Opiate anticipation, opiate induced anatomical changes in hypocretin (Hcrt, orexin) neurons and opiate induced microglial activation are blocked by the dual Hcrt receptor antagonist suvorexant, while opiate analgesia is maintained.

We previously found that heroin addiction in humans is accompanied by an increase in the number of detected Hcrt neurons and a decrease in their soma size. We now show that the increased number of Hcrt cells visible after morphine treatment is likely the result of increased Hcrt production in neurons having sub-detection levels of the peptides. We find that morphine increases Hcrt projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase enzyme (TH) and the number of TH positive cells in VTA, with no changes in the adjacent substantia nigra. We find that the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, microglial activation and morphine anticipatory behavior, but does not diminish morphine analgesia. These findings suggest that combined administration of opiates and suvorexant may be a less addictive way of administering opiates for pain relief in humans.