The tetrapeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) and peptides structurally related to it, have been isolated from molluscan ganglia. They have widespread actions on both invertebrate and vertebrate tissues and there is increasing evidence that they are an important group of invertebrate peptide neurotransmitters. It is of interest that the primary amino acid sequence of FMRFamide forms the C-terminal tetrapeptide of an enkephalin-like heptapeptide (Met-enkephalin-ArgPhe) isolated from bovine adrenal medulla and striatum. Antisera to FMRFamide have been shown to react in radioimmunoassay and immunohistochemistry with material in the central nervous system of various vertebrate species, but the identity of this material, and in particular its relationship to the opioid heptapeptide, remains uncertain. We have used antibodies specific for the C-terminus of FMRFamide in radioimmunoassays to monitor purification of the material in chicken brain. We describe here the sequence of one of the peptides obtained. It is a biologically active peptide which does not seem to be related to other known vertebrate neuropeptides.

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We have investigated the pathway and the mechanism by which cholecystokinin octapeptide (CCK-8), given systemically, may influence the discharge of brain stem neurons that have an input from the stomach. Extracellular recordings were made from neurons in the nucleus of the solitary tract (NTS), where vagal afferents terminate, and from neighboring regions of the dorsal medial medulla. Gastric distension and CCK-8 injected intra-aortically close to the stomach evoked either excitatory or inhibitory responses that were abolished by cervical vagal section. In animals from which the celiac/superior mesenteric ganglia were removed, or the gastric antrum resected 2 weeks earlier, responses to gastric distension and CCK-8 were maintained. The effects of CCK-8 are unlikely to be secondary to changes in smooth muscle tone because CCK-8 decreased pressure in the body of the stomach, while distension increased it. Moreover, intravenous noradrenaline and vasoactive intestinal peptide had effects similar to CCK-8 on intragastric pressure, but evoked different patterns of responses from brain stem neurons. The results are consistent with the idea that CCK-8 acts directly on vagal mechanoreceptive endings in the gastric corpus wall. It is well known that peripheral administration of CCK-8 influences short-term regulation of food intake. The effects described here may reflect the pathway by which peripheral CCK influences CNS function.

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Since the enkephalins were first isolated a number of opioid peptides have been discovered, including a heptapeptide with the sequence Tyr-Gly-Gly-Phe-Met-Arg-Phe (Met-enkephalin-Arg6-Phe7). The heptapeptide was first isolated from chromaffin granules in bovine adrenal medulla, but using immunochemical techniques it has now been identified in human, rat and bovine brains. The C-terminal tetrapeptide of this molecule (Phe-Met-Arg-Phe) occurs in amidated form as the molluscan peptide FMRFamide. Antisera raised against FMRFamide have revealed immunoreactive material in the brains of several vertebrate species, including the rat where it occurs in nerve cell bodies and terminals. I now report that ionophoretically applied FMRFamide has an excitatory effect on rat medullary neurones which is unaffected by the opiate antagonist naloxone. In contrast, Met-enkephalin-Arg6-Phe7 and leucine-enkephalin (Leu-enkephalin) have predominantly depressant effects, which suggests that FMRFamide acts at a separate receptor.