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GRP and Pavlov's dogs
  1. M FELDMAN
  1. Department of Veterans Affairs North Texas Health Care System
  2. and Department of Internal Medicine
  3. University of Texas Southwestern Medical Center
  4. Dallas, TX, USA
  5. mark.feldman{at}med.va.gov

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The cephalic phase of gastric acid secretion has been a topic of great interest to physiologists and physicians since its description by Pavlov 100 years ago.1 In classic “sham” feeding studies performed on dogs equipped with an oesophageal stoma and a gastric fistula, Pavlov demonstrated that food was a prompt and powerful stimulant of gastric secretion. This stimulation occurred despite the fact that the ingested food entered the dog's mouth and pharynx and exited through the stoma, never actually reaching the stomach. Pavlov went on to demonstrate that severing the vagus nerves just above the diaphragm abolished the gastric acid secretory response to sham feeding in dogs. His experiments demonstrated that sham feeding elicited a potent gastric acid secretory response via the vagus nerves.

Although experiments involving surgically created fistulas could not be conducted in humans, in the 1970s Knutson and Olbe developed a “modified” sham feeding technique to study the cephalic phase of gastric acid secretion in patients with duodenal ulcer disease.2-4 Patients chewed and expectorated appetising food without swallowing it, and a tube inserted into the stomach collected gastric fluid for acid analysis. Using modified sham feeding in healthy volunteers, Richardson et aldemonstrated that the cephalic phase of gastric acid secretion accounted for half of the acid secreted during the first postprandial hour.5 The thought and taste of food were more important secretory stimulants than the sight or smell of a meal.6Acetylcholine and histamine were demonstrated to be important mediators of the cephalic phase of gastric acid secretion in humans because injection of either the muscarinic antagonist atropine or the histamine H2 receptor antagonist cimetidine markedly attenuated the acid secretory response to modified sham feeding.7 8 Much as Pavlov had demonstrated in dogs, clinical investigators found that the cephalic phase of gastric acid secretion in humans could also be abolished by surgical vagotomy, even by a proximal selective vagotomy which preserved the vagal innervation of the gastric antrum and pylorus.2 9

The antral hormone gastrin is released into the blood during the cephalic phase of gastric acid secretion in humans.4-7 9 10 Although the amount of gastrin released during modified sham feeding is small in comparison with the amount released during normal eating, the serum increase in gastrin probably contributes to a substantial proportion of the acid secreted during modified sham feeding. In contrast with acid secretion, cephalic-vagal release of gastrin cannot be blocked by large doses of atropine.7 In fact, atropine potentiates gastrin release during modified sham feeding, indicating that an inhibitory vagal-cholinergic pathway normally operates to limit gastrin release during the cephalic phase. In support of this mechanism, augmentation of gastrin release during modified sham feeding has been demonstrated after proximal selective vagotomy.9 The non-cholinergic neurotransmitter that is responsible for release of gastrin from the antrum of the stomach during the cephalic phase in humans is not known but gastrin releasing peptide (GRP) has been a prime candidate.

GRP is the mammalian analogue of bombesin, a 14 amino acid peptide which was first isolated from the skin of two frogs,Bombina bombina andBombina variegata variegata.11 12 Both bombesin and GRP are potent gastrin releasers and acid secretogogues when injected into humans.13-16 Soon after bombesin was discovered in frog skin, a similar gastrin releasing peptide was extracted from the non-antral portion of the pig stomach.17 18 Using specific antibodies to bombesin/GRP, GRP was later demonstrated in the human stomach by immunostaining.19 Of interest, GRP neurones are actually denser in the fundic (oxyntic) mucosa, where acid secreting parietal cells are located, than in the antral (pyloric) mucosa, where gastrin cells (G cells) are located.19

Until recently, no specific GRP antagonist has been available to explore GRP as a potential physiological mediator of vagally mediated gastrin release or of acid secretion during the cephalic phase in humans. Now, a novel synthetic peptide that is a specific peripheral GRP receptor antagonist (GRP-RA) has been tested by Hildebrandet al, and their interesting results are reported in this issue of Gut (see page23).20 Surprisingly, the GRP-RA had no effect on the amount of gastrin released in response to modified sham feeding or in response to normal eating. This suggests that the term “gastrin releasing peptide” may be a misnomer, at least with regard to the physiological action of this neuropeptide. Thus the identity of the non-cholinergic non-GRP stimulant of antral gastrin release during the cephalic phase of acid secretion remains to be determined; it is even possible that the “stimulant” is in fact removal of an endogenous gastrin inhibitor, such as antral somatostatin.

An equally important finding in the study by Hildebrandet al was that the same dose of GRP receptor antagonist that had no detectable effect on gastrin release (500 μg/kg/h) abolished the gastric acid secretory response to modified sham feeding, and it also abolished acid secretion in response to intravenous GRP infusion. This striking observation implies a critical role for GRP neurones, presumably those located in the fundic (oxyntic) mucosa, in the regulation of gastric acid secretion during the cephalic phase. Activated by the thought, taste, smell, and sight of food, the vagus nerves may stimulate release of GRP from these intramural gastric neurones, which then might evoke acetylcholine release from postganglionic neurones, with acetylcholine binding muscarinic receptors located on parietal cells. This hypothetical cascade remains to be tested experimentally. It is conceivable that drugs that selectively inhibit GRP receptors in the stomach can be developed as acid antisecretory drugs, resulting in a “medical” vagotomy. We have learned a great deal about the cephalic phase of acid secretion since the pioneering studies in Pavlov's dogs, but clearly we still have a great deal more to learn. Neuronal GRP appears to be a critical piece of the puzzle.

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