Mu-opioid mediated discriminative stimulus effects of fentanyl and xylazine: Dose-response and time-course studies

Xylazine-adulterated fentanyl (i.e., "tranq-dope") has been identified as a national public health threat in the United States. Despite the increasing prevalence of this drug combination, little is known about the interactions between fentanyl and xylazine on measures directly relevant to their addiction liability. The primary objective of this study was to determine whether xylazine enhances or prolongs the mu-opioid mediated discriminative stimulus effects of fentanyl. To this end, male and female Long-Evans rats were trained to discriminate the prototypical mu-opioid agonist, morphine, from saline, and substitution tests were conducted with fentanyl, xylazine, and fentanyl-xylazine combinations. Fentanyl substituted fully for the morphine training stimulus, whereas xylazine failed to substitute fully for the morphine stimulus up to doses that significantly decreased responding. In drug combination tests, xylazine did not influence the acute effects of fentanyl; however, xylazine dose-dependently increased the duration of fentanyl's stimulus effects. These data indicate that xylazine does not produce discriminative stimulus effects like prototypical mu-opioid agonists but prolongs the mu-opioid mediated discriminative stimulus effects of fentanyl, which may partially explain its use in some populations who misuse opioids.