PHYSIOLOGY AND PHARMACOLOGY OF NEUROPEPTIDES

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The neuroregulation of peripheral physiological functions by several neuropeptides and LiCl continued with 1) a comparative analysis between central and peripheral mode of action, 2) involvement of inhibitors of arachidonate metabolism in brain, and 3) correlation of brain mu-receptors to the inhibition of the gastric secretory processes. Dose response curves and time course analysis reveal that neuropeptides act only within the brain (icv administration) to suppress gastric acid secretion. Salmon calcitonin, however, is the exception, being two times more effective sc than icv. Currently CGRP (calcitonin gene-related peptide), a peptide whose biological properties differ from that of calcitonin, is being investigated as well as CRF to determine the extent of involvement of ACTH/beta-endorphin in the inhibition of gastric secretion. In addition, the mechanism of action of TRF and ANF, which both increase secretion, are under study, as positive controls. LiCl, a modulator of manic depression which reduces gastric ulcer formation in those patients, inhibits gastric acid release: icv more than iv more than sc administration in effectiveness. The direct involvement of neuropeptides and LiCl on preventing experimentally-induced ulcers is also being studied. In addition to the involvement of the cyclooxygenase pathway (through use of inhibitors which reverse the suppression of gastric secretion by neuropeptides), the lipooxygenase pathway (which yields leukotrienes) is implicated, since the inhibitor NGA increases secretion in the presence of neuropeptides. The use of specific mu-receptor agonists were used to probe gastric secretion in rat brain synaptosomes: DAGO, a mu-specific enkephalin analogue, as well as dermorphin (DM) and dimeric DM analogues, suppress gastric secretion, while DADLE (a delta-agonist) is ineffective at the same dose. A positive correlation exists between the suppression of gastric acid output and high affinity mu-receptors. This research will terminate on 30 September 1988.