sincalide and Substance-Related-Disorders

Generation and/or interruption of cell signalling by neuropeptides has been shown to be essentially, although not exclusively, mediated by one or several membrane-bound enzymes, giving rise to the concept of selective versus dual enzyme inhibitors. Because most of these enzymes are zinc metallopeptidases, novel inhibitors are now being designed based on the structure of these proteins. The physiological role of neuropeptides and their relationships with other peptide systems can be investigated by comparing results obtained using peptidase inhibitors and selective receptor antagonists with those obtained using mice in which genes encoding the various components of a peptide system have been deleted. The potential use of peptidase inhibitors, compared with exogenous agonists, as therapeutic agents (particularly as analgesics or antidepressants) and their use in the investigation of the neurobiology of drug abuse will be discussed with particular focus on enkephalins and cholecystokinin 8 (CCK-8).

Topics: Animals; Anxiety; Depression; Dopamine; Enkephalins; Enzyme Inhibitors; Humans; Metalloendopeptidases; Mice; Neuropeptides; Pain; Protease Inhibitors; Receptors, Cholecystokinin; Receptors, Opioid; Reward; Sincalide; Substance-Related Disorders

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.

Topics: Animals; Autoradiography; Binding Sites; Cholecystokinin; Drug Tolerance; Female; Gene Expression; In Situ Hybridization; Morphine; Narcotics; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Sincalide; Substance-Related Disorders; Supraoptic Nucleus