Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation.
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.
Philippe
David
D
Equipe Mixte INSERM 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, Centre Hospitalier Universitaire, Lille, France.
Dubuquoy
Laurent
L
Groux
Hervé
H
Brun
Valérie
V
Chuoï-Mariot
Myriam Tran Van
MT
Gaveriaux-Ruff
Claire
C
Colombel
Jean-Frédéric
JF
Kieffer
Brigitte L
BL
Desreumaux
Pierre
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; D009270:Naloxone; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase