteric neurons have been deeply studied, the enteric glial cells (EGCs) have received less attention. However, these are immune-competent cells that contribute to the maintenance of the GI tract homeostasis through supporting epithelial integrity, providing neuroprotection, and influencing the GI motor function and sensation. The endogenous cannabinoid system (ECS) includes endogenous classical cannabinoids (anandamide, 2-arachidonoylglycerol), cannabinoid-like ligands (oleoylethanolamide (OEA) and palmitoylethanolamide (PEA)), enzymes involved in their metabolism (FAAH, MAGL, COX-2) and classical (CB1 and CB2) and non-classical (TRPV1, GPR55, PPAR) receptors. The ECS participates in many processes crucial for the proper functioning of the GI tract, in which the EGCs are involved. Thus, the modulation of the EGCs through the ECS might be beneficial to treat some dysfunctions of the GI tract. This review explores the role of EGCs and ECS on the GI tract functions and dysfunctions, and the current knowledge about how EGCs may be modulated by the ECS components, as possible new targets for cannabinoids and cannabinoid-like molecules, particularly those with potential nutraceutical use.

Nutraceuticals and Enteric Glial Cells.

Until recently, glia were considered to be a structural support for neurons, however further investigations showed that glial cells are equally as important as neurons. Among many different types of glia, enteric glial cells (EGCs) found in the gastrointestinal tract, have been significantly underestimated, but proved to play an essential role in neuroprotection, immune system modulation and many other functions. They are also said to be remarkably altered in different physiopathological conditions. A nutraceutical is defined as any food substance or part of a food that provides medical or health benefits, including prevention and treatment of the disease. Following the description of these interesting peripheral glial cells and highlighting their role in physiological and pathological changes, this article reviews all the studies on the effects of nutraceuticals as modulators of their functions. Currently there are only a few studies available concerning the effects of nutraceuticals on EGCs. Most of them evaluated molecules with antioxidant properties in systemic conditions, whereas only a few studies have been performed using models of gastrointestinal disorders. Despite the scarcity of studies on the topic, all agree that nutraceuticals have the potential to be an interesting alternative in the prevention and/or treatment of enteric gliopathies (of systemic or local etiology) and their associated gastrointestinal conditions.

Peripherally acting opioid analgesics and peripherally-induced analgesia.

The management of pain, particularly chronic pain, is still an area of medical need. In this context, opioids remain a gold standard for the treatment of pain. However, significant side effects, mainly of central origin, limit their clinical use. Here, we review recent progress to improve the therapeutic and safety profiles of opioids for pain management. Characterization of peripheral opioid-mediated pain mechanisms have been a key component of this process. Several studies identified peripheral µ, δ, and κ opioid receptors (MOR, DOR, and KOR, respectively) and nociceptin/orphanin FQ (NOP) receptors as significant players of opioid-mediated antinociception, able to achieve clinically significant effects independently of any central action. Following this, particularly from a medicinal chemistry point of view, main efforts have been directed towards the peripheralization of opioid receptor agonists with the objective of optimizing receptor activity and minimizing central exposure and the associated undesired effects. These activities have allowed the characterization of a great variety of compounds and investigational drugs that show low central nervous system (CNS) penetration (and therefore a reduced side effect profile) yet maintaining the desired opioid-related peripheral antinociceptive activity. These include highly hydrophilic/amphiphilic and massive molecules unable to easily cross lipid membranes, substrates of glycoprotein P (a extrusion pump that avoids CNS penetration), nanocarriers that release the analgesic agent at the site of inflammation and pain, and pH-sensitive opioid agonists that selectively activate at those sites (and represent a new pharmacodynamic paradigm). Hopefully, patients with pain will benefit soon from the incorporation of these new entities.

Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?

Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.

Mast Cell Regulation and Irritable Bowel Syndrome: Effects of Food Components with Potential Nutraceutical Use.

Mast cells are key actors in inflammatory reactions. Upon activation, they release histamine, heparin and nerve growth factor, among many other mediators that modulate immune response and neuron sensitization. One important feature of mast cells is that their population is usually increased in animal models and biopsies from patients with irritable bowel syndrome (IBS). Therefore, mast cells and mast cell mediators are regarded as key components in IBS pathophysiology. IBS is a common functional gastrointestinal disorder affecting the quality of life of up to 20% of the population worldwide. It is characterized by abdominal pain and altered bowel habits, with heterogeneous phenotypes ranging from constipation to diarrhea, with a mixed subtype and even an unclassified form. Nutrient intake is one of the triggering factors of IBS. In this respect, certain components of the daily food, such as fatty acids, amino acids or plant-derived substances like flavonoids, have been described to modulate mast cells' activity. In this review, we will focus on the effect of these molecules, either stimulatory or inhibitory, on mast cell degranulation, looking for a nutraceutical capable of decreasing IBS symptoms.

