title: Ketamine attenuates and reverses morphine tolerance in rodents.
abstract: BACKGROUND
  The development of tolerance complicates the use of morphine to manage persistent pain. N-methyl-D-aspartate receptor antagonists can attenuate or reverse morphine tolerance. The authors studied ketamine's ability to modulate morphine tolerance.
  
  
  METHODS
  Tolerance was produced in mice given morphine subcutaneously and was assessed by a cumulative dose-response analysis using the tail-flick test. The ability of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and after morphine to attenuate the development of tolerance was assessed. The ability of 10 mg/kg ketamine to reverse tolerance produced by the subcutaneous implantation of morphine pellets to mice was also assessed. Rats were made tolerant to intraspinal morphine and the effects of the coadministration of 12 micrograms intraspinal ketamine were assessed.
  
  
  RESULTS
  Morphine given subcutaneously produced a fivefold increase in the median effective (ED50) dose of morphine, which was dose-dependently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED50 produced by morphine pellets was completely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED50, which was almost completely attenuated by the coadministration of intraspinal ketamine.
  
  
  CONCLUSIONS
  Systemically administered ketamine attenuates and reverses systemically induced morphine tolerance in mice, and intraspinal ketamine attenuates tolerance produced by intraspinal morphine in rats.
authors.affiliation: Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
authors.forename: N
authors.initials: N
authors.lastname: Shimoyama
authors.forename: M
authors.initials: M
authors.lastname: Shimoyama
authors.forename: C E
authors.initials: CE
authors.lastname: Inturrisi
authors.forename: K J
authors.initials: KJ
authors.lastname: Elliott
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
chemical_list: D000701:Analgesics, Opioid; D000778:Anesthetics, Dissociative; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D009020:Morphine