Augmented orexin/hypocretin signaling underlies negative affect during acute oxycodone abstinence in rats.

Opioid use disorder (OUD) is associated with a withdrawal-induced negative affective state, which contributes to uncontrolled use via negative reinforcement. The orexin (hypocretin) system is implicated in physical opioid withdrawal. We sought to test whether the orexin system is involved in negative affect during withdrawal from chronic prescription opioid exposure. Rats received non-contingent saline or oxycodone over 21d and were assessed for behaviors indicative of negative affect. We tested whether chronic oxycodone was associated with changes in orexin cell number or activity. We used chemogenetics in transgenic rats to modulate the activity of orexin neurons to determine their functional role in development of negative affect. Chronic oxycodone induced a negative affective state during acute abstinence that included relative weight loss, allodynia, and anhedonia-, anxiety, and despair-like behaviors. Oxycodone treatment was associated with an increase in the number and activity of orexin-immunoreactive neurons; the magnitude of negative affect severity directly correlated with the number of activated orexin neurons during acute abstinence. Chronic chemogenetic inhibition of orexin neurons concomitant with oxycodone exposure attenuated development of affective symptoms. Our data support a role for the orexin system in opioid withdrawal-associated negative affect and highlight this system as a potential treatment target for OUD.