Targeting the orexin system for prescription opioid use disorder: Orexin-1 receptor blockade prevents oxycodone taking and seeking in rats.

Prescription opioids, such as oxycodone, are potent analgesics that are used to treat and manage pain. However, oxycodone is one of the most commonly abused prescription drugs. Finding an effective strategy to prevent prescription opioid use disorder is urgent. Orexin receptors (OrxR1 and OrxR2) have been implicated in the regulation of motivation, arousal, and stress, making them possible targets for the treatment of substance use disorder. To study the significance of environmental stimuli in maintaining the vulnerability to relapse to oxycodone use, resistance to the extinction of oxycodone-seeking behavior that was elicited by an oxycodone-related stimulus was examined. Rats were trained to self-administer oxycodone in the presence of a contextual/discriminative stimulus (SD). Using this procedure, the rats readily acquired oxycodone self-administration and exhibited increases in physical signs of opioid withdrawal. Following extinction, response-reinstating effects of re-exposure to the SD perseverated. We then tested whether OrxR blockade prevents oxycodone intake and relapse. The effects of the OrxR1 antagonist SB334867 and OrxR2 antagonist TCSOX229 on oxycodone self-administration were tested. SB334867 significantly decreased oxycodone self-administration, whereas TCSOX229 did not produce any effect. To investigate whether OrxR1 and OrxR2 blockade prevents oxycodone seeking, the rats were tested for the ability of SB334867 and TCSOX229 to prevent the SD-induced conditioned reinstatement of oxycodone-seeking behavior. SB334867 decreased oxycodone-seeking behavior, whereas TCSOX229 was ineffective. These results suggest that OrxR1 antagonism prevents excessive prescription opioid use and relapse and might be beneficial for the treatment of prescription opioid use disorder.