Bruce, Daniel2024-01-192024-01-192020-08https://hdl.handle.net/11299/260157University of Minnesota Ph.D. dissertation. August 2020. Major: Pharmacology. Advisor: George Wilcox. 1 computer file (PDF); vii, 154 pages.The peripherally-restricted combination of loperamide and oxymorphindole is a potent and efficacious preclinical analgesic treatment that relieves the behavioral hyperalgesia caused by inflammatory, post-operative and neuropathic pain states. The combination displayed analgesic synergy across all assays, pain conditions and species tested here, and was also effective in a non-evoked measure of spontaneous pain. From a clinical translation standpoint, the combination confers a protective phenotype relative to clinically approved opioids, demonstrated by the lack of constipation at therapeutic doses, no respiratory depression even at supratherapeutic doses, chronic therapeutic dosing that is devoid of analgesic tolerance, and significantly limited risk for self-administration. Mechanistically, the combination exerts its analgesic action by binding to opioid receptors¬—specifically MOR-DOR heteromers—on peripheral sensory afferent neurons, preferentially activating G protein-dependent signaling cascades to reduce neuronal excitability. Taken together, this thesis provides strong support for the continued investigation into peripheral opioid mechanisms and analgesic synergy as a path forward in our continued fight to develop better pharmacological pain treatment paradigms.enaddictionanalgesiabehavioral pharmacologychronic painopioidperipheral nervous systemThesis or Dissertation