DOI
https://doi.org/10.25772/4CKX-HY41
Defense Date
2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmacology & Toxicology
First Advisor
Matthew Banks
Second Advisor
Sidney Negus
Third Advisor
Katherine Nicholson
Fourth Advisor
Kimberle Jacobs
Fifth Advisor
Pamela Knapp
Abstract
Mu-opioid receptor (MOR) agonists are effective agents for pain management, but are also limited by a number of undesirable effects. One approach to enhance the therapeutic effects and minimize the undesirable effects of MOR agonists may be to combine MOR agonists with an adjunct targeting a different receptor system. This targeted medical approach, known as “combination therapy”, aims to augment the desired effects of the MOR agonist (i.e. antinociception) and/or diminish the undesirable deleterious side effects of the MOR agonist. This dissertation investigated the utility of this approach in an assay of thermal nociception and schedule-controlled responding in male rhesus monkeys with three aims. One aim determined the utility of N-methyl D-aspartate (NMDA) receptor antagonists to selectively enhance MOR agonist antinociception. A second identified the pharmacological determinants of antinociceptive interactions between a nociceptin opioid peptide (NOP) receptor agonist and MOR agonists. A third aim investigated the potential for fixed-proportion mixtures of a competitive MOR antagonist and MOR agonist to manipulate antinociceptive efficacy. Experimental results did not support the utility of NMDA antagonists as adjuncts to selectively enhance MOR agonist antinociception. Furthermore, the antinociceptive interactions between a NOP agonist and MOR agonists were modest and occurred under a narrow range of conditions. Finally, fixed proportion MOR antagonist-agonist mixtures were effective in manipulating antinociceptive in vivo efficacy. In conclusion, this dissertation does not provide strong empirical evidence that a combination therapy approach will result in clinically effective and selective enhancement of MOR agonist analgesia. The dissertation concludes with proposed strategies and novel preclinical methods to enhance preclinical-to-clinical translation of effective candidate analgesics.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-11-2019