Painful neurotrophins and their role in visceral pain.

Beyond their well-known role in embryonic development of the central and peripheral nervous system, neurotrophins, particularly nerve growth factor and brain-derived neurotrophic factor, exert an essential role in pain production and sensitization. This has mainly been studied within the framework of somatic pain, and even antibodies (tanezumab and fasinumab) have recently been developed for their use in chronic somatic painful conditions, such as osteoarthritis or low back pain. However, data suggest that neurotrophins also exert an important role in the occurrence of visceral pain and visceral sensitization. Visceral pain is a distressing symptom that prompts many consultations and is typically encountered in both 'organic' (generally inflammatory) and 'functional' (displaying no obvious structural changes in routine clinical evaluations) disorders of the gut, such as inflammatory bowel disease and irritable bowel syndrome, respectively. The present review provides a summary of neurotrophins as a molecular family and their role in pain in general and addresses recent investigations of the involvement of nerve growth factor and brain-derived neurotrophic factor in visceral pain, particularly that associated with inflammatory bowel disease and irritable bowel syndrome.

Probiotics in digestive, emotional, and pain-related disorders.

In recent years, interest in the relationship between gut microbiota and disease states has grown considerably. Indeed, several strategies have been employed to modify the microbiome through the administration of different diets, by the administration of antibiotics or probiotics, or even by transplantation of feces. In the present manuscript, we focus specifically on the potential application of probiotics, which seem to be a safe strategy, in the management of digestive, pain, and emotional disorders. We present evidence from animal models and human studies, notwithstanding that translation to clinic still deserves further investigation. The microbiome influences gut functions as well as neurological activity by a variety of mechanisms, which are also discussed. The design and performance of larger trials is urgently needed to verify whether these new strategies might be useful not only for the treatment of disorders affecting the gastrointestinal tract but also in the management of emotional and pain disorders not directly related to the gut.

X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin.

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin.

Effects of vincristine and monosodium glutamate on gastrointestinal motility and visceral sensitivity.

BACKGROUND: Chemotherapy-induced adverse effects are an unresolved nightmare. In preclinical studies in rats, the food additive monosodium glutamate (MSG) improved some of the side effects caused by cisplatin, but its effects in other models of chemotherapy-treated animals are not well known. The aim of this study was to test if MSG may improve some of the adverse effects induced by vincristine in rats. METHODS: Young male Wistar rats were exposed or not to MSG (4 g L-1 ) in drinking water from week 0 till 1 week after treatment (week 3). Rats received two cycles of five daily intraperitoneal (ip) injections (Monday to Friday, weeks 1 and 2) of either saline (2 mL kg-1 ) or vincristine (0.1 mg kg-1 ). Gastrointestinal motility was measured in vivo by radiological methods after the first and tenth ip administrations. On week 3, the threshold for mechanical somatic and colorectal sensitivity was recorded using Von Frey filaments applied to the paws and an intracolonic balloon, respectively. Finally, samples of the terminal ileum and distal colon were histologically evaluated in sections. KEY RESULTS: Vincristine reduced body weight gain, food intake, and upper gastrointestinal transit, caused somatic (but not visceral) hypersensitivity and increased the thickness of the submucosal and muscle layers of the small intestine. In vincristine-treated animals, MSG partially prevented gastrointestinal dysmotility and reduced visceral sensitivity but did not improve structural alterations of the small intestine. CONCLUSIONS & INFERENCES: MSG could be used as an adjuvant to conventional treatments to improve some gastrointestinal dysfunctions caused by chemotherapy.

Neuro-Gastro-Cannabinology: A Novel Paradigm for Regulating Mood and Digestive Health.

The maintenance of homeostasis in the gastrointestinal (GI) tract is ensured by the presence of the endocannabinoid system (ECS), which regulates important physiological activities, such as motility, permeability, fluid secretion, immunity, and visceral pain sensation. Beside its direct effects on the GI system, the ECS in the central nervous system indirectly regulates GI functions, such as food intake and energy balance. Mounting evidence suggests that the ECS may play an important role in modulating central neurotransmission which affects GI functioning. It has also been found that the interaction between the ECS and microbiota affects brain and gut activity in a bidirectional manner, and a number of studies demonstrate that there is a strong relationship between GI dysfunctions and mood disorders. Thus, microbiota can regulate the tone of the ECS. Conversely, changes in intestinal ECS tone may influence microbiota composition. In this mini-review, we propose the concept of neuro-gastro-cannabinology as a novel and alternative paradigm for studying and treating GI disorders that affect mood, as well as mood disorders that imbalance GI physiology. This concept suggests the use of prebiotics or probiotics for improving the tone of the ECS, as well as the use of phytocannabinoids or endocannabinoid-like molecules, such as palmitoylethanolamide, to restore the normal intestinal microbiota. This approach may be effective in ameliorating the negative effects of GI dysfunctions on mood and/or the effects of mood disorders on digestive health.

