Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
American Journal Of Pathology (Impact Factor: 4.59). 08/2011; 179(2):673-83. DOI: 10.1016/j.ajpath.2011.04.032
Source: PubMed


Opiates have long been used as analgesics to relieve pain associated with various medical conditions. Here, we evaluated the effect and mechanism of mu opioid signaling on the intestinal wound healing response and assessed downstream pathways known to be protective against intestinal injury. Mice (C57BL/6) were exposed to 3% dextran sodium sulfate (DSS) for 7 days or 4% DSS for 5 days followed by 7 days of water. The mu opioid receptor (MOR)-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA) and the antagonist cyprodime were injected s.c. daily for in vivo studies or used for in vitro analysis. We found that MOR activation attenuated DSS-induced histologic and gross intestinal injury and weight loss; diminished Ifng, Tnf, and Il6 mRNA expression; and promoted intestinal healing during recovery. DALDA also enhanced colonocyte proliferation (Ki-67 staining) by 350%. MOR activation increased Stat3 phosphorylation in both DALDA-treated mice and the CMT-93 cell line. Importantly, DALDA-induced colonocyte migration was completely ablated by shStat3 knockdown. Together, this work shows that MOR activation protects against and enhances recovery from DSS-induced intestinal injury. This is associated with an increase in Stat3 activation. Furthermore, Stat3 is required for DALDA-induced colonocyte migration. Consequently, manipulation of MOR signaling may represent a novel means to promote mucosal healing and to maintain intestinal homeostasis after intestinal injury.

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Available from: Jason R Goldsmith, Jun 18, 2014
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    • "Similarly , in our studies on Fischer 344 rats, morphine delivered via osmotic pumps implanted subcutaneously away from the wound site did not have any effect on wound closure, but topically applied opioids on the wound accelerated closure [104]. MOR signaling has been shown to heal the intestinal injury in mice [107]. Deletion of MOR resulted in thinner epidermis in mice [108]. "
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    • "We recently showed that the MOR agonist DALDA protects against DSS-induced intestinal injury through wound healing and proliferative responses in mice (Goldsmith et al., 2011). DALDA promoted intestinal proliferation in glafenine-exposed fish consistent with the previously reported properties of the drug (Goldsmith et al., 2011). However, other zebrafish bioactive proliferative factors (mEGF and hIGF1) (Pozios et al., 2001; Pang and Ge, 2002) failed to prevent glafenine-injury, suggesting that proliferation is not the primary protective mechanism of DALDA in this model. "
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