Mechanisms of repeated opioid use dependent remodeling in respiratory control

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ABSTRACT Alzheimer’s disease (AD) is estimated to afflict nearly 13 million Americans by 2050. As no current therapies have been proven to reverse or stop the progression of the disease, AD is on track to become a greater burden to the American healthcare system. This is further compounded by a lack of understanding into the factors influencing the onset and progression of AD. While there is a growing recognition between the importance of opioid receptor-based neuromodulation and AD-related pathogenesis, the impact that opioid use has on the progression of AD is poorly understood. The ongoing opioid epidemic and continued prescription of opioids among individuals with AD and related dementia (ADRD) may be significant factors that influence the trajectory of AD progression later in life. However, a significant knowledge gap exists in understanding the unintended consequences of repeat opioid use (ROU) on ADRD-related pathogenesis. The parent grant aims (1) to understand the consequences of ROU on the control of breathing. This supplement builds on this foundation with the objective to understand how opioid modulation impacts the pathogenesis and behavioral phenotypes related to AD. We hypothesize that ROU exacerbates amyloid β burden and neurocognitive deficits related to AD while the severity of the AD phenotype may be ameliorated by targeted inhibition of the mu opioid receptor. To test this, we propose two aims that: (1) examines how repeat opioid use influences histological changes associated with AD and cognitive performance in a mouse model of AD; and (2) determines how the severity of AD-related phenotypes may be impacted by inhibition of endogenous MOR activity. Therefore, we will provide greater resolution in understanding how targeting opioid modulation may influence the pathogenesis of ADRD. These advancements may lead to novel efficacious preventive strategies to address ADRD and monitor the progression of ADRD.