Altered cholecystokinin binding site density in the supraoptic nucleus of morphine-tolerant and -dependent rats

The processes underlying the development of neuronal tolerance to and dependence upon opiates are not yet fully understood. To evaluate a possible role for cholecystokinin (CCK) in these processes, quantitative receptor autoradiography and in situ hybridisation histochemistry were used to study both the density and distribution of sulphated CCK octapeptide (CCK8S) binding sites and preproCCK peptide mRNA levels within the dorsal (oxytocin neurone-rich) supraoptic nuclei of rats given an intracerebroventricular (i.c.v.) infusion of morphine over 5 days, which is known to induce tolerance and dependence in mechanisms regulating oxytocin neurones. Specific CCK8S binding was significantly increased in the supraoptic nuclei of both morphine-dependent and salt-loaded (2% sodium chloride to drink for 48 h) rats compared to their respective controls (P < 0.05). In situ hybridisation histochemistry revealed no difference in preproCCK mRNA levels within supraoptic neurones of (i.c.v.) morphine-treated compared with either i.c.v. vehicle-treated or untreated control animals. These results suggest that CCK receptor mechanisms involved in the control of magnocellular oxytocin neurone activation are upregulated during chronic morphine treatment, and this may favour increased sensitivity to CCK, thereby offsetting the inhibitory actions of morphine, contributing to tolerance and perhaps to the withdrawal excitation characteristic of dependence.