PHYSIOLOGY AND PHARMACOLOGY OF NEUROPEPTIDES

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The central neuroregulation of peripheral events by peptide hormones is a relatively new field. The intracerebral ventricular (icv) administration of bombesin, dermorphin (a frog-skin derived opiate heptapeptide), calcitonin (salmon) and lithium (the drug of choice for manic depression) effectively decreased all parameters of gastric secretion in pylorus-ligated fasted rats: neutralized acidic pH, reduced hydrogen ion concentration, and decreased volume of stomach secretions. However, subcutaneous (sc) injections of these peptides yielded differential effects relative to icv: bombesin was very weakly active (without a dose-response curve), while dermorphin was 0.0003 as potent; calcitonin, on the other hand, exhibited twice the activity sc as icv. Lithium chloride was effective both icv and sc, although the reduced response by sc is in keeping with the dilution of lithium throughout the body. Both bombesin and lithium appear to act centrally, perhaps through a common mechanism, on gastric secretion via products of arachidonate metabolism (e.g., prostaglandins) since their effects can be blocked by several cyclooxygenase inhibitors (indomethacin, diclofenac, naproxen, ketoprofen). Lithium and bombesin, which produce a similar effect and involve prostaglandins, do so through different routes; bombesin levels in the hypothalamus are unaffected by icv administered lithium. Several dimeric analogues of dermorphin (2 chains of dermorphin linked though the C-terminal amide nitrogen either directly or through methylene bridges) were tested for their ability to suppress gastric secretion and correlate that effect with an analysis of delta and mu receptors in brain synaptosomes. Only those analogues exhibiting mu-selectivity were active in vivo and their spectrum of bioactivity on gastric secretion were distinct from dermorphin. Although dermorphin requires central mu-type opiate receptors for gastric secretion, the role of calcitonin is less clear and may involve multiple interacting mechanisms.