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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    ABSTRACT: Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.
    01/2015; 2015:1-10. DOI:10.1155/2015/540154
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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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    ABSTRACT: Beside their analgesic properties, opiates exert beneficial effects on the intestinal wound healing response. In this study, we investigated the role of mu-opioid receptor (MOR) signaling on the unfolded protein response (UPR) using a novel zebrafish model of NSAID-induced intestinal injury. The NSAID glafenine was administered to 5 days-post-fertilization (dpf) zebrafish larvae for up to 24h in the presence or absence of the MOR-specific agonist DALDA. By analysis with histology, transmission electron microscopy, and vital dye staining, glafenine-treated zebrafish showed evidence of endoplasmic reticulum (ER) and mitochondrial stress with disrupted intestinal architecture and halted cell stress responses, alongside accumulation of apoptotic intestinal epithelial cells in the lumen. While the early UPR marker BiP was induced with glafenine-injury, downstream atf6 and s-xbp1 expression were paradoxically not increased, explaining the halted cell stress responses. The mu-opioid agonist DALDA protected against glafenine-induced injury through induction of atf6-dependent UPR. Our findings show that DALDA prevents glafenine-induced epithelial damage through induction of effective UPR.
    Disease Models and Mechanisms 08/2012; 6(1). DOI:10.1242/dmm.009852 · 4.97 Impact Factor
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    • "KLF5 can regulate cytokine production in response to injury or other stimuli [32], [33], [34], and multiple cytokine-induced signaling pathways converge on the key transcription factor STAT3 [35]. Moreover, activated STAT3 is critical both for protection against colitis and for the restoration of intestinal integrity during colitis [8], [9], [10], [11], [12]. We hypothesized that the protective effect of KLF5 following intestinal mucosal injury by DSS was mediated by activation of the JAK/STAT pathway. "
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    ABSTRACT: Inflammatory bowel disease (IBD), which is characterized by chronic or recurring inflammation of the gastrointestinal tract, affects 1.4 million persons in the United States alone. KLF5, a Krüppel-like factor (KLF) family member, is expressed within the epithelia of the gastrointestinal tract and has been implicated in rapid cell proliferation, migration, and remodeling in a number of tissues. Given these functions, we hypothesized that constitutive Klf5 expression would protect against the development of colitis in vivo. To examine the role of KLF5 in vivo, we used the Villin promoter to target Klf5 to the entire horizontal axis of the small intestine and colon. Villin-Klf5 transgenic mice were born at normal Mendelian ratios and appeared grossly normal to at least 1 year of age. Surprisingly, there were no significant changes in cell proliferation or in the differentiation of any of the intestinal lineages within the duodenum, jejunum, ileum, and colon of Villin-Klf5 mice, compared to littermate controls. However, when Villin-Klf5 mice were treated with dextran sodium sulfate (DSS) to induce colitis, they developed less colonic injury and significantly reduced disease activity scores than littermate controls. The mechanism for this decreased injury may come via JAK-STAT signaling, the activation of which was increased in colonic mucosa of DSS treated Villin-Klf5 mice compared to controls. Thus, KLF5 and its downstream mediators may provide therapeutic targets and disease markers for IBD or other diseases characterized by injury and disruption of intestinal epithelia.
    PLoS ONE 05/2012; 7(5):e38338. DOI:10.1371/journal.pone.0038338 · 3.23 Impact Factor
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