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Gastric opioid peptides : their biochemical forms, receptor distribution, release and actions Nishimura, Erica


Gastric opioid peptides were characterized on the basis of their biochemical forms, sites of action, mode of release and effects on endocrine secretions of the stomach. Partial purification of opioid-like material from extracts of the corpus/antrum region of the rat stomach was carried out by Sephadex G-50 gel filtration chromatography followed by adsorption onto Amberlite XAD-2 resin. A single peak of opioid activity was determined by both radioreceptor assay (RRA) and bioassay. By high performance liquid chromatography (HPLC) this peak was resolved into several distinct components identified by their retention times and measurement by RRA and/or radioimmunoassay (RIA) as corresponding to methionine-enkephalin (met-enk), leucine-enkephalin (leu-enk), met-enk-arg-gly-leu, met-enk-arg-phe, as well as dynorphins 1-13, 1-17, and 1-8. Trypsin digestion of partially purified extracts resulted in an overall increase in opioid activity, suggesting the presence of larger, inactive forms which may function as precursors. The sites of opioid peptide action were inferred from autoradiographic demonstrations of the distribution of tritium-labelled opioid ligand binding. In the fundic region of the rat stomach mu- and delta-type opioid receptors were localized in the circular muscle, muscularis mucosae, suggesting that here the opioid peptides may be involved in the regulation of motor activity. In the corpus and antrum, these two opioid receptor types were found to be associated with the deepmuscular plexus in some areas, but predominantly in the submucosal plexus and mucosa where the opioid peptides may act to directly affect gastric endocrine and exocrine secretions. Mu-type ligands also bound to the circular muscle and myenteric plexus. Intestinal tissue demonstrated mu- and delta-opioid binding sites throughout the mucosa, extending to the tips of the villi, implicating their involvement in the regulation of intestinal fluid and electrolyte absorption. Using the isolated, perfused rat stomach preparation, endogenous leu-enk was found to be released into the gastric vasculature in response to potassium depolarization and to the nicotinic cholinergic agonist dimethyl-phenyl-piperazinium (DMPP). The muscarinic cholinergic agonist, methacholine, had no effect. Exogenously infused met-enk caused a prompt dose-dependent, naloxone sensitive inhibition of gastric inhibitory polypeptide (GlP)-stimulated somatostatin (SLI) secretion. A similar, but reduced effect was observed with dynorphin 1-13. Neither atropine nor hexamethonium affected the met-enk inhibition of GIP-stimulated SLI; therefore, it was proposed that met-enk was acting directly on the D-cells to inhibit somatostatin secretion, possibly by interacting with mucosal opioid receptors demonstrated by autoradiography. These results, demonstrating the presence of endogenous gastric opioid peptides of both the enkephalin and dynorphin families and the widespread distribution of opioid receptors in the gastrointestinal tract, coupled with the observed release of endogenous gastric leu-enk, and potent effects of opioid peptides on SLI secretion from the stomach, indicate that theopioid peptides are important physiological regulators of gastric and intestinal functions.

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