Long-lasting sensitization towards morphine in motoric and limbic areas as determined by c-fos expression in rat...

Chronic application of morphine leads to the development of tolerance towards several of its effects, e.g., analgesia or respiratory depression. Simultaneously, however, sensitization arises which becomes apparent in behavioral tests as increased locomotion or increased self-application. A human correlate for the latter may be the increasing craving for opioids in addicts. To identify brain areas involved in these long-lasting processes, we studied the expression of the transcription factor c-fos by in situ hybridization in rat brain as a marker for changes in gene expression after single or repeated morphine applications in the animals. The only c-fos signal that exceeded 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 delineated morphine-induced c-fos synthesis in the dorsomedial and lateral striatum, lateral septum, medial mammillary nuclei, anterior thalamus and, in part masked by a high background due to injection stress, in the cingulate cortex. Most of these areas belong to the limbic system or are closely associated with it. The c-fos response was inducible by morphine in pretreated animals for up to 8 weeks after finishing the repeated application scheme. Retrograde tracing studies revealed that the dorsomedial part of the striatum, which was strongly labeled with the c-fos probe, received inputs from limbic 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 application, whereas the observed sensitization in several limbic brain areas might reflect emotional phenomena like increased self-administration in rats or drug craving in humans.