Abstract Opioid addiction has reached epidemic levels and imposes a tremendous socioeconomic burden in the United States. Repetitive drug use forms powerful memories associating drug-evoked experiences with its proximal environmental cues. These memories are major obstacles for successfully treating addiction, since even after a prolonged period of abstinence, re-exposure to such cues often triggers craving that promotes relapse. Sleep is important for memory consolidation and opioid addicts have a disrupted sleep/wake cycle. Whether the sleep disorder in opioid addicts contributes to the long-lasting opioid-associated memories is largely unknown. In our preliminary studies, we found that a polysynaptic pathway from the paraventricular nucleus of the thalamus (PVT) to the lateral hypothalamus (LH) plays an important role in the maintenance of the opioid-associated memories. Disruption of neural activities in either the PVT-to-NAcc or the NAcc-to-LH pathway can block the retrieval of the opioid-associated memories and prevent relapse. Interestingly, hypocretin (Hcrt) neurons in the LH strongly innervate the PVT and this is required for maintaining the wakefulness. Given the well-established roles of the Hcrt neurons in drug seeking, we hypothesis that the PVT-NAcc-LH (Hcrt)-PVT loop links sleep disorders in opioid addicts with their long-lasting drug- associated memories. In this proposal, we propose to (1) determine whether Hcrt neurons in the LH are the major target of the NAcc input; (2) examine whether manipulating the LH (Hcrt)-PVT pathway can effectively prevent relapse; and (3) test whether sleep intervention could be an effective strategy to prevent relapse. Our work will inspire the development of novel strategy to treat opioid abuse.

Narrative Opioid abuse disrupts many physiological functions, including sleep/wake cycle. Patients with chronic pain tend to sleep poorly and abuse opioid-based pain killers as sedatives, causing a vicious circle of poor restorative sleep and drug use. Here we will investigate the connection between brain circuits associated with opioid use and sleep regulation. We expect that selective interventions to sleep and consolidation of memories associated with opioid use may alleviate and reduce cravings and relapse of opioid use.