Chronic pain (CP) is a cardinal feature of a diverse spectrum of diseases including arthritis, migraine, cancer, metabolic disorders, and neuropathies; it afflicts at least 20? 30% of Americans. Opioids remain the pharmacological cornerstone of CP therapy, despite potentially harmful side effects. In addition to the high propensity for developing opioid addiction, insomnia-type sleep problems associated with daytime sleepiness and depression occur in approximately 90% of those receiving long-term opioid treatment to reduce suffering from CP. Importantly, sleep disorder is a serious risk factor for suicidal ideation in CP patients receiving opioid therapy. Therefore, understanding the cellular mechanisms and neuronal circuits contributing to sleep disturbances associated with long-term opioid therapy in those suffering from chronic pain is absolutely critical for determining whether sleep disruption is a modifiable risk factor for suicidal ideation. Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting to the suprachiasmatic nucleus and other sleep-promoting brain centers are the principal conduits responsible for photoentrainment of sleep/wake cycle. We found that ipRGCs express -opioid receptors (MORs) and our preliminary data shows that MOR specific agonists strongly attenuate light-evoked firing of ipRGCs. Strong evidence suggests that systemically applied opioids cross the tight blood/retina barrier and reach ipRGCs. The objectives of the current proposal are to analyze how opioids alter light-evoked activity of ipRGCs and to study the behavioral consequences of opioid modulation of ipRGC-mediated photoentrainment of circadian sleep/wake cycles. The results of this project will provide a mechanistic description of a novel neural pathway by which systemically administered opioids alter light-driven behavior, including sleep/wake cycle. Additionally, the data will predict the feasibility of using MOR selective antagonists for focal targeting of MORs expressed by ipRGCs to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.
Inadequate sleep duration and daytime sleepiness are commonly reported health problems in chronic pain (CP) patients who receive long-term opioid treatment. Importantly, sleep disruption is a serious risk factor for suicidal ideation in CP patients receiving opioid therapy. We will study a novel, neuronal pathway that is likely to be critical in mediating these important adverse opioid effects on the sleep/wake cycle. We will investigate if this pathway might be therapeutically targeted to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.
