KETAMINE ATTENUATES AND REVERSES MORPHINE-TOLERANCE IN RODENTS

Background: The development of tolerance complicates the use of morphi ne to manage persistent pain. N-methyl-D-aspartate receptor antagonist s can attenuate or reverse morphine tolerance. The authors studied ket amine's ability to modulate morphine tolerance. Method: Tolerance was produced in mice given morphine subcutaneously and was assessed by a c umulative dose-response analysis using the tail-flick test. The abilit y of ketamine at 0.3, 3, or 10 mg/kg given subcutaneously before and a fter 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 lets to mice was also as sessed. Rats were made tolerant to intraspinal morphine and the effect s of the coadministration of 12 mu g intraspinal ketamine were assesse d. Results: Morphine given subcutaneously produced a fivefold increase in the median effective (ED(50)) dose of morphine, which was dose-dep endently attenuated by subcutaneously administered ketamine. A tenfold increase in the morphine ED(50) produced by morphine pellets was comp letely reversed by ketamine given subcutaneously. Intraspinal morphine produced a 46-fold increase in its ED(50), which was almost completel y attenuated by the coadministration of Intraspinal ketamine. Conclusi ons: Systemically administered ketamine attenuates and reverses system ically induced morphine tolerance in mice, and intraspinal ketamine at tenuates tolerance produced by intraspinal morphine in rats.