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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 23, 2005; DOI: 10.1124/jpet.105.091991

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Received for publication July 5, 2005.
Revised August 30, 2005.
Accepted for publication September 15, 2005.

ANTI-EXUDATIVE EFFECTS OF OPIOIDS AND EXPRESSION OF {kappa}-AND {delta}-OPIOID RECEPTORS DURING INTESTINAL INFLAMMATION IN MICE: INVOLVEMENT OF NITRIC OXIDE

Natalia Jimenez 1, Margarita M Puig 2, Olga Pol 3*

1 Institut Municipal Investigacio Medica 2 Hospital del Mar. Universitat Autonoma de Barcelona 3 Institut de Recerca. Hospital de la Santa Creu i Sant Pau. Universitat Autonoma de Barcelona

* Address correspondence to: E-mail: opol{at}santpau.es

Abstract

The study evaluates the effects of {kappa}- (KOR), {delta}- (DOR) and µ-(MOR) opioid receptor agonists on the inhibition of plasma extravasation during acute and chronic intestinal inflammation in mice. The anti-exudative effects of KOR and DOR agonists in animals treated with NOS inhibitors and their protein levels in the gut (whole jejunum and mucosa) and spinal cord of mice with chronic intestinal inflammation were also measured. Inflammation was induced by the intragastric administration of one (acute) or two (chronic) doses of croton oil. Plasma extravasation was measured using Evan's blue (EB) and protein levels by Western blot and immunoprecipitation. Plasma extravasation was significantly increased 2.7 times during chronic inflammation. The potency of the KOR agonist, (U50,488H) inhibiting plasma extravasation was enhanced 26.3 times during chronic when compared to acute inflammation. DPDPE (a DOR agonist) was also 11.8 times more potent during chronic inflammation, whereas the anti-exudative effects of fentanyl (a MOR agonist) were not significantly altered. Receptor-specific antagonists reversed the effects. Protein levels of KOR and DOR in the whole jejunum and mucosa were significantly increased after chronic inflammation. Treatment with NOS inhibitors (L-NAME or L-NIL) diminished plasma extravasation and inhibited the increased anti-exudative effects of U50,488H and DPDPE during chronic intestinal inflammation. The data shows that the enhanced anti-exudative effects of KOR and DOR agonists could be related to an increased expression of KOR and DOR in the gut, and that the release of nitric oxide may play a role augmenting the effects of opioids during chronic inflammation.


Key words: inflammation, intestine, nitric oxide, opioid receptor, plasma extravasation, protein




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