Defense Date

2025

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology and Biophysics

First Advisor

Hamid Akbarali

Second Advisor

Charles Anderson

Third Advisor

Liya Qiao

Abstract

Constipation is a major clinical obstacle associated with opioids, prompting patients to discontinue treatment due to pain, discomfort, and psychosocial stressors. Moreover, chronic users become tolerant to the analgesic effects of opioids, but not to their constipating effects. Upon cessation of long-term treatment, serious diarrhea–among other somatic signs of withdrawal–may ensue. These symptoms become a driving factor for relapse, causing patients to restart opioid treatment. In this study, we aim to understand mechanisms that contribute to opioid tolerance and withdrawal in the colon. Previous findings suggest that constipation occurs partly due to the colon’s lack of tolerance to opioids’ inhibitory effects on transit. Our data shows that colonic tissue which was exposed to 4 days of in-vivo ramping doses of morphine injections demonstrated similar basal motility compared to morphine-naive tissue, suggesting that tolerance develops in the colon. We also demonstrate naloxone-precipitated withdrawal behavior in these chronic morphine-treated tissue, demonstrating a link between colonic withdrawal and tolerance. Drawing upon previous work from our lab, we investigated the role of cholinergic signaling and how it may impact withdrawal. We are specifically interested in lynx1, a negative allosteric modulator of ɑ3ꞵ4 nAChRs. Chronic morphine-treated lynx1 knockout tissue experienced significantly heightened withdrawal compared to WT. This finding implicates cholinergic signaling as a major contributor in the colon’s withdrawal response and may propose lynx1 as an interventional candidate in attenuating GI withdrawal.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-10-2025

Download

Share

COinS