Intestinal inflammation enhances the inhibitory effects of opioids on intestinal permeability in mice.
The inhibitory effects of central and peripherally acting opioid agonists on intestinal permeability (PER) were evaluated during acute and chronic intestinal inflammation in mice. Inflammation was induced by the intragastric (p.o.) administration of one (acute) or two (chronic) doses of croton oil (CO), whereas controls received saline (SS). Intestinal PER was assessed by the blood-to-lumen transfer of 51Cr-ethylenediaminetetraacetate (51Cr-EDTA). CO significantly increased PER during acute (2.5 times) and chronic (3.2 times) inflammation. The potency of s.c. morphine-inhibiting PER was enhanced 3.8 and 8.7 times in acute and chronic CO, whereas that of s.c. fentanyl was increased 2.0 and 4.3 times, respectively, compared with SS. Similarly, s.c. [D-Pen(2,5)]-enkephalin was 4.7 and 11.1 times more potent during acute and chronic CO, and the E(max) values of the dose-response curves increased 35% during inflammation. The potency of s.c. U50,488H was 5.6 (acute) and 6.7 times (chronic) greater compared with SS. All effects were reversed by specific antagonists. The i.p. administration of beta-funaltrexamine differentially blocked morphine effects during acute and chronic CO, suggesting that the effects are mediated by different populations of functional mu-opioid receptors (OR). The increase in potencies of s.c. PL017 and ICI-204,448 during CO were comparable to those observed with fentanyl and U50,488H and their effects were antagonized by s.c. naloxone methiodide. Moreover, the potency of the agonists during inflammation was unaltered when administered i.c.v. The results show that intestinal inflammation enhances the effects of delta- > mu- > kappa-opioid agonists on PER by activation of peripheral OR.
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Anesthesiology Research Unit, Institut Municipal d'Investigación Mèdica, Department of Anesthesiology, Hospital Universitario del Mar, Barcelona, Spain.
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Puig
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D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003436:Croton Oil / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004751:Enteritis / Q000378:metabolism / Q000503:physiopathology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007276:Injections, Intraventricular; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D017480:Receptors, sigma / Q000187:drug effects
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; D003436:Croton Oil