Thursday, November 21, 2024
11/21/2024
Project Summary Adolescence is a crucial period of brain development with robust hormonal, physiological, behavioral, and neurochemical changes. Long-term use of both alcohol and opioids results in increased pain sensitivity or hyperalgesia. Adolescent opioid use, through prescription and recreational use, is a growing problem in the United States and is known to increase the likelihood of future misuse of substances that include but are not limited to alcohol. That said, very little is known about the neuroplasticity that occurs during adolescent opioid exposure (AOE) and how it may affect alcohol use and alcohol-related outcomes during adulthood – here, we propose a set of experiments that focus on the latter of these two topics by testing AOE effects on alcohol- induced allodynia in adult mice. We will test the prediction that the central nucleus of the amygdala (CeA), a brain region modulated by opioid and alcohol use and important for pain modulation, and more specifically that protein kinase C-δ+ (PKCδ) cells in this brain region, are important in mediating AOE effects on alcohol-induced allodynia later in life. CeA PKCδ cells are hyperexcitable in animals with chronic neuropathic pain, and CeA PKCδ cell function is altered by alcohol and opioids. It is not known how CeA PKCδ cell+ neurons are affected by AOE, what their role is in alcohol-induced allodynia in adults, and what role it might play AOE enhancement of alcohol effects on pain-related outcomes. Our global hypothesis is that early-life exposure to opioids will increase the magnitude of alcohol-induced allodynia in adulthood, and this enhancement will be mediated by CeA PKCδ neurons. To test this, we will expose adolescent male and female wild type and PKCδ:cre mice to chronic oxycodone, then expose them to chronic alcohol during adulthood, with appropriate controls for each condition. We will use circuit-based approaches to inhibit the activity of CeA PKCδ+ cells to investigate the role of these cells in AOE enhancement of alcohol-induced allodynia in adult mice.
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