Dependency on sex and stimulus quality of nociceptive behavior in a conscious visceral pain rat model.

Visceral pain may be influenced by many factors. The aim of this study was to analyze the impact of sex and quality of intracolonic mechanical stimulus on the behavioral manifestations of visceral pain in a preclinical model. Male and female young adult Wistar rats were sedated, and a 5 cm long latex balloon was inserted into the colon. Sedation was reverted and behavior was recorded. The pressure of the intracolonic balloon was gradually increased using a sphygmomanometer. Visceral sensitivity was measured as abdominal contractions in response to mechanical intracolonic stimulation. Two different types of stimulation were used: tonic and phasic. Phasic stimulation consisted of repeating several times (3x) the same short stimulus (20 s) within a 5 min interval allowing a 1 min break between individual stimuli. For tonic stimulation the stimulus was maintained throughout the whole 5 min interval. Both phasic and tonic stimulation produced a pressure-dependent increase of abdominal contractions. The abdominal response was more intense under phasic than under tonic stimulation, but with differences depending on the sex of the animals: females exhibited more contractions than males and of similar duration at all pressures, whereas duration of contractions pressure-dependently increased in males. The duration of tonically stimulated contractions was lower and not sex- or pressure-dependent. In the rat, responses to colonic distension depend on the quality of the stimulus, which also produces sex-dependent differences that must be taken into account in the development of models of pathology and visceral pain treatments.

Cannabinoid pharmacology and therapy in gut disorders.

Cannabis sp. and their products (marijuana, hashish…), in addition to their recreational, industrial and other uses, have a long history for their use as a remedy for symptoms related with gastrointestinal diseases. After many reports suggesting these beneficial effects, it was not surprising to discover that the gastrointestinal tract expresses endogenous cannabinoids, their receptors, and enzymes for their synthesis and degradation, comprising the so-called endocannabinoid system. This system participates in the control of tissue homeostasis and important intestinal functions like motor and sensory activity, nausea, emesis, the maintenance of the epithelial barrier integrity, and the correct cellular microenvironment. Thus, different cannabinoid-related pharmacological agents may be useful to treat the main digestive pathologies. To name a few examples, in irritable bowel syndrome they may normalize dysmotility and reduce pain, in inflammatory bowel disease they may decrease inflammation, and in colorectal cancer, apart from alleviating some symptoms, they may play a role in the regulation of the cell niche. This review summarizes the main recent findings on the role of cannabinoid receptors, their synthetic or natural ligands and their metabolizing enzymes in normal gastrointestinal function and in disorders including irritable bowel syndrome, inflammatory bowel disease, colon cancer and gastrointestinal chemotherapy-induced adverse effects (nausea/vomiting, constipation, diarrhea).

Preclinical evaluation of the effects on the gastrointestinal tract of the antineoplastic drug vincristine repeatedly administered to rats.

BACKGROUND: Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and motility or its long-term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects. METHODS: Rats received saline or vincristine (0.1 mg kg-1 , ip) daily for 10 days. Evaluations were performed during treatment and 2-6 weeks after. Somatic mechano-sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole-mount myenteric plexus preparations. KEY RESULTS: Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS-immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization. CONCLUSIONS AND INFERENCES: Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine-induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long-lasting.

Nomogramas para el diagnóstico de hipertensión arterial en la adolescencia. La experiencia autóctona debe ser siempre la mejor / Nomograms for diagnosis of arterial hypertension in adolescence. The native experience must always be the best

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Caracterización fluoroscópica en rata de la dismotilidad colónica asociada a tratamiento con morfina / Fluoroscopic characterization of colonic dysmotility in rat associated with morphine treatment

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Alterations in the small intestinal wall and motor function after repeated cisplatin in rat.

