Toll-like receptor 4 deficient mice do not develop remifentanil-induced mechanical hyperalgesia

Abstract

Background: 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.

Objective: The aim of this study was to determine whether mice without the Tlr4 gene (Tlr4) would not develop remifentanil-induced hyperalgesia.

Design: An experimental randomised animal study.

Setting: Experimental Unit, Complutense University of Madrid, Madrid, Spain.

Animals: Twelve adult female wild-type mice and 12 adult Tlr4 mice.

Interventions: Under sevoflurane anaesthesia, a 1-h, constant rate subcutaneous infusion of remifentanil (4 μg kg min) or 0.9% saline.

Main outcome measures: 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.

Results: 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).

Conclusion: Tlr4 receptor involvement is suggested in the development of remifentanil-induced hyperalgesia in mice.

Trial registration: CEA-UCM 107/2012.