Peripheral effects of opioids in a model of chronic intestinal inflammation in mice.
The study describes a model of chronic intestinal inflammation in mice. Inflammation was induced by the administration of one dose of croton oil (CO) (acute CO) or two doses (chronic CO) of intragastric CO, whereas controls received saline (SS); GI transit was measured with charcoal. Chronic CO induced intestinal inflammation substantiated by optical microscopy, weight loss (20%) and a 25% increase in GI transit. The ED50 values in SS animals were 1.67 +/- 0.13 mg/kg for morphine and 0.038 +/- 0.006 mg/kg for fentanyl; chronic CO significantly decreased the ED50 values to 0.16 +/- 0.03 mg/kg (morphine) and 0.006 +/- 0.0005 mg/kg (fentanyl). Thus the potency of morphine increased 10.4 times and that of fentanyl 6.3 times. The effects of enkephalin, but not those of U-50488H, were also significantly enhanced during chronic CO. The antitransit effects of p.o. loperamide increased 11.7 times during chronic CO. All effects were reversed by specific antagonists. The fraction of the active opioid receptor that mediates the antitransit effects of morphine was evaluated using beta-funaltrexamine. In chronic CO, the doses of beta-funaltrexamine needed to antagonize 1 mg/kg of morphine were significantly higher than in SS and acute CO, and the ED50/KA ratio was 20 times lower. These results suggest an increase in the active concentration of mu-opioid receptors during chronic inflammation.
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Anesthesiology Research Unit, IMIM, Department of Anesthesiology, Hospital Universitario del Mar, Barcelona, Spain.
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D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002248:Carbon Monoxide; D004751:Enteritis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005772:Gastrointestinal Transit / Q000187:drug effects*; D007583:Jejunum / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000627:therapeutic use*; D011957:Receptors, Opioid / Q000096:biosynthesis
D000930:Antidiarrheals; D009292:Narcotic Antagonists; D009294:Narcotics; D011957:Receptors, Opioid; D009271:Naltrexone; D008139:Loperamide; C024524:beta-funaltrexamine; D009020:Morphine; D002248:Carbon Monoxide