Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice

Tan-No, Koichi; Niijima, Fukie; Nakagawasai, Osamu; Sato, Terukazu; Satoh, Susumu; Tadano, Takeshi

doi:10.1016/j.ejps.2003.08.004

Cited by 50 publications

(37 citation statements)

References 19 publications

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“…In the present studies, loperamide was more potent in mice than in rats, consistent with the significant increased murine potency observed by others [15] . Generally, loperamide acts at peripheral opioid receptors [16] to decrease both small intestinal and colonic transit [17][18][19][20] , but its effects in IBS diarrhea are variable and primarily associated with reduced urgency [17] .…”

Section: Discussionsupporting

confidence: 79%

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

et al. 2007

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Background/Aims: Phosphodiesterase type 4 (PDE4) has been previously shown to regulate colonic contractile activity in vitro. In this study, the effects of PDE4 inhibition were assessed in a model of stress-induced defecation previously demonstrated to be due to increased colonic transit/evacuation. Methods: Rats were individually placed in a mild restraint cage and placed into a 12°C environment (cold-restraint stress) for 60 min. Mice received restraint (only) stress at room temperature for 30 min. Loperamide (positive control compound) or two different PDE4 inhibitors (rolipram and roflumilast) were administered orally at several doses to the rodents 1 h before stress began. Vehicle alone was administered for comparison. The number of fecal pellets expelled during stress (fecal pellet output), total fecal pellet wet weight and total fecal water content were measured. Results: Loperamide produced a dose-related decrease (ID₅₀s in mg/kg) in fecal pellet output (rat = 7.4, mouse = 0.7) and significantly decreased fecal wet weight (72.9%) and decreased fecal percent water content (9.4%). The two PDE4 inhibitors produced a similar dose-related inhibition of fecal pellet output. Rolipram exhibited ID₅₀s in rat and mouse of 14.1 and 27.1, respectively. Rolipram significantly decreased fecal wet weight (58.8%) but increased fecal percent water content (15.0%). For roflumilast, ID₅₀s were 24.2 mg/kg and 12.4 in the rat and mouse, respectively. Although roflumilast also significantly (p < 0.05) decreased fecal wet weight (47.2%), it did not significantly increase fecal percent water content. Conclusions: These data indicate that PDE4 inhibition is effective in reducing rodent stress-induced defecation, provides the first functional data on a potential role for PDE4 activity in the colonic evacuation response to stress, and indicates the potential utility of PDE4 inhibitors in functional bowel disease such as irritable bowel syndrome requires further evaluation.

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Section: Discussionsupporting

confidence: 79%

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

et al. 2007

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“…8A]. Loperamide decreased ITR%, which is consistent with the results of previous studies [34], and MOE inhibited this loperamide-induced ITR% decrease [ITR% for loperamide was 34.4 ± 1.5%, while it was 46.1 ± 0.8% for loperamide with MOE ( p < 0.001); Fig. 8A].…”

Section: Resultssupporting

confidence: 81%

Magnolia Officinalis Bark Extract Induces Depolarization of Pacemaker Potentials Through M2 and M3 Muscarinic Receptors in Cultured Murine Small Intestine Interstitial Cells of Cajal

Kim¹,

Han

Kim³

et al. 2017

Cell Physiol Biochem

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Background: Magnolia officinalis Rehder and EH Wilson (M. officinalis) are traditional Chinese medicines widely used for gastrointestinal (GI) tract motility disorder in Asian countries. We investigated the effects of an ethanol extract of M. officinalis (MOE) on the pacemaker potentials of cultured interstitial cells of Cajal (ICCs) in vitro and its effects on GI motor functions in vivo. Methods: We isolated ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record the pacemaker potentials in cultured ICCs in vitro. Both gastric emptying (GE) and intestinal transit rates (ITRs) were investigated in normal and GI motility dysfunction (GMD) mice models in vivo. Results: MOE depolarized ICC pacemaker potentials dose-dependently. Pretreatment with methoctramine (a muscarinic M₂ receptor antagonist) and 4-DAMP (a muscarinic M₃ receptor antagonist) inhibited the effects of MOE on the pacemaker potential relative to treatment with MOE alone. In addition, MOE depolarized pacemaker potentials after pretreatment with Y25130 (a 5-HT₃ receptor antagonist), GR113808 (a 5-HT₄ receptor antagonist) or SB269970 (a 5-HT₇ receptor antagonist). However, pretreatment with RS39604 (a 5-HT₄ receptor antagonist) blocked MOE-induced pacemaker potential depolarizations. Intracellular GDPβS inhibited MOE-induced pacemaker potential depolarization, as did pretreatment with Ca²⁺ free solution or thapsigargin. In normal mice, the GE and ITR values were significantly and dose-dependently increased by MOE. In loperamide-and cisplatin-induced GE delay models, MOE administration reversed the GE deficits. The ITRs of the GMD mice were significantly reduced relative to those of normal mice, which were significantly and dose-dependently reversed by MOE. Conclusion: These results suggest that MOE dose-dependently depolarizes ICCs pacemaker potentials through M₂ and M₃ receptors via internal and external Ca²⁺ regulation through G protein pathways in vitro. Moreover, MOE increased GE and ITRs in vivo in normal and GMD mouse models. Taken together, the results of this study show that MOE have the potential for development as a gastroprokinetic agent in GI motility function.

