• Delia Aguado, Mariana Abreu, Javier Benito, Javier García-Fernández, and Ignacio A Gómez de Segura.
• From the Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain (DA, IAGDS), Laboratory of Respiration Physiology, Carlos Chagas Filho Institute of Biophysics, CCS, Federal University of Rio de Janeiro, Rio de Janeiro, Brasil (MA), Department of Clinical Sciences, Veterinary Faculty, Université de Montréal, Saint Hycianthie, Quebec, Canada (JB) and Department of Anaesthesiology and Critical Care, Puerta de Hierro University Hospital, Madrid, Spain (JGF).
• Eur J Anaesthesiol. 2015 Apr 1; 32 (4): 248-54.

BackgroundThe antidepressant amitriptyline, the inhibitor of microglia activation minocycline, and the neurokinin-1 antagonist maropitant have all been used to prevent or treat hyperalgesia and opioid tolerance.ObjectivesTo determine the effect of amitriptyline, minocycline, maropitant, independently or with remifentanil, on the sevoflurane minimum alveolar concentration in rats and whether these drugs may block opioid-induced hyperalgesia and acute opioid tolerance under inhalational anaesthesia.DesignA randomised, laboratory study.SettingExperimental Unit, La Paz University Hospital, Madrid, Spain.AnimalsOne hundred and fourteen adult male Wistar rats.InterventionsIntraperitoneal administration of amitriptyline (10 and 50  mg  kg-1), minocycline (30 and 100  mg  kg-1), maropitant (10 and 30 mg  kg-1) or isotonic saline, combined with a constant rate intravenous infusion of remifentanil (240 μg  kg-1  h-1) or saline.Main Outcome MeasuresSevoflurane minimum alveolar concentration was determined before and after administration of the drugs; acute opioid tolerance was defined as a decreased ability of remifentanil to reduce the minimum alveolar concentration in the short term. In addition, mechanical nociceptive thresholds were determined before and after these treatments. Opioid-induced hyperalgesia was defined as an increase in mechanical nociceptive thresholds after opioid administration.ResultsAmitriptyline, minocycline and maropitant reduced minimum alveolar concentration up to 24 (8)%, 23 (6)% and 15 (5)%, respectively (P <0.001). Remifentanil alone reduced minimum alveolar concentration by 36 (6)% (P <0.001), and in combination with amitriptyline, minocycline and maropitant, the reduction was 76 (9)%, 75 (16)% and 59 (5)%, respectively (P <0.001). An acute tolerance effect (P < 0.01) and a decrease in the mechanical nociceptive thresholds were observed with remifentanil in all groups.ConclusionAmitriptyline, minocycline and maropitant reduced the minimum alveolar concentration and potentiated the remifentanil minimum alveolar concentration reduction but failed to block opioid-induced hyperalgesia and acute opioid tolerance.

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