The development of tolerance to chronically administered methadone and morphine was examined in a rat model of neuropathic pain after ischemic nerve injury. In drug naive neuropathic rats systemically administered morphine or methadone similarly and dose-dependently alleviated mechanical allodynia. Tolerance to the anti-hyperalgesic effect of equally effective doses of morphine (10mg/kg) or methadone (5mg/kg) developed upon administration twice daily. However, the rate of tolerance development was significantly slower for methadone in comparison to morphine. Chronic morphine treatment for 14 days induced almost complete loss of the anti-allodynic effect to morphine, whereas methadone still had partial effect after 21 days of chronic treatment. Partial cross-tolerance was observed between morphine and methadone. It is suggested that the delayed development of tolerance to methadone in neuropathic rats may be related to the higher intrinsic activity of methadone compared to morphine, as well as the N-methyl-D-aspartate receptor blocking property of methadone. The latter may also contribute to preservation of mu-opioid anti-nociception following chronic methadone treatment.