Morphine and methadone pre-exposures differently modify brain regional Fos protein expression and locomotor activity responses to morphine challenge in the rat

Methadone is commonly used in substitution therapy of heroin addicts; hence, its potential for modifying reactions to opiates is of clinical importance. We compared the effects of repeated daily and every-other-day pre-exposure of rats to s.c. morphine and methadone on locomotor activity and CNS neuronal activation (as assessed by Fos immunohistochemistry) responses to s.c. morphine challenge given 2 weeks after the completion of the pretreatment. The challenge revealed behavioral sensitization after daily morphine pretreatment only. Dorsomedial striatum and basolateral amygdaloid nucleus showed robust morphine-induced Fos protein induction that was unaffected by the pretreatments tested. Centrolateral striatum, shell and core of the nucleus accumbens, paraventricular thalamic nucleus and some layers of motor and somatosensory cortices showed but negligible Fos protein induction in drug-naive rats; this response was markedly enhanced by morphine pretreatment only, which effect might be related to the emergence of opiate addiction. Minor Fos responses to morphine were also found in layers IV and VI of the somatosensory cortex and layer VI of the insular cortex of the drug-naïve rats; these responses were significantly enhanced both by morphine and methadone pretreatment. The similarity of methadone and morphine pretreatments’ effects in the latter cortical regions might be relevant to the ability of methadone to alleviate signs of abstinence syndrome and craving in heroin addicts. In summary, this study revealed differing and relatively long-lasting effects of prolonged administration of morphine and methadone on the profile of behavioral and CNS neuronal activation responses to morphine challenge in the rat.