Amitriptyline, minocycline and maropitant reduce the sevoflurane minimum alveolar concentration and potentiate remifentanil but do not prevent acute opioid tolerance and hyperalgesia in the rat A randomised laboratory study

BACKGROUND The 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. OBJECTIVES To 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. DESIGN A randomised, laboratory study. SETTING Experimental Unit, La Paz University Hospital, Madrid, Spain. ANIMALS One hundred and fourteen adult male Wistar rats. INTERVENTIONS Intraperitoneal 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 mg kg(-1) h(-1)) or saline. MAIN OUTCOME MEASURES Sevoflurane 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. RESULTS Amitriptyline, 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. CONCLUSION Amitriptyline, 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.