Xylazine reduces methamphetamine-induced hyperlocomotion in rats through κ-opioid and α2-adrenoceptor mechanisms

Xylazine, a veterinary anesthetic, is an adulterant in fentanyl and heroin that worsens opioid-related adverse effects. Two recent evidences - one epidemiological and the other pharmacological - have emerged regarding xylazine. Epidemiologically, xylazine co-use with methamphetamine (METH) is increasing; for example, in a recent toxicology report, xylazine was detected in 30% of human METH samples. Pharmacologically, xylazine is not only an α2-adrenoceptor agonist but also a full κ-opioid receptor agonist. Here, we determined effects of xylazine (1, 2.5, 5 mg/kg) on METH (1 mg/kg)-induced hyperlocomotion and investigated α2-adrenoceptor and κ-opioid receptor mechanisms. Hyperlocomotion was selected because it is a well-characterized preclinical effect of METH. In METH-naïve rats, xylazine transiently reduced locomotor activity. For co-administration with METH, xylazine dose-dependently reduced hyperlocomotion evoked by METH. In rats pretreated with the α2-adrenoceptor antagonist yohimbine (1 mg/kg), xylazine did not reduce METH-induced hyperlocomotion. Pretreatment with the competitive κ-opioid receptor antagonist LY2456302 (30 mg/kg) also attenuated xylazine's suppression of METH-induced hyperlocomotion. In xylazine-naïve rats, neither LY2456302 (30 mg/kg) or yohimbine (1 mg/kg) affected METH-evoked hyperlocomotion or spontaneous locomotor activity. Our results show that METH-evoked hyperlocomotion is sensitive to κ-opioid and α2-adrenergic receptor activity and suggest both receptor systems contribute to xylazine's in vivo pharmacological profile.