The U.S government has declared an opioid crisis in the country and federal health agencies are adopting emergency measures to obviate the high mortality associated with prescription opioid drug use. There is an increased risk for sleep disordered breathing (SDB), sleep-related hypoventilation and irregular breathing in individuals on chronic prescription opioid medications. Almost 30% of a veteran sleep clinic population had opioid-associated central sleep apnea (CSA). Gravely, in a national sample of Veterans, sleep apnea was a significant risk factor for opioid-related toxicity and overdose and the presence of CSA combined with chronic prescription opioid use compounded the mortality risk. There are only limited and partially effective therapies for this sleep disorder. Nevertheless, the exact mechanisms by which opioids produce SDB in adults remain unclear, and varied and conflicting ventilatory control mechanisms have been suggested. Thus, we will systematically investigate the chemoreceptor control mechanisms contributing to the increased propensity of SDB associated with chronic prescription opioid use. We will investigate the effects of chronic opioid use on ventilatory chemoresponsiveness and cerebrovascular responsiveness to carbon-dioxide and determine whether modifying these mechanisms with hyperoxia or acetazolamide will mitigate opioid-related SDB/CSA. The information garnered from the proposed experiments will drive development of novel personalized therapies to reduce SDB associated with chronic opioids in Veterans and, ultimately, will positively impact their long-term health and well-being.