The Effects of the Toll-Like Receptor 4 Antagonist, Ibudilast, on Sevoflurane's Minimum Alveolar Concentration and the Delayed Remifentanil-Induced Increase in the Minimum Alveolar Concentration in Rats.

Anesth Analg 2016 May;122(5):1370-6

From the *Comparative Pain Research Group, Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain; †Clinical Service of Anesthesia, Faculty of Veterinary Medicine, Department of Clinical Sciences, University of Montreal (UdM), Saint-Hyacinthe, Quebec, Canada; ‡Experimental Surgery Unit, La Paz University Hospital (HULP), Madrid, Spain; and §Mathematics Faculty, Department of Statistics and Operations Research, Complutense University of Madrid (UCM), Madrid, Spain.

Background: Ultralow doses of naloxone, an opioid and toll-like receptor 4 antagonist, blocked remifentanil-induced hyperalgesia and the associated increase in the minimum alveolar concentration (MAC), but not tolerance. The aim was to determine the effects of the toll-like receptor 4 antagonist, ibudilast, on the MAC in the rat and how it might prevent the effects of remifentanil.

Methods: Male Wistar rats were randomly allocated to 5 treatment groups (n = 7 per group): 10 mg/kg ibudilast intraperitoneally, 240 µg/kg/h remifentanil IV, ibudilast plus remifentanil, remifentanil plus naloxone IV, or saline. The sevoflurane MAC was determined 3 times in every rat and every day (days 0, 2, and 4): baseline (MAC-A) and 2 further determinations were made after treatments, 1.5 hours apart (MAC-B and MAC-C).

Results: A reduction in baseline MAC was produced on day 0 by ibudilast, remifentanil, remifentanil plus ibudilast, remifentanil plus naloxone (P < 0.01), but not saline. Similar effects were found on days 2 and 4. A tolerance to remifentanil was found on days 0, 2, and 4, which neither ibudilast nor naloxone prevented. The MAC increase produced by remifentanil on day 4 (P = 0.001) was prevented by either ibudilast or naloxone.

Conclusions: Ibudilast, besides reducing the MAC, prevented the delayed increase in baseline MAC produced by remifentanil but not the increase in MAC caused by tolerance to remifentanil.

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http://dx.doi.org/10.1213/ANE.0000000000001171DOI Listing
May 2016
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