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INFLAMMATION AND IMMUNOPHARMACOLOGY

Antiexudative Effects of Opioids and Expression of - and - Opioid Receptors during Intestinal Inflammation in Mice: Involvement of Nitric Oxide

Anesthesiology Research Unit, Institut Municipal d'Investigació Médica, Department of Anesthesiology, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain (N.J., M.M.P.); and Laboratori de Neurofarmacologia Molecular, Institut de Recerca, Hospital de la Santa Creu i Sant Pau and Institut de Neurociéncies, Universitat Autònoma de Barcelona, Barcelona, Spain (O.P.)

The study evaluates the effects of - (KOR), - (DOR), and µ-opioid receptor (MOR) agonists on the inhibition of plasma extravasation during acute and chronic intestinal inflammation in mice. The antiexudative effects of KOR and DOR agonists in animals treated with nitric oxide synthase (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 Evans blue 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 trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolydinyl)cyclohexyl]-benzeneazetamine (U50,488H) inhibiting plasma extravasation was enhanced 26.3 times during chronic compared with acute inflammation. [D-Pen²,D-Pen⁵]-Enkephalin (DPDPE) (a DOR agonist) was also 11.8 times more potent during chronic inflammation, whereas the antiexudative 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 N-nitro-L-arginine methyl ester or L-N⁶-(1-iminoethyl)-lysine hydrochloride diminished plasma extravasation and inhibited the increased antiexudative effects of U50,488H and DPDPE during chronic intestinal inflammation. The data show that the enhanced antiexudative 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.

Address correspondence to: Dr. Olga Pol, Laboratori de Neurofarmacologia Molecular, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Edifici C-Z, 08193 Barcelona, Spain. E-mail: opol{at}santpau.es