Diarrhea associated with intestinal inflammation increases the potency of mu and delta opioids on the inhibition of gastrointestinal transit in mice.
The aim of the study was to determine the effects of intestinal inflammation induced by croton oil on the antitransit action of systemically administered receptor-specific opioids. Our hypothesis was that inflammation would "sensitize" opioid receptors in peripheral and/or central terminals of myenteric and submucous plexus neurons and enhance the effects of exogenously administered opioids. Diarrhea was induced by p.o. administration of croton oil and was demonstrated by weight loss and increased gastrointestinal transit. Histologically, an increased number of clear vesicles in the cytoplasm of jejunal epithelial cells and enlarged spaces filled with fine granular material in the extravascular compartment were observed. Subcutaneous morphine and fentanyl produced dose-related inhibitions of gastrointestinal transit in saline-treated controls with ED50 values of 1.24 +/- 0.06 and 0.036 +/- 0.010 mg/kg, respectively. In animals with diarrhea, dose-response curves were parallel and shifted to the left with a significant decrease in ED50 values of 2.95 times for morphine and 1.89 for fentanyl. The effects of the delta agonist Tyr-D-Pen-Gly-Phe-D-Pen, but those of U50,488H [trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolydynil)cyclohexyl) benzeneazetamine] also were increased significantly during diarrhea associated with inflammation. Naloxone (0.1 mg/kg), MR-2266 [(-)-a-5,9-diethyl-2'-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan] (3 mg/kg) and naltrindole (1 mg/kg) antagonized the effects of the receptor-specific opioid agonists used in the study. Our results show that the potency of s.c. mu and delta opioids is increased during inflammation of the gut and that the effect is mediated by the same type of opioid receptors present in the noninflamed tissue. These results support the view that a sensitization of opioid receptors occurs during acute inflammation of the gut.
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Department of Anesthesiology, Hospital Universitario del Mar, Barcelona, Spain.
Ferrer
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Puig
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D000595:Amino Acid Sequence; D000818:Animals; D003436:Croton Oil; D003864:Depression, Chemical; D003967:Diarrhea / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology; D007583:Jejunum / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009294:Narcotics / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D012680:Sensitivity and Specificity; D012965:Sodium Chloride
D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D012965:Sodium Chloride; D003436:Croton Oil