BACKGROUND: Gastrointestinal adverse effects occurring during cancer chemotherapy are well known and feared; those persisting once treatment has finished are relatively unknown. We characterized the alterations occurring in the rat small intestine, after repeated treatment with cisplatin. METHODS: Male Wistar rats received saline or cisplatin (2 mg kg-1  week-1 , for 5 weeks, ip). Gastric motor function was studied non-invasively throughout treatment (W1-W5) and 1 week after treatment finalization (W6). During W6, upper gastrointestinal motility was also invasively studied and small intestinal samples were collected for histopathological and molecular studies. Structural alterations in the small intestinal wall, mucosa, submucosa, muscle layers, and lymphocytic nodules were histologically studied. Periodic acid-Schiff staining and immunohistochemistry for Ki-67, chromogranin A, and neuronal-specific enolase were used to detect secretory, proliferating, endocrine and neural cells, respectively. The expression of different markers in the tunica muscularis was analyzed by RT/qPCR. KEY RESULTS: Repeated cisplatin induced motility alterations during and after treatment. After treatment (W6), the small intestinal wall showed histopathological alterations in most parameters measured, including a reduction in the thickness of circular and longitudinal muscle layers. Expression of c-KIT (for interstitial cells of Cajal), nNOS (for inhibitory motor neurons), pChAT, and cChAT (for excitatory motor neurons) increased significantly (although both ChATs to a lesser extent). CONCLUSIONS & INFERENCES: Repeated cisplatin induces relatively long-lasting gut dysmotility in rat associated with important histopathological and molecular alterations in the small intestinal wall. In cancer survivors, the possible chemotherapy-induced histopathological, molecular, and functional intestinal sequelae should be evaluated.

Computer vision-based diameter maps to study fluoroscopic recordings of small intestinal motility from conscious experimental animals.

BACKGROUND: When available, fluoroscopic recordings are a relatively cheap, non-invasive and technically straightforward way to study gastrointestinal motility. Spatiotemporal maps have been used to characterize motility of intestinal preparations in vitro, or in anesthetized animals in vivo. Here, a new automated computer-based method was used to construct spatiotemporal motility maps from fluoroscopic recordings obtained in conscious rats. METHODS: Conscious, non-fasted, adult, male Wistar rats (n=8) received intragastric administration of barium contrast, and 1-2 hours later, when several loops of the small intestine were well-defined, a 2 minutes-fluoroscopic recording was obtained. Spatiotemporal diameter maps (Dmaps) were automatically calculated from the recordings. Three recordings were also manually analyzed for comparison. Frequency analysis was performed in order to calculate relevant motility parameters. KEY RESULTS: In each conscious rat, a stable recording (17-20 seconds) was analyzed. The Dmaps manually and automatically obtained from the same recording were comparable, but the automated process was faster and provided higher resolution. Two frequencies of motor activity dominated; lower frequency contractions (15.2±0.9 cpm) had an amplitude approximately five times greater than higher frequency events (32.8±0.7 cpm). CONCLUSIONS & INFERENCES: The automated method developed here needed little investigator input, provided high-resolution results with short computing times, and automatically compensated for breathing and other small movements, allowing recordings to be made without anesthesia. Although slow and/or infrequent events could not be detected in the short recording periods analyzed to date (17-20 seconds), this novel system enhances the analysis of in vivo motility in conscious animals.

May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

BACKGROUND: The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. METHODS: Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg-1 injection-1 , 1 injection day-1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg-1 injection-1 , cumulative dose of 300 mg kg-1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. KEY RESULTS: As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. CONCLUSIONS AND INFERENCES: 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.

Gastrointestinal dysfunction and enteric neurotoxicity following treatment with anticancer chemotherapeutic agent 5-fluorouracil.

