Neuropharmacology of Xylazine and Fentanyl Interactions

About This Grant

ABSTRACT In recent years the 2AR adrenergic receptor (2AR) agonist xylazine has been incorporated in the illicit use of fentanyl, resulting in serious adverse pharmacological effects in users that are poorly understood. The synergistic interactions between mu-opioid receptors and 2AR adrenergic receptors have been long described. Additionally, the ameliorating effects that 2AR adrenergic receptor agonists exert on withdrawal from chronic exposure to mu-opioid receptor agonists is well-established. However, the interaction between xylazine and mu- opioid receptor agonists has been minimally investigated. We have previously extensively evaluated neuropharmacological interactions between clinically used 2AR adrenergic receptor agonists (e.g. clonidine, dexmedetomidine, brimonidine, and moxonidine) and opioid agonists ; we have also defined the mechanism of such interactions both in opioid-naïve rodents and those chronically exposed to opioids. We have also have established a model of fentanyl self-administration in mice. Applying these approaches to evaluation of the combination of xylazine with fentanyl will characterize the neuropharmacology of their interaction. The objective of this application is to test the combination of xylazine and fentanyl in pre-clinical models of analgesia, sedation, opioid tolerance, opioid withdrawal, and opioid self- administration. The central hypothesis of this application is that the pharmacology of the xylazine interaction with opioids is similar to that of the clinically used 2AR agonists. This proposal has two specific aims: i) Define the neuropharmacological mechanisms of xylazine when given alone and in combination with fentanyl. ii) Define the mechanism of the impact of xylazine on oral fentanyl self- administration. At the completion of our research, our expected outcomes are that we will have determined the neuropharmacological interactions of xylazine with fentanyl in well defined measures of analgesia, sedation, opioid analgesic tolerance and withdrawal and opioid self-administration. Our studies will have a positive impact because knowledge gained from pursuit of this program will significantly expand the current understanding of fentanyl and xylazine interactions, which is currently very limited. Such information will inform future approaches aimed at addressing harms associated with the introduction of xylazine into the illicit fentanyl use environment.