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Heroin addicts can benefit from methadone substitution therapy. However, little is known about the significance of pre-exposure to opioids for psychoactive effects of methadone. We modeled some behavioral and neurobiological aspects of the opioid abuse-related phenomena in Sprague-Dawley rats, using morphine (10 mg/kg/day) or methadone (1 or 2 mg/kg/day) treatment (14 doses over a 16-day period) followed by 2-week withdrawal and methadone challenge; control rats were given 0.9% NaCl treatment and methadone challenge by the same schedule. Locomotor response to the challenge showed substantial enhancement only after the morphine treatment. Fos immunohistochemistry in selected brain regions including cortex, nucleus accumbens, striatum and some parts of the hippocampus, thalamus and amygdala also revealed marked differences between the effects of the tested treatments. Sensitization of Fos response was found in a few regions of the morphine-treated rats. The rats given the higher methadone dose treatment showed a fairly weak tendency for sensitization that reached significance only in somatosensory cortex layer IV. The rats given the lower methadone dose treatment showed a weak while widespread tendency for an opposite change, which reached significance in cingulate cortex layer II/III and resulted in significant differences in Fos response between these rats and the morphine-treated rats in most regions studied. These results indicate that lasting neuroplastic changes associated with the sensitization caused by (sub)chronic exposure to opioids are relatively mild for methadone as compared to those caused by morphine, and suggest that psychoactive effects of methadone can be notably enhanced by past opiate use.
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