• Delia Aguado, Rocío Bustamante, and Ignacio A Gómez de Segura.
• From the Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain (DA, RB, IAG).
• Eur J Anaesthesiol. 2018 Jul 1; 35 (7): 505-510.

BackgroundDrugs 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.ObjectiveThe aim of this study was to determine whether mice without the Tlr4 gene (Tlr4) would not develop remifentanil-induced hyperalgesia.DesignAn experimental randomised animal study.SettingExperimental Unit, Complutense University of Madrid, Madrid, Spain.AnimalsTwelve adult female wild-type mice and 12 adult Tlr4 mice.InterventionsUnder sevoflurane anaesthesia, a 1-h, constant rate subcutaneous infusion of remifentanil (4 μg kg min) or 0.9% saline.Main Outcome MeasuresMechanical 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.ResultsBaseline 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).ConclusionTlr4 receptor involvement is suggested in the development of remifentanil-induced hyperalgesia in mice.Trial RegistrationCEA-UCM 107/2012.

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