New Pieces for an Old Puzzle: Approaching Parkinson's Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.

Probiotics and Probiotic-like Agents against Chemotherapy-Induced Intestinal Mucositis: A Narrative Review.

Cancer chemotherapy has allowed many patients to survive, but not without risks derived from its adverse effects. Drugs, such as 5-fluorouracil, irinotecan, oxaliplatin, methotrexate, and others, as well as different drug combinations trigger intestinal mucositis that may cause or contribute to anorexia, pain, diarrhea, weight loss, systemic infections, and even death. Dysbiosis is a hallmark of chemotherapy-induced intestinal mucositis and diarrhea, and, therefore, strategies aimed at modulating intestinal microbiota may be useful to counteract and prevent those dreadful effects. This narrative review offers an overview of the studies performed to test the efficacy of probiotics and probiotic-like agents against chemotherapy-induced intestinal mucositis and its consequences. Microbiota modulation through the oral administration of different probiotics (mainly strains of Lactobacillus and Bifidobacterium), probiotic mixtures, synbiotics, postbiotics, and paraprobiotics has been tested in different animal models and in some clinical trials. Regulation of dysbiosis, modulation of epithelial barrier permeability, anti-inflammatory effects, modulation of host immune response, reduction of oxidative stress, or prevention of apoptosis are the main mechanisms involved in their beneficial effects. However, the findings are limited by the great heterogeneity of the preclinical studies and the relative lack of studies in immunocompromised animals, as well as the scarce availability of results from clinical trials. Despite this, the results accumulated so far are promising. Hopefully, with the aid of these agents, intestinal mucositis will be less impactful to the cancer patient in the near future.

Radiographic and histopathological study of gastrointestinal dysmotility in lipopolysaccharide-induced sepsis in the rat.

BACKGROUND: Sepsis is a highly incident condition in which a cascade of proinflammatory cytokines is involved. One of its most frequent consequences is ileus, which can increase mortality. Animal models such as that induced by systemic administration of lipopolysaccharide (LPS) are useful to deeply evaluate this condition. The effects of sepsis on the gastrointestinal (GI) tract have been explored but, to our knowledge, in vivo studies showing the motor and histopathological consequences of endotoxemia in an integrated way are lacking. Our aim was to study in rats the effects of sepsis on GI motility, using radiographic methods, and to assess histological damage in several organs. METHODS: Male rats were intraperitoneally injected with saline or E. coli LPS at 0.1, 1, or 5 mg kg-1 . Barium sulfate was intragastrically administered, and X-rays were performed 0-24 h afterwards. Several organs were collected for organography, histopathology, and immunohistochemistry studies. KEY RESULTS: All LPS doses caused gastroparesia, whereas changes in intestinal motility were dose-and time-dependent, with an initial phase of hypermotility followed by paralytic ileus. Lung, liver, stomach, ileum, and colon (but not spleen or kidneys) were damaged, and density of neutrophils and activated M2 macrophages and expression of cyclooxygenase 2 were increased in the colon 24 h after LPS 5 mg kg-1 . CONCLUSIONS AND INFERENCES: Using radiographic, noninvasive methods for the first time, we show that systemic LPS causes dose-, time-, and organ-dependent GI motor effects. Sepsis-induced GI dysmotility is a complex condition whose management needs to take its time-dependent changes into account.

Radiographic assessment of the impact of sex and the circadian rhythm-dependent behaviour on gastrointestinal transit in the rat.

Relatively little is known about the influence of sex and the circadian rhythm on gastrointestinal transit. However, these factors could have an important impact on aspects such as digestion, oral absorption of drugs or the clinical manifestation of gastrointestinal diseases, among others. Remarkably, preclinical models have scarcely taken these factors into consideration. In this study, we assessed the gastrointestinal transit of young adult Wistar Han rats of both sexes, under normal and inverted light cycle. To do this, serial radiographs were taken for 24 h (T0-T24) after intragastric barium administration and subsequently analysed to construct transit curves for each gastrointestinal region. Under a normal light cycle, transit curves were similar, except for a slower transit in females compared with males from T8 to T24. Under the inverted cycle, there was a significant acceleration in stomach emptying (similar in both sexes), emptying of the small intestine (even faster in females) and filling of the caecum and colon (which was also even faster in females). This study confirms, using X-ray non-invasive methods for the first time, that both sex and circadian rhythm (probably through its effect on behaviour) influence gastrointestinal transit in laboratory animals.