BACKGROUND AND AIMS: In morphine addicted patients, chronic treatment with various abusers is interspersed with drugfree periods (periods of sleep or unsuccessful attempts to treat). These repeated withdrawal periods may intensify the withdrawal episode. These data inspired us to examine if repeated withdrawal periods has the effect on the severity of naloxone-induced withdrawal signs in rats. We also investigated the effect of A1 and A2A receptors in observed withdrawal signs. Additionally, to elucidate the mechanisms underlying the effects of repeated morphine withdrawal signs, neurochemical experiments were performed. METHODS: To obtain the state of dependence, the animals were treated with increasing doses of morphine, twice a day, for 8 days. To demonstrate the effect of sporadic treatment with morphine, we divided rats into two groups: continuously and sporadically treated with morphine. In sporadic group, morphine administration was modified by adding 3 morphine-free periods. On the 9th day of the study, the subsequent dose of morphine was injected. 1 hour later, the naloxone, was administrated for induction of morphine withdrawal signs in rats. Then, animals were placed into cylinders and jumpings were recorded for period 30 min. After decapitation, a neurochemical study, using HPLC-ED method was made. The concentration of dopamine and its metabolites was assessed in three brain structures (striatum, hippocampus, prefrontal cortex). RESULTS: We confirmed that sporadic treatment with morphine induced the intensification of morphine withdrawal signs, and administration of both adenosine agonists reduced the severity of them. In neurochemical experiments we demonstrated significant differences in the release in dopamine and its metabolites in studied brain areas. CONCLUSION: The recognition of neurochemical mechanisms, underlying the behavioral changes, may have an important role for further exploration of the various effects of repeated morphine withdrawal signs.
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