Project Summary/Abstract Physicians, who were previously told that it is medical malpractice to undertreat pain, are now told that they must avoid prescribing opioids whenever possible because of the risk of addiction. However, while analgesics such as nonsteroidal anti-inflammatory drugs are effective in relieving mild pain, they do not provide nearly the relief of severe pain that opioids do. Our recent work suggests that it may be possible to secure potent relief for severe pain with opioids, with a greatly reduced risk of addiction. In 2018 we reported that the brains of human heroin addicts had an average 54% increase in the number of “detectable” hypocretin (Hcrt=orexin) neurons and a 22% shrinkage of these neurons[1]. We found that these changes can outlast drug intake for at least 3 years. We further reported that similar changes in Hcrt neuron number and size could be induced by longterm daily administration of addictive doses of morphine to mice. We showed that these changes were not a result of neurogenesis, rather resulting from increased Hcrt synthesis in “Hcrt neurons” not producing detectable amounts of the Hcrt peptides at baseline. Subsequently, Aston-Jones's group reported a similar increase in the number of detectable Hcrt neurons in cocaine and fentanyl addicted rats, indicating that this is a correlate of several types of addiction. We had reported in 2000 that the loss of, on average, 90% of Hcrt neurons was the cause of human narcolepsy [2,3]. Narcoleptic humans have an extremely low rate of drug abuse, despite their prescribed daily use of addictive drugs, consistent with an important role for Hcrt in addiction. We find that morphine treated “narcoleptic” mice, in which Hcrt neurons had been selectively ablated, have greatly reduced naloxone triggered aversion, i.e. are “less addicted.” Recently we reported that chronic opioid administration greatly increases the projections of Hcrt neurons to locus coeruleus [4] and to the ventral tegmental area (Fig 5), regions linked to addiction. We now find that the addiction-associated changes in behavior and in Hcrt neuron number and size produced by morphine in mice are completely prevented by the dual Hcrt receptor antagonist suvorexant. Our pilot data indicates that the analgesic effect of morphine is not diminished by suvorexant. We will compare the effectiveness of suvorexant with Hcrt-R1 and Hcrt-R2 antagonists in reducing opiate induced changes in Hcrt neurons, and in reducing opiate anticipation and naloxone induced aversion. We will determine if Hcrt-R1 or Hcrt-R2 blockers affect morphine analgesia. We will determine the effect of Hcrt antagonists on the activity of Hcrt neurons after morphine and on opioid induced increases in Hcrt axonal projections, using quantitative confocal microscopy, electrical recording of unit activity and in vivo calcium imaging of Hcrt neurons. Our pilot data suggest that it may soon be possible to relieve severe pain with opioids without cau...