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“…To test whether the observed small-intestinal hypermotility contributed to the clearance of Giardia, we treated mice with loperamide, a drug that inhibits intestinal transit by activating -opioid receptors in the gastrointestinal tract (2,13,21). Drug treatment was started at the time of peak G. muris infection (day 7) to ensure that pharmacologically induced changes in motility would not interfere with the initial establishment of the infection.…”

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confidence: 99%

Adaptive Immunity-Dependent Intestinal Hypermotility Contributes to Host Defense against Giardia spp

Andersen¹,

Gillin

Eckmann³

2006

Infect Immun

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Humans infected with Giardia exhibit intestinal hypermotility, but the underlying mechanisms and functional significance are uncertain. Here we show in murine models of giardiasis that small-intestinal hypermotility occurs in a delayed fashion relative to peak parasite burden, is dependent on adaptive immune defenses, and contributes to giardial clearance.Infection with Giardia lamblia is one of the most common causes of diarrheal disease worldwide (22). This protozoan pathogen colonizes the small intestine and can attach to the epithelium but does not invade the mucosa. Infections are normally self-limiting, since immunocompetent hosts can control and typically eradicate G. lamblia, a process that involves CD4 T cells and the generation of secretory immunoglobulin A (IgA) and other, poorly understood effectors (6,8,9,18). Despite the frequently severe clinical symptoms, diarrhea, abdominal pain, malabsorption, and weight loss, infection is not accompanied by significant mucosal inflammation (12). These observations suggest that inflammatory mediators may not be important for parasite-induced diarrhea, although the mechanisms governing diarrhea in giardiasis are poorly understood. Giardia has not been shown to release enterotoxins that might account for the disturbance of intestinal fluid absorption or secretion. A reduction in absorptive surface due to a loss of epithelial microvilli occurs upon Giardia infection in mice (16), which could lead to osmotically driven diarrhea associated with malabsorption, but the absolute surface reduction is modest compared to the predicted anatomical reserve of the small intestine. Humans infected with G. lamblia exhibit signs of intestinal hypermotility upon radiological examination (15), a phenomenon also observed in experimentally infected Mongolian gerbils (5). The underlying mechanisms and functional significance of these findings are presently unclear. Therefore, the goal of the present study was to test the hypothesis that intestinal hypermotility represents a host defense mechanism against Giardia, using murine models of giardiasis.Adult C57BL/6, SCID, and neuronal nitric oxide synthase (nNOS)-deficient mice were obtained from The Jackson Laboratory (Bar Harbor, ME). For infections with Giardia muris, cysts were purified by sucrose flotation, counted in a hemocytometer under a phase-contrast microscope, and given by oral gavage in water at 10 4 cysts/mouse in 0.2 ml (9). For G. lamblia infections, trophozoites of the GS/M strain (ATCC 50580) (11) were grown in TYIS-33 medium and given by oral gavage at 10 7 /mouse in 0.2 ml of the same medium (9). Small-intestinal motility was determined by a modified test meal method. Mice were fasted overnight and given 0.2 ml of a suspension of 10 6 fluorescent polystyrene beads (10-m-diameter Fluoresbrite YG carboxylate microspheres; Polysciences, Inc., Warrington, PA) (19) and 6% carmine dye in 5% gum arabic in phosphatebuffered saline (PBS). After 20 min, the small intestine was removed rapidly, and the position of the carmine dy...

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Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice

Cited by 50 publications

References 19 publications

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice

Magnolia Officinalis Bark Extract Induces Depolarization of Pacemaker Potentials Through M2 and M3 Muscarinic Receptors in Cultured Murine Small Intestine Interstitial Cells of Cajal

Adaptive Immunity-Dependent Intestinal Hypermotility Contributes to Host Defense against Giardia spp

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