Defense Date

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Hamid I. Akbarali

Abstract

Opioids are excellent pain relievers. A major side-effect of chronic opioid treatment is constipation whereas withdrawal following chronic exposure leads to diarrhea and increased gastrointestinal motility. These effects of chronic opioids are mediated by μ-opioid receptors expressed on enteric neurons. Previous studies have shown that chronic opioids enhance sensitivity to nicotine in the gastrointestinal tract. This suggested that prokinetic effects of nicotine mediated through the activation of nicotinic acetylcholine receptors (nAChRs) may be useful in reversing opioid-induced constipation. The goal of this dissertation was to investigate the nAChR subtype expressed on enteric neurons and their role in reversing opioid-induced constipation. The effect of nicotine on small intestinal transit and fecal pellet output were determined in-vivo in morphine-pelleted mice xiii (75 mg for 4 days). Nicotine-induced currents were measured by whole-cell voltage clamp in isolated adult mouse myenteric neurons treated with morphine over short term (10 mins) and long term (16-20 hrs). Following long term morphine exposure in-vivo (morphine pellet – 4 days), nicotine increased fecal pellet output, and enhanced small intestinal transit. The prokinetic effect of nicotine was not seen in placebo pelleted mice or after acute morphine (10 mg/kg, 30 min). Peak-amplitude of nicotine-induced inward currents in isolated neurons was also enhanced after long-term but not short term exposure to morphine. Nicotine-induced currents were inhibited by mecamylamine (10 μM) and α-conotoxin AUIB (3 μM), suggesting the expression of α3β4 subtype of nAChRs on enteric neurons. Conversely, NS3861, a partial agonist at α3β4 nAChR enhanced fecal pellet expulsion in a dose-dependent manner in chronic but not acute morphine treated mice. Overall, our findings suggest that the efficacy of nAChR agonists on enteric neurons is enhanced after chronic morphine exposure and activation of α3β4 subtype of nAChR reverses chronic but not acute morphine induced constipation. In conclusion, development of peripherally selective α3β4 partial agonists may be of therapeutic benefit in treatment of chronic opioid-induced constipation.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-10-2015

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