Berezin, Casey-Tyler, authorVigh, Jozsef, advisorHentges, Shane, committee memberBailey, Susan, committee memberMontgomery, Tai, committee member2023-08-282023-08-282023https://hdl.handle.net/10217/237012Opioids, such as the prototypical opioid morphine, primarily exert their analgesic and rewarding effects through μ-opioid receptors (MORs), and it has been shown that acute morphine treatment negatively impacts sleep/wake behavior through MORs. Continued opioid administration exacerbates sleep/wake disturbances, such that approximately 80% of chronic users report persistent sleep disturbances, including insomnia and daytime sleepiness. These opioid-induced sleep disturbances (OISD) are associated with negative outcomes such as increased drug craving, relapse and negative affect (i.e. anxiety/depression), as well as hyperalgesia in chronic pain patients. Therefore, therapeutic interventions for OISD are expected to improve the outcomes of long-term opioid use in general. However, the neuronal population(s) and cellular mechanism(s) mediating sleep/wake changes in response to chronic opioid treatment are not currently known. Although many neuronal populations in the brain contribute to sleep/wake behavior, the photoentrainment of sleep/wake cycles to environmental light/dark cycles is uniquely regulated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Importantly, light-evoked firing by ipRGCs is modulated by activation of their MORs, and endogenous MOR activation has been shown to modulate an ipRGC-driven behavior, the pupillary light reflex. Additionally, opioids (e.g. morphine) are routinely detected in the human eye to diagnose overdose-related deaths, and morphine accumulates in the mouse retina upon chronic systemic administration. Therefore, the central hypothesis addressed in the current work is that the bioavailability of opioids (i.e. endogenous opioid peptides and/or opioid drugs) in the retina contributes to the modulation of sleep/wake behavior. In Chapter 2, we show that endogenous opioid peptides in the retina contribute to healthy sleep/wake behavior. Using a mouse model with a cell-specific knockout of MORs expressed by ipRGCs (McKO), we show that endogenous activation of these MORs is important for maintaining activity and suppressing slow-wave sleep during the mouse's active period. Concurrent work showed that the MORs expressed by ipRGCs also contribute to morphine-driven changes in sleep/wake behavior during a chronic treatment paradigm. Thus, both endogenous opioid peptides and opioid drugs modulate sleep/wake behavior via the activation of the MORs expressed by ipRGCs. Systemically applied opioid drugs penetrate the blood-retina barrier and accumulate in the retina. Thus, ipRGCs may be liable to opioid modulation throughout chronic opioid treatment, contributing to the development and persistence of OISD. In Chapter 3, we investigate the relationship between opioid transporter expression at the blood-retina barrier and morphine deposition in the retina. We show that low expression of the opioid extruder permeability glycoprotein (P-gp) may allow morphine to persist in the retina, compared to the brain where P-gp expression is high and morphine is more quickly cleared from the tissue. In Chapter 4, we discuss how upregulation of P-gp at the blood-retina barrier via the non-steroidal anti-inflammatory drug diclofenac may reduce opioid bioavailability in the retina, thereby alleviating OISD. This work demonstrates a previously unknown contribution of ipRGC signaling to opioid-modulated sleep/wake changes, and identifies a potential therapeutic target for OISD.born digitaldoctoral dissertationsengCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.endogenous opioidsopioid receptorretinamorphineblood-retina barrierphotoentrainmentText