Morphine is one of the most widely used drugs for the treatment of pain but its clinical efficacy is limited by adverse effects including persistent constipation and colonic inflammation. Morphine-induced colonic inflammation is facilitated by microbial dysbiosis and bacterial translocation. In this study, we demonstrate that secondary inflammation and persistent constipation are modulated by enteric glia. In chronic morphine treated mice (75 mg morphine pellet/5 days), ATP-induced currents were significantly enhanced in enteric glia isolated from the mouse colon myenteric plexus. Chronic morphine resulted in significant disruption of the colonic epithelium and increased Il-1β in the myenteric plexus. The increase in ATP-induced currents, IL-1β expression and ATP release were also observed in isolated glia treated with lipopolysaccharide (LPS) consistent with bacterial translocation as a potential mediator of chronic morphine-induced inflammation. These effects of LPS were reversed by carbenoxolone, a connexin43 hemichannel blocker. In-vivo treatment with carbenoxolone (25 mg/kg) prevented 1) ATP-induced currents in enteric glia, 2)the decrease in neuronal density, and 3) colonic inflammation in chronic morphine treated mice. Inhibition of connexin43 in enteric glia also reversed morphine mediated decrease in gastrointestinal transit. These findings indicate that bacterial translocation-induced enteric glial activation and inflammation is a significant modulator of morphine-related constipation.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5733 |
| Date | 01 January 2016 |
| Creators | Bhave, Sukhada |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © Sukhada Bhave |
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