Author ORCID Identifier

Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Hamid Akbarali


In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises of whether the secondary release of bacterial products and pro-inflammatory cytokines can modulate antinociceptive tolerance development. This dissertation examines how gut bacteria depletion with antibiotics modulates the pharmacodynamic properties of chronic morphine in mice. Utilizing a “top-down” experimental approach, this is characterized at the whole-animal, single-cell, and molecular level via behavioral assays of antinociception, whole-cell patch-clamp recordings in DRG neurons, and analysis of tetrodotoxin-resistant (TTX-R) Na+ channel kinetics, respectively. Our findings collectively indicate that the gastrointestinal microbiome is an important modulator of antinociceptive tolerance development with chronic morphine administration.


© Ryan Mischel

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