BACKGROUND: The use of the anticancer chemotherapeutic agent 5-fluorouracil (5-FU) is often limited by nausea, vomiting, constipation, and diarrhea; these side-effects persist long after treatment. The effects of 5-FU on enteric neurons have not been studied and may provide insight into the mechanisms underlying 5-FU-induced gastrointestinal dysfunction. METHODS: Balb/c mice received intraperitoneal injections of 5-FU (23 mg/kg) 3 times/week for 14 days. Gastrointestinal transit was analysed in vivo prior to and following 3, 7, and 14 days of 5-FU treatment via serial x-ray imaging. Following 14 days of 5-FU administration, colons were collected for assessment of ex vivo colonic motility, gross morphological structure, and immunohistochemical analysis of myenteric neurons. Fecal lipocalin-2 and CD45+ leukocytes in the colon were analysed as markers of intestinal inflammation. KEY RESULTS: Short-term administration of 5-FU (3 days) increased gastrointestinal transit, induced acute intestinal inflammation and reduced the proportion of neuronal nitric oxide synthase-immunoreactive neurons. Long-term treatment (7, 14 days) resulted in delayed gastrointestinal transit, inhibition of colonic migrating motor complexes, increased short and fragmented contractions, myenteric neuronal loss and a reduction in the number of ChAT-immunoreactive neurons after the inflammation was resolved. Gross morphological damage to the colon was observed following both short- and long-term 5-FU treatment. CONCLUSIONS & INFERENCES: Our results indicate that 5-FU induces accelerated gastrointestinal transit associated with acute intestinal inflammation at day 3 after the start of treatment, which may have led to persistent changes in the ENS observed after days 7 and 14 of treatment contributing to delayed gastrointestinal transit and colonic dysmotility.

X-ray analysis of gastrointestinal motility in conscious mice. Effects of morphine and comparison with rats.

BACKGROUND: Non-invasive methods to study gastrointestinal (GI) motility are of high interest, particularly in chronic studies. Amongst these, radiographic techniques after contrast intragastric administration may offer many advantages. In previous studies, we have successfully and reproducibly applied these techniques together with a semiquantitative analysis method to characterize the effect of different drugs, acutely or repeatedly administered in rat models, but we have never before used these techniques in mice. These are very convenient in basic research. Our aim was to determine if our method is also valid in mice. Additionally, we determined the effect of morphine on GI motor function in both species. METHODS: Animals received an intraperitoneal administration of morphine (at 10 and 5 mg/kg for rats and mice, respectively). Twenty min later, barium contrast (at 2 g/mL) was gavaged (2.5 and 0.4 mL for rats and mice respectively) and serial X-rays were obtained 0-8 h after contrast. X-rays were analyzed as previously described, using a semiquantitative score to build motility curves for each GI region. KEY RESULTS: Motility was much faster in mice than in rats for all GI regions. Morphine at the doses used significantly depressed motility in both species to a similar extent if the whole gut or the upper GI regions (stomach, small intestine) were considered, although its effect seemed to be more intense in the lower GI regions (caecum, colorectum) in rats than in mice. CONCLUSIONS & INFERENCES: We have validated our X-rays method for its use in mice.

In vitro and non-invasive in vivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat.

BACKGROUND: Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats. METHODS: Male Wistar rats were used for in vitro and in vivo studies. The effect of AM841 was tested on electrically induced twitch contractions of GI preparations (in vitro) and on GI motility measured radiographically after contrast administration (in vivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841. KEY RESULTS: AM841 dose-dependently reduced in vitro contractile activity of rat GI preparations via CB1R, but not CB2R or opioid receptors. In vivo, AM841 acutely and potently reduced gastric emptying and intestinal transit in a dose-dependent and AM251-sensitive manner. The in vivo GI effects of AM841 at 0.1 mg/kg were comparable to those induced by WIN at 5 mg/kg. However, at this dose, AM841 did not induce any sign of the cannabinoid tetrad, whereas WIN induced significant central effects. CONCLUSIONS & INFERENCES: The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.

Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats.

BACKGROUND: Monosodium glutamate (MSG) is a flavor-enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. METHODS: Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. KEY RESULTS: Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. CONCLUSIONS & INFERENCES: Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research.

Cannabinoids may worsen gastric dysmotility induced by chronic cisplatin in the rat.

