Long-lasting sensitization towards morphine in motoric and limbic areas asdetermined by c-fos expression in rat brain

Chronic application of morphine leads to the development of tolerance towar ds several of its effects, e.g., analgesia or respiratory depression. Simul taneously, however, sensitization arises which becomes apparent in behavior al tests as increased locomotion or increased self-application. A human cor relate for the latter may be the increasing craving for opioids in addicts. To identify brain areas involved in these long-lasting processes, we studi ed the expression of the transcription factor c-fos by in situ hybridizatio n in rat brain as a marker for changes in gene expression after single or r epeated morphine applications in the animals. The only c-Sos signal that ex ceeded background after a single dose of morphine (50 mg/kg) was a diffuse expression in the lateral septum. In contrast, repeated dosage twice daily for 10 days and ascending from 10 to 50 mg/kg resulted in a sharply delinea ted morphine-induced c-fos synthesis in the dorsomedial and lateral striatu m, lateral septum, medial mammillary nuclei, anterior thalamus and, in part masked by a high background due to injection stress, in the cingulate cort ex. Most of these areas belong to the limbic system or are closely associat ed with it. The c-fos response was inducible by morphine in pretreated anim als for up to 8 weeks after finishing the repeated application scheme. Retr ograde tracing studies revealed that the dorsomedial part of the striatum, which was strongly labeled with the c-fos probe, received inputs from limbi c as well as from motoric parts of the thalamus and cortex. Therefore, the sensitization of morphine-induced c-fos expression in parts of the striatum seems to correlate with the locomotor effects of repeated morphine applica tion, whereas the observed sensitization in several limbic brain areas migh t reflect emotional phenomena like increased self-administration in rats or drug craving in humans. (C) 1999 Elsevier Science B.V. All rights reserved .