Date of Degree

12-2023

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Pharmaceutical Sciences

Advisor

Helmut Gottlieb

Advisor

Jessica Bradley

Advisor

Lila LaGrange

Abstract

Heart failure is a prevalent and debilitating disease associated with high morbidity and mortality rates worldwide and is the leading cause of death in the United States. While various therapeutic strategies have been developed and approved to manage heart failure, exploration of novel targets and mechanisms are essential for improving patient outcomes. This thesis investigates the therapeutic potential of the central activation of opioid receptor-like 1 (ORL-1) by nociceptin in a rodent heart failure model.

Furthermore, this study aims to elucidate the central mechanisms underlying nociceptin induced cardiovascular and renal effects in heart failure. This involves investigating neuronal pathways and neuronal and neurotransmitter systems influenced by nociceptin administration using immunohistochemical methods and urinalysis for sodium and potassium.

The findings of this thesis demonstrated greater expression of the excitatory neuromarker c-Fos in the parvocellular paraventricular nucleus (PVN) of the hypothalamus. Less expression was observed from neurons in the supraoptic nucleus and the magnocellular PVN in nearly all of the models tested. Heart failure models treated with nociceptin demonstrated less expression of c-Fos in the PVN than the untreated heart failure models. While it appears that ejection fraction was higher than anticipated and vasopressin was not fully activated in the heart failure models from the lack of c-Fos expression in the SON, these results still demonstrate decreased sympathetic nerve activity in the treated heart failure group compared to the untreated heart failure group. These results imply that the treated groups experienced reduction of heart rate, blood pressure, and a decrease in renal sympathetic nerve activity (RSNA) causing the models to excrete more fluids in the form of urine.

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