BACKGROUND: Although cannabinoids have traditionally been used for the treatment and/or prevention of nausea and/or emesis, anorexia and weight loss induced by clinical use of antineoplastic drugs, their efficacy and safety in long-term treatments are still controversial. Our aim was to analyze the effects of the non-selective cannabinoid agonist WIN 55 212-2 (WIN) on gastrointestinal (GI) dysmotility and other adverse effects induced by repeated cisplatin administration in the rat. METHODS: Male Wistar rats received two intraperitoneal injections once a week for 4 weeks: the first one was WIN, at non-psychoactive doses (0.5 or 1 mg kg(-1)), its vehicle or saline; the second one was cisplatin (2 mg kg(-1)) or saline. Radiographic techniques were used to determine the acute (after first dose), chronic (after last dose), and residual (1 week after treatment finalization) effects of cisplatin and/or WIN on GI motility. Bodyweight gain, food ingestion, and mechanical sensitivity were also tested. KEY RESULTS: Weekly cisplatin induced mechanical allodynia, which WIN prevented, as well as weight gain reduction and anorexia, which WIN did not. Gastric emptying was dose-dependently delayed by cisplatin and this effect was enhanced upon chronic treatment. WIN aggravated cisplatin-induced gastric dysmotility. One week after treatment finalization, only minor alterations of GI motor function were found in rats treated with cisplatin, WIN or both. CONCLUSIONS & INFERENCES: WIN weekly administered at low doses prevents neuropathy, but does not prevent anorexia or weight loss and aggravates gastric dysmotility induced by cisplatin. Cannabinoids should be handled with caution if chronically administered during chemotherapy.

Fisioterapia preventiva en las disfunciones del suelo pélvico en el posparto / Preventive physical therapy in pelvic floor dysfunction during postpartum

Se realizó una revisión bibliográfica acerca de la actuación de la fisioterapia como prevención de las disfunciones del suelo pélvico en el posparto, para conocer los métodos terapéuticos más empleados. La búsqueda se llevó a cabo de septiembre del 2011 a enero del 2012 en las bases de datos ENFISPO, Pedro, CINAHL, CSIC, Cochrane Library Plus en español, Cochrane Library, Medline, Pubmed, Wos, Scopus y Sport Discus with full text. Atendiendo a los criterios de inclusión y exclusión, se analizaron 14 documentos, en los que se hallaron como procedimientos más utilizados en el periodo posnatal los ejercicios de Kegel, los ejercicios hipopresivos y los ejercicios depresivos con el bebé.Se ha encontrado escasa bibliografía acerca de las técnicas para la prevención de disfunciones en el posparto. Los métodos que se utilizan no suponen una sobrecarga a nivel asistencial para el fisioterapeuta (AU)

We made a systematic review on physical therapy as a method to prevent pelvic floor dysfunction in the postpartum period and to determine the most common therapeutic methods used. The search was carried out from September 2011 to January 2012 using the following databases: ENFISPO, Pedro, CINAHL, CSIC, Spanish Library Cochrane Plus, Cochrane Library, Medline, Pubmed, Wos, Scopus and Sport Discus with full text. Following the inclusion and exclusion criteria, in 14 studies we found that the most frequently used methods during postnatal period are Kegel exercises, hypopressives exercises and depressive exercises with the baby. Little bibliography was found on methods to prevent pelvic floor dysfunction in the postpartum period. The methods used do not involve an overload level on the care level for the physical therapist (AU)

Cannabinoid-induced delayed gastric emptying is selectively increased upon intermittent administration in the rat: role of CB1 receptors.

