enkephalin--ala(2)-mephe(4)-gly(5)- and Colitis

Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis.. The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO-an MOR agonist), 0.3 mg/kg BW (DPDPE-a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone-a non-selective OR antagonist, GLPG 0974-a FFAR2 antagonist, GSK 137647-a FFAR4 agonist and AH 7614-a FFAR4 antagonist) for 4 days.. Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group.. Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed.

Topics: Aniline Compounds; Animals; Butyrates; Colitis; Disease Models, Animal; Drug Synergism; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Inflammation; Ligands; Male; Mice; Mice, Inbred BALB C; Naloxone; Narcotic Antagonists; Peroxidase; Receptors, G-Protein-Coupled; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides; Thiophenes; Xanthenes

μ opioid receptors (μORs) are expressed by neurons and inflammatory cells, and mediate immune response. We tested whether activation of peripheral μORs ameliorates the acute and delayed phase of colitis.. C57BL/6J mice were treated with 3% dextran sodium sulfate (DSS) in water, 5 days with or without the peripherally acting μOR agonist, [D-Ala2, N-Me-Phe4, Gly5-ol]-Enkephalin (DAMGO) or with DAMGO+μOR antagonist at day 2-5, then euthanized. Other mice received DSS followed by water for 4 weeks, or DSS with DAMGO starting at day 2 of DSS for 2 or 3 weeks followed by water, then euthanized at 4 weeks. Disease activity index (DAI), histological damage, and myeloperoxidase assay (MPO), as index of neutrophil infiltration, were evaluated. Cytokines and μOR mRNAs were measured with RT-PCR, and nuclear factor-kB (NF-kB), the antiapoptotic factor Bcl-xL, and caspase 3 and 7 with Western blot.. DSS induced acute colitis with elevated DAI, tissue damage, apoptosis and increased MPO, cytokines, μOR mRNA, and NF-kB. DAMGO significantly reduced DAI, inflammatory indexes, cytokines, caspases, and NF-kB, and upregulated Bcl-xL, effects prevented by μOR antagonist. In DSS mice plus 4 weeks of water, DAI, NF-kB, and μOR were normal, whereas MPO, histological damage, and cytokines were still elevated; DAMGO did not reduce inflammation, and did not upregulate Bcl-xL.. μOR activation ameliorated the acute but not the delayed phase of DSS colitis by reducing cytokines, likely through activation of the antiapoptotic factor, Bcl-xL, and suppression of NF-kB, a potentiator of inflammation.

Topics: Animals; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Inflammation; Mice; Mice, Inbred C57BL; Receptors, Opioid, mu

The physiologic role of the mu opioid receptor (MOR) in gut nociception, motility, and secretion is well established. To evaluate whether MOR may also be involved in controlling gut inflammation, we first showed that subcutaneous administration of selective peripheral MOR agonists, named DALDA and DAMGO, significantly reduces inflammation in two experimental models of colitis induced by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) or peripheral expansion of CD4(+) T cells in mice. This therapeutic effect was almost completely abolished by concomitant administration of the opioid antagonist naloxone. Evidence of a genetic role for MOR in the control of gut inflammation was provided by showing that MOR-deficient mice were highly susceptible to colon inflammation, with a 50% mortality rate occurring 3 days after TNBS administration. The mechanistic basis of these observations suggests that the anti-inflammatory effects of MOR in the colon are mediated through the regulation of cytokine production and T cell proliferation, two important immunologic events required for the development of colon inflammation in mice and patients with inflammatory bowel disease (IBD). These data provide evidence that MOR plays a role in the control of gut inflammation and suggest that MOR agonists might be new therapeutic molecules in IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4-Positive T-Lymphocytes; Colitis; Colon; Cytokines; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, SCID; Naloxone; Narcotic Antagonists; Oligopeptides; Peroxidase; Receptors, Opioid, mu; Trinitrobenzenesulfonic Acid