The involvement of nitric oxide in the enhanced expression of mu-opioid receptors during intestinal inflammation in mice.
Intestinal inflammation enhances the potency of mu-opioid receptor (MOR) agonists inhibiting gastrointestinal transit and increases the expression of MOR in mice intestine. The precise mechanisms implicated in the increased expression of MOR during intestinal inflammation are not known. The aim of the study is to evaluate if nitric oxide released during intestinal inflammation could modulate MOR gene expression and affect gastrointestinal transit. Intestinal inflammation was induced by the intragastric administration of croton oil. In CD-1 mice, with and without inflammation, we evaluated the anti-transit effects of morphine in animals treated with NOS inhibitors (L-NAME and L-NIL) and the intestinal levels of iNOS enzyme mRNA. The anti-transit effects of morphine and the expression of MOR mRNA in the gut of wild-type (WT) and iNOS-/- mice were also assessed. Gastrointestinal transit was measured with charcoal meal and mRNA levels determined by real-time PCR. In CD-1 mice, inflammation induced a 10-fold increase (P<0.0001) in iNOS mRNA levels in the gut. The absence of iNOS gene and treatment of CD-1 mice with L-NAME or L-NIL abolished the increased antitransit effects of morphine observed during inflammation. Moreover, although the basal levels of MOR mRNA were similar in WT and iNOS animals (-/-), intestinal inflammation only increased the MOR expression in the gut of WT (P<0.01) but not in iNOS-/- mice. The results suggest that nitric oxide derived from the increased expression of iNOS is implicated in the enhanced effects of morphine and in the upregulation of MOR gene transcription observed during intestinal inflammation.
Pol
Olga
O
Anesthesiology Research Unit, Institut Municipal d'Investigació Mèdica, Universitat Autònoma de Barcelona, Hospital del Mar, Doctor Aiguader 80, Barcelona 08003, Spain. opol@hsp.santpau.es
Sasaki
Masayuki
M
Jiménez
Natàlia
N
Dawson
Valina L
VL
Dawson
Ted M
TM
Puig
Margarita M
MM
D000818:Animals; D003436:Croton Oil; D004751:Enteritis / Q000139:chemically induced / Q000503:physiopathology*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*
C090663:N(6)-(1-iminoethyl)lysine; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D009569:Nitric Oxide; D009020:Morphine; D003436:Croton Oil; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester