Investigating NOP agonists as a novel treatment for chronic pain-associated sleep disruptions

PROJECT SUMMARY Chronic pain is a debilitating disorder that effects 50.2 million people and is characterized by persistent pain lasting three months or longer and negatively impacts mood, cognition, sleep, health, and quality of life. Sleep disturbances are reported by 50-80% of patients with chronic pain that are not adequately targeted by traditional analgesics. Given the importance of sleep in regulating general brain health and contributing to daily function, developing novel analgesics that improve sleep disruptions represent a critical unmet need. Using electroencephalography (EEG) in rats, we will 1) examine the duration and severity of sleep-disruptions in a rodent model of sub-chronic neuropathic pain (partial sciatic nerve ligation; PSNL); 2) examine how current analgesics oxycodone and gabapentin influence sleep and pain sensitivity in this model; and 3) investigate the effects of Nociceptin/Orphanin Opioid (NOP) receptor agonists on sleep and pain. Similar to MOR agonists, NOP agonists demonstrate analgesic activity, yet in contrast with MOR agonists, demonstrate low abuse liability and improve sleep. I expect that PSNL will produce extensive disruptions in sleep duration and quality, lasting 2-3 weeks. I hypothesize that oxycodone will significantly decrease sleep duration and quality in PSNL rats, and that gabapentin will not impact sleep, both within analgesic dose ranges. Lastly, I hypothesize that NOP agonists will reduce pain sensitivity and increase sleep duration and quality in PSNL rats. Collectively, these studies will reiterate the importance of sleep disruptions associated with pain states, highlight unmet need for novel treatments specifically targeting sleep disruptions, and test the viability of NOP agonists for the treatment of chronic pain.