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Drugs with antagonistic actions on the Toll-like receptor 4 (Tlr4), such as naloxone at ultra low doses, have been used to inhibit opioid-induced hyperalgesia in rodents suggesting the involvement of this receptor and pathway on opioid-induced hyperalgesia.The aim of this study was to determine whether mice without the Tlr4 gene (Tlr4−/−) would not develop remifentanil-induced hyperalgesia.An experimental randomised animal study.Experimental Unit, Complutense University of Madrid, Madrid, Spain.Twelve adult female wild-type mice and 12 adult Tlr4−/− mice.Under sevoflurane anaesthesia, a 1-h, constant rate subcutaneous infusion of remifentanil (4 μg kg−1 min−1) or 0.9% saline.Mechanical nociceptive thresholds were evaluated using a von Frey hair test before (baseline) and on days 5, 6 and 7 after treatment. Hyperalgesia was considered to be a decrease in the mechanical nociceptive threshold. Changes in mechanical nociceptive thresholds in the different groups were compared with one-sided paired t tests.Baseline mechanical nociceptive thresholds were similar in all groups (2.2 ± 0.1 g). Remifentanil produced a 24% decrease in mechanical nociceptive thresholds in the wild-type mice (1.7 ± 0.0 g, averaged over 3 days, P = 0.00021), whereas the nociceptive thresholds were not changed in Tlr4−/− mice (2.2 ± 0.1 g, P = 0.857) or in mice receiving 0.9% saline (Tlr4−/−, 2.2 ± 0.1 g, P = 0.807; wild-type, 2.2 ± 0.1 g, P = 0.962).Tlr4 receptor involvement is suggested in the development of remifentanil-induced hyperalgesia in mice.CEA-UCM 107/2012.