Acute fentanyl and xylazine co-exposure uniquely increase the excitability of dopamine type 2 receptor-expressing striatal medium spiny neurons.

Co-exposure to fentanyl, a μ-opioid receptor (MOR) agonist, and xylazine, a pan-α2-adrenoceptor (α2AR) agonist, results in deleterious interactions thought to ensue from the augmentation of the negative consequences of fentanyl by xylazine. Ex vivo striatal slice electrophysiology was used to investigate the effects of fentanyl (100 nM) and xylazine (10 µM) co-exposure on dopamine type 2 receptor-(D2) expressing dorsolateral medium spiny neurons (MSN)s. Although the acute application of either fentanyl or xylazine caused some decreases in D2 MSN firing rates at greater stimulus currents, co-exposure dysregulated D2 MSN excitability-resulting in paradoxical increases in excitability at lower stimulating currents, a more robust decrease in firing frequencies at higher stimulus currents, and overall increases in the initial momentary frequency of action potentials. The pan-opioid receptor and selective α2A-AR antagonists, naloxone (10 µM) and BRL 44408 (1 µM), respectively, assessed the contributions of these receptor types. BRL 44408 and naloxone each partially negated the interactive effects of fentanyl and xylazine co-exposure suggesting the involvement of α2A-ARs and MORs. Our findings underscore the unique consequences and complex nature of opioid and nonopioid receptor interactions in mediating the combined effects of fentanyl and xylazine in the striatum, which may contribute to the enhancement of fentanyl's reinforcing properties and underlie reported neurological complications including postural abnormalities and dystonia seen with opioid use disorder.NEW & NOTEWORTHY Acute fentanyl and xylazine co-exposure increased the excitability of striatal dopamine receptor-(D2) expressing medium spiny neurons (MSNs) to lower intensity currents, whereas higher intensity stimuli decreased firing rates and increased the initial momentary frequency of action potentials. Fentanyl or xylazine exposure decreased D2 MSN excitability at higher current intensities with near additive decreases following co-exposure. Fentanyl and xylazine interact to selectively alter D2 MSN excitability potentially contributing to dystonia and enhancing fentanyl's reinforcing properties.