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Xylazine-induced diuresis in rats is attenuated by κ-opioid receptor and α2-adrenoceptor antagonists

Year: 2026
Type: article
Abstract: Xylazine is an α2 adrenoceptor agonist approved for use in veterinary medicine as an analgesic and sedative. However, the recent use of xylazine as adulterant with opioids has created a public health emergency due to an increased number of addiction-related deaths and adverse effects. As a result, xylazine's pharmacological profile has been revisited, and it has been found to act as a full agonist at κ-opioid receptors. Because increased urine output is a well-established effect of κ-opioid receptor agonists, we determined if κ-opioid receptors are involved in xylazine-induced diuresis. Adult male Sprague-Dawley rats were used. A dose-response curve was first established through systemic administration of xylazine. Rats were injected with xylazine (1.25, 2.5, or 5 mg/kg) or saline and then placed into metabolic cages for 2 h for urine collection. Xylazine doses of 2.5 and 5 mg/kg significantly increased urine output compared to saline-injected rats, indicating that xylazine caused diuresis. Next, rats were pretreated with saline; a κ-opioid receptor antagonist, 5'-guanidinonaltrindole (5'-GNTI) (0.01-0.1 mg/kg); or an α2-adrenoceptor antagonist, yohimbine (0.3-1 mg/kg). Thirty minutes later, rats were injected with saline or a fixed dose of xylazine (2.5 mg/kg) and urine was collected for 2 h. Pretreatment with either 5'-GNTI or yohimbine significantly decreased xylazine-induced diuresis. Our findings suggest that xylazine-induced diuresis is mediated by both κ-opioid receptors and α2-adrenoceptors, highlighting the importance of considering κ-opioid receptor activation when evaluating in vivo pharmacological effects of xylazine.
DOI: 10.1007/s00210-026-05565-6
Institution: Temple University
Language: English
Open Access status: hybrid
Estimated APC paid: $4,790
OpenAlex ID: W7164936650
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Cites: 39
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