title: Ketamine and remifentanil interactions on the sevoflurane minimum alveolar concentration and acute opioid tolerance in the rat.
abstract: BACKGROUND
  Ketamine is used at low doses for its analgesic and antihyperalgesic properties when combined with opioids but also when opioid-induced hyperalgesia and tolerance appear. In this study we determined the interaction of ketamine and remifentanil on the minimum alveolar concentration (MAC) of sevoflurane in rats and to determine whether ketamine may block acute opioid tolerance (AOT).
  
  
  METHODS
  Male Wistar rats were anesthetized with sevoflurane, and the MAC was determined before and after ketamine administration (10, 20, 40, and 80 mg kg(-1) or saline) alone or combined with remifentanil (120 and 240 μg kg(-1) h(-1), low and high doses, respectively). One additional group received the lowest ketamine dose after starting a remifentanil infusion. Finally, naloxone was administered to determine the potential action of ketamine on opioid receptors. MAC was determined from intratracheal gas samples, and tail clamping was used as a supramaximal stimulus. End-tidal anesthetic concentrations were assayed using a side stream gas analyzer. Statistical analysis was performed with an analysis of variance.
  
  
  RESULTS
  Ketamine and remifentanil dose-dependently reduced the MAC. Adding the low dose of remifentanil to ketamine did not improve the MAC reduction, whereas the high dose of remifentanil enhanced ketamine reduction in a subadditive fashion. Nevertheless, ketamine was unable to block the development of AOT to remifentanil at either dose. Finally, naloxone blocked the MAC reduction produced by ketamine.
  
  
  CONCLUSIONS
  A subadditive effect between ketamine and remifentanil was found on the sevoflurane MAC reduction rats. In addition, ketamine was unable to block AOT. The clinical relevance of these findings should be elucidated in future studies to reduce anesthetic requirements.
authors.affiliation: Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid, Avda, Puerta de Hierro s/n, 28040 Madrid, Spain.
authors.forename: Delia
authors.initials: D
authors.lastname: Aguado
authors.forename: Mariana
authors.initials: M
authors.lastname: Abreu
authors.forename: Javier
authors.initials: J
authors.lastname: Benito
authors.forename: Javier
authors.initials: J
authors.lastname: García-Fernández
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Gómez de Segura
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000704:Analysis of Variance; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077208:Remifentanil; D000077149:Sevoflurane
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D009292:Narcotic Antagonists; D010880:Piperidines; D009270:Naloxone; D000077149:Sevoflurane; D007649:Ketamine; D000077208:Remifentanil