BACKGROUND: Cannabinoids acutely administered depress central, cardiovascular and gastrointestinal functions. These effects might be modified upon repeated administration. Compared to the effects induced by daily administration, those induced by intermittent administration are less known. The effect of intermittent treatment with the CB1/CB2 cannabinoid agonist WIN55,212-2 (WIN) was studied in the rat. METHODS: Male rats received saline, vehicle or WIN at 0.5 (low-WIN) or 5 (high-WIN) mg kg(-1) week(-1) for 4 weeks. WIN effects on the central nervous system (cannabinoid tetrad tests), cardiovascular function and gastrointestinal motor function were evaluated after the first and last doses, and, where appropriate, 1 week after the last dose. To determine the involvement of CB1 receptors in the chronic effect of WIN, the CB1 receptor antagonist/inverse agonist AM251 (1 mg kg(-1)) was used. KEY RESULTS: High- (but not low-) WIN induced the four signs of the cannabinoid tetrad, and reduced gastrointestinal motility, but did not alter cardiovascular parameters. Upon chronic intermittent administration, tolerance did not clearly develop to WIN effects. Quite the opposite, depression of gastric emptying was intensified. No effect was long-lasting. Repeated administration of AM251 was more efficacious than single administration to block WIN chronic central effects, but the opposite occurred regarding lower intestinal motility. CONCLUSIONS & INFERENCES: Upon intermittent administration, hypersensitization may develop to some effects (particularly delayed gastric emptying) induced by cannabinoid agonists. CB1 antagonists/inverse agonists may show different efficacy upon repeated or single administration to block cannabinoid-induced central and gastrointestinal effects. Thus, cannabinoid effects are dependent on the pattern of drug administration.

Enteric neuropathy evoked by repeated cisplatin in the rat.

BACKGROUND: Acute administration of the antitumoral drug cisplatin can induce nausea/emesis and diarrhea. The long-term effects of cisplatin on gastrointestinal motility, particularly after repeated administration, are not well known. Because cisplatin is highly neurotoxic, myenteric neurons can be affected. Our aim was to study the prolonged effects of repeated cisplatin administration in a rat model, focusing on gastrointestinal motor function and myenteric neurons. METHODS: Rats received saline or cisplatin (1 or 3 mg kg(-1), i.p.) once weekly for 5 weeks. One week after treatment, both upper gastrointestinal transit and colonic activity were evaluated, and tissue samples from ileum, colon and rectum were processed for histological analysis. Intestinal transit was measured invasively (charcoal method). Colonic activity was determined electromyographically. The gut wall structure was evaluated in sections using conventional histology and immunohistochemistry. Whole-mount preparations from the distal colon were labeled for different markers, including nitric oxide synthase (NOS) and calcitonin-gene related peptide (CGRP) to determine relative proportions of myenteric neurons vs the total neuronal population labeled with HuC/D. KEY RESULTS: One week after repeated cisplatin exposure, the upper gastrointestinal transit rate and colonic activity were dose-dependently reduced. The number of NSE- or HuC/D-immunoreactive myenteric neurons per ganglion was decreased; the proportion of CGRP-immunoreactive neurons was decreased, whereas that of NOS-immunoreactive cells was increased. CONCLUSIONS & INFERENCES: Chronic cisplatin may induce an enteric neuropathy characterized by changes in myenteric neurons associated with marked gastrointestinal motor dysfunction.

Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica.

BACKGROUND: Chemotherapy induces nausea/emesis and gastrointestinal dysmotility. Pica, the ingestion of non-nutritive substances, is considered as an indirect marker of nausea/emesis in non-vomiting species, like the rat. Cisplatin is the most emetogenic antitumoral drug. In the rat, acute cisplatin induces pica and gastric dysmotility in a temporally related manner, but the effects of chronic cisplatin are not well known. This study analyzed the effects of chronic cisplatin on pica and on gastrointestinal motor function in the rat, using radiographic, non-invasive methods. METHODS: Rats received saline or cisplatin (1-3 mg kg(-1), i.p.) once a week for four consecutive weeks. Serial X-rays were taken 0-8 h after administration of barium sulfate, which was given intragastrically immediately after the first and last cisplatin administrations and 1 week after treatment finalization. Pica (i.e., kaolin intake) was measured in isolated rats. KEY RESULTS: Cisplatin delayed gastric emptying and induced acute (during the 24 h following each administration) pica. Upon chronic administration, these effects were exacerbated. In addition, basal kaolin intake was enhanced (facilitated) and gastric distension induced. Delayed gastric emptying and gastric distension were not apparent 1 week after treatment, but basal kaolin intake was still elevated. CONCLUSIONS & INFERENCES: Whereas gastric dysmotility induced by cisplatin is parallel to the development of acute pica and might underlie facilitation of pica throughout chronic treatment, it does not explain its long-term maintenance. These findings should be taken into account in the search for new antiemetic strategies.

