Abstract
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 β-funaltrexamine. In chronic CO, the doses of β-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 μ-opioid receptors during chronic inflammation.
Footnotes
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Send reprint requests to: Margarita M. Puig, M.D., Ph.D., Prof. and Chair, Dept. of Anesthesiology, Hospital Universitario del Mar, Passeig Marı́tim, 25-29, 08003 Barcelona, Spain.
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↵1 This work was partially supported by grants from CICYT #PM96-0039, Madrid and Fundació La Marató de TV3 #2032/97, Barcelona, Spain.
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↵2 Preliminary results were presented at the 5th European Society of Anaesthesiologists, Lausanne, Switzerland, May 1997.
- Abbreviations:
- OR
- opioid receptor
- CO
- croton oil
- SS
- saline
- GIT
- gastrointestinal transit
- β-FNA
- β-funaltrexamine
- DPDPE
- enkephalin, [D-Pen2,5]
- U-50488H
- trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolydynil) cyclohexyl)benzeneazetamine
- MR-2266
- (−)-a-5,9-diethyl-2′-hydroxy-2-(3-furylmethyl)-6,7-benzomorphan
- ANOVA
- analysis of variance
- Received December 16, 1997.
- Accepted June 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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