Opioid-induced neuroanatomical, microglial and behavioral changes are blocked by suvorexant without diminishing opioid analgesia

Heroin use disorder in humans and chronic opioid administration to mice result in an increase in the number and a decrease in the size of detected hypocretin (Hcrt, or orexin) neurons. Chronic morphine administration to mice increases Hcrt axonal projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase (TH) in VTA and the number of detected TH+ cells in VTA, and activates VTA and hypothalamic microglia. Co-administration of morphine with the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, the increase in Hcrt projections to the VTA and microglial activation in the VTA and hypothalamus. Co-administration of suvorexant with morphine also prevents morphine anticipatory behavior and reduces opioid withdrawal symptoms. However, suvorexant does not diminish morphine analgesia. Here we show that combined administration of opioids and suvorexant may reduce the addiction potential of opioid use for pain relief in humans while maintaining the analgesic effects of opioids. The authors demonstrate that, in a mouse model of heroin use disorder, co-administration of morphine and suvorexant prevented both morphine-induced anatomical changes in hypocretin neurons and morphine anticipation and reduced morphine withdrawal behavior but spared analgesia, suggesting applications for reducing opioid addiction potential in humans.