The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212-2 on gastrointestinal motility in the rat.

BACKGROUND: In the absence of pathology, cannabinoid-induced depression of gastrointestinal (GI) motility is thought to be mediated primarily by CB1 receptors, whereas the role of CB2 receptors is still unclear. The aim of this work was to radiographically analyze the acute effect of the mixed cannabinoid agonist WIN 55,212-2 (WIN) on GI motor function in the rat, focusing on the involvement of CB1 and CB2 receptors. METHODS: Male Wistar rats received different doses of WIN and both psychoactivity (cannabinoid tetrad) and GI motility (radiographic analysis) were tested. The duration of WIN effect on GI motility was also radiographically analyzed. Finally, the involvement of the different cannabinoid receptors on WIN-induced alterations of GI motility was analyzed by the previous administration of selective CB1 (AM251) and CB2 (SR144528 or AM630) antagonists. After administration of contrast medium, alterations in GI motility were quantitatively evaluated in serial radiographs by assigning a compounded value to each region of the GI tract. KEY RESULTS: Low, analgesic doses of WIN delayed intestinal transit, but high, psychoactive doses were required to delay gastric emptying. Acute WIN effects on GI motility were confined to the first few hours after administration. AM251 partially counteracted the effect of WIN on GI motility. Surprisingly, SR144528 (but not AM630) enhanced WIN-induced delayed gastric emptying. CONCLUSIONS & INFERENCES: X-ray analyses confirm that cannabinoids inhibit GI motility via CB1 receptors; in addition, cannabinoids could influence motility through interaction with a SR144528-sensitive site. Further studies are needed to verify if such site of action is the CB2 receptor.

Selective lack of tolerance to delayed gastric emptying after daily administration of WIN 55,212-2 in the rat.

The use of cannabinoids to treat gastrointestinal (GI) motor disorders has considerable potential. However, it is not clear if tolerance to their actions develops peripherally, as it does centrally. The aim of this study was to examine the chronic effects of the cannabinoid agonist WIN 55,212-2 (WIN) on GI motility, as well as those in the central nervous and cardiovascular systems. WIN was administered for 14 days, at either non-psychoactive or psychoactive doses. Cardiovascular parameters were measured in anaesthetized rats, whereas central effects and alterations in GI motor function were assessed in conscious animals using the cannabinoid tetrad and non-invasive radiographic methods, respectively. Tests were performed after first (acute effects) and last (chronic effects) administration of WIN, and 1 week after discontinuing treatment (residual effects). Food intake and body weight were also recorded throughout treatment. Blood pressure and heart rate remained unchanged after acute or chronic administration of WIN. Central activity and GI motility were acutely depressed at psychoactive doses, whereas non-psychoactive doses only slightly reduced intestinal transit. Most effects were reduced after the last administration. However, delayed gastric emptying was not and could, at least partially, account for a concomitant reduction in food intake and body weight gain. The remaining effects of WIN administration in GI motility were blocked by the CB1 antagonist AM 251, which slightly accelerated motility when administered alone. No residual effects were found 1 week after discontinuing cannabinoid treatment. The different systems show differential sensitivity to cannabinoids and tolerance developed at different rates, with delayed gastric emptying being particularly resistant to attenuation upon chronic treatment.