Author ORCID Identifier
https://orcid.org/0000-0001-9104-7151
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Hamid I. Akbarali
Second Advisor
William L. Dewey
Third Advisor
M. Imad Damaj
Fourth Advisor
I. Scott Ramsey
Fifth Advisor
John Grider
Abstract
Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity (OIH) and chemotherapy induced hypersensitivity (CIH) are characterized by an increased sensitivity to painful stimuli which can significantly reduce the quality of life for individuals on either drug(s). Here we demonstrate the nociceptive hypersensitivity associated with repeated administration of morphine (opioid) and paclitaxel (chemotherapeutic) treatment can be reversed by oral supplementation with the short chain fatty acid (SCFA) sodium butyrate (NaBut). In two separate mouse behavioral models for nociceptive hypersensitivity, we found that thermal hyperalgesia (for OIH) and cold allodynia (for CIH) were prevented by treatment with oral butyrate (4 days OIH and 12 days for CIH) (p.o, b.i.d). Electrophysiological recordings of small diameter dorsal root ganglia (DRG) neurons from morphine and paclitaxel treated mice showed an increase in neuronal hyperexcitability in both drug models which was likewise prevented by oral butyrate treatment. Using colonic conditioned media obtained from excised colon segments we found that gut mediators of morphine treated mice can induce hyperexcitability in naïve DRG neurons, but such enhanced excitability is not present when animals are co-treated with NaBut suggesting gut derived mediators modulate neuronal hyperexcitability. In vitro NaBut treatment did not prevent morphine-induced excitability, suggesting an indirect role of butyrate in modulating neuronal hypersensitivity. Lastly, we found a significant shift in the steady state voltage dependence of activation of voltage-gated sodium channels after repeated morphine administration which was recovered in the presence of NaBut suggesting a possible mechanism by which NaBut reduces neuronal hyperexcitability after repeated morphine exposure. These data taken together suggest that gut derived mediators affect opioid and chemotherapeutic-induced neuronal hypersensitivity that is prevented by the SCFA butyrate.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-27-2024