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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

Ruiz-Pérez, Daniel DVM, MS; Benito, Javier DVM, MS; Polo, Gonzalo DVM; Largo, Carlota DVM, PhD, MS; Aguado, Delia DVM, PhD, MS; Sanz, Luis PhD; Gómez de Segura, Ignacio A. DVM, PhD, Dip ECVAA, Dip ECLAM

doi: 10.1213/ANE.0000000000001171
Anesthetic Pharmacology: Research Report

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.

Supplemental Digital Content is available in the text.Published ahead of print February 8, 2016

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.

Daniel Ruiz-Pérez, DVM, MS, is currently affiliated with the Experimental Surgery Unit, La Paz University Hospital (HULP), Madrid, Spain.

Accepted for publication December 8, 2015.

Published ahead of print February 8, 2016

Funding: This study has been funded by the Spanish Government (grant PI11-01241).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Ignacio A. Gómez de Segura, DVM, PhD, Veterinary Faculty, Department of Animal Medicine and Surgery, Complutense, University of Madrid (UCM), Avda, Puerta de Hierro s/n, 28040, Madrid, Spain. Address e-mail to

© 2016 International Anesthesia Research Society