Radiographic dose‐dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea‐like behavior

Abstract

Background Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea‐like behavior). Methods Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg−1). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X‐rays were taken 0‐8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. Key Results Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose‐dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. Conclusions and inferences Our results suggest that loperamide‐induced nausea and gastric dysmotility might be temporally dissociated.

Effects of the food additive monosodium glutamate on cisplatin‐induced gastrointestinal dysmotility and peripheral neuropathy in the rat

“…This relaxes the stomach, particularly the fundus 18 , through the activation of the vagovagal reflex, resulting in 5-HT 3 antagonists-sensitive delayed gastric emptying and distension 17,18 , as well as gastric retention of food 60,61 and probably gas 61 . As described 17,43,62 , cisplatin-induced gastric dysmotility was "pica" (an indirect marker of nausea in non-vomiting species 64 ) in rats 16,18,40,43,45,46 .…”

“…As described 17,43,62 , cisplatin‐induced gastric dysmotility was aggravated after the fifth cisplatin injection compared with the first one but was resolved 1 week after treatment cessation. Indeed, serotonin‐mediated cisplatin‐induced gastric dysmotility is an acute event occurring within the 24 h after administration, associated with the development of acute nausea and vomiting in humans 8 (and animal species displaying the vomiting reflex, like ferrets 63 ), and acute “pica” (an indirect marker of nausea in non‐vomiting species 64 ) in rats 16,18,40,43,45,46 .…”

“…Each of these parameters was scored and a sum (0–12 points) was made. The X‐ray images were digitized, and the size and density of contrast were analyzed for stomach, caecum and fecal pellets, with the aid of an image analysis system (Image J 1.38 for Windows, National Institute of Health, USA, free software: http://rsb.info.nih.gov/ij/; see Figure S1, for further description 46 ). The number and diameter of fecal pellets within the colorectum was also determined for each rat at each time point.…”

“…While taking the radiographs, the qualified investigator remained at least 2 m away from the X-ray source. Films were developed in a http://rsb.info.nih.gov/ij/; see Figure S1, for further description 46 ).…”

“…Compared with control animals, density of nNOS-IR fibers was slightly (but not significantly) reduced in all other experimental groups ( Figure S5C). Cisplatin reduces body weight gain 43,45 and food intake 16,40,46,51,52 . However, anorexia was not evident, maybe because we estimated daily food intake from weekly measurements, and anorexia might be restricted to the first 24 h after each cisplatin administration, with compensatory increases afterwards 16,40 .…”