delta-Opioid receptor-mediated increase in cortical extracellular levels of cholecystokinin-like material by subchronic morphine in rats

Numerous pharmacological data indirectly support the idea that interactions between cholecystokinin (CCK) and opioids participate in the development o f tolerance to morphine. Biochemical investigations were performed with the aim of directly assessing the status of such interactions in morphine trea ted rats. Tolerance to the alkaloid after s.c. implantation of morphine pel lets for three days was not associated with any change in the levels of bot h CCK like-material (CCKLM) and proCCK mRNA in the frontal cortex. However, microdialysis in the freely moving rat showed that this morphine treatment produced a significant increase (+40%) of the cortical spontaneous CCKLM o utflow, which could be completely prevented by intracortical infusion of na loxone (10 mu M) The opioid receptors responsible for morphine-induced cort ical CCKLM overflow appeared to be of the delta type because intracortical infusion of selective delta-opioid receptor antagonists such as naltriben ( 10 mu M) and 7-benzylidenenaltrexone (10 mu M) also prevented the effect of morphine, whereas CTOP (10 mu M), a selective mu-opioid receptor antagonis t, and nor-binaltorphimine (10 mu M), a selective K-opioid receptor antagon ist, were inactive. These data indicate that morphine tolerance is associat ed with delta-opioid receptor mediated activation of cortical CCKergic syst ems in rats. (C) 2000 Elsevier Science Ltd. All rights reserved.