I. Introduction II. Biosynthesis of TRH and Other pro-TRH-Derived Peptides A. Biosynthesis and processing of pro-TRH B. Intracellular sites of pro-TRH processing C. Tissue-specific processing of pro-TRH D. The role of PCs and CPs E. Neuropeptide and catecholamine regulation of Pro-TRH biosynthesis and processing F. Glucocorticoids modulate the biosynthesis and processing of pro-TRH G. Leptin regulates pro-TRH biosynthesis III. Function of TRH A. The HPT axis B. Extrahypophysiotropic TRH IV. Function of non-TRH pro-TRH-Derived Peptides A. prepro-TRH160–169 (pST10) B. prepro-TRH178–199 (pFE22) C. prepro-TRH178–185 and prepro-TRH186–199 (pFQ7 and pSE14) D. prepro-TRH53–74 (pFT22) E. prepro-TRH83–106 (pEH24) and prepro-TRH208–255 F. TRH-Gly V. Non-TRH pro-TRH-Derived Peptides Outside of the CNS VI. TRH and Other pro-TRH-Derived Peptide Receptors A. The TRH receptor B. The prepro-TRH160–169 (pST10) receptor VII. TRH Degradation VIII. Concluding Remarks

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The biology of pro-thyrotropin-releasing hormone-derived peptides.

Inhibition of inositol phospholipid breakdown by D2 dopamine receptors in dissociated bovine anterior pituitary cells.

There is clear evidence in rats that TRH acts in the brain to stimulate gastric acid, pepsin, and serotonin secretion, mucosal blood flow, contractility, emptying, and ulceration through activation of parasympathetic outflow to the stomach (TABLE 3). A number of TRH analogues, including some devoid of TSH-releasing activity, mimic the effects of TRH. The most sensitive TRH sites of action to elicit gastric acid secretion and motility are located in the dorsal vagal complex and include the dorsal vagal, nucleus tractus solitarius, and nucleus ambiguus. The gastrointestinal tract is one of the most responsive visceral systems to the central effects of TRH, because doses in the range of 1-10 pmol in the dorsal vagal complex stimulate gastric function, whereas stimulation of cardiovascular and respiratory function on microinjection of the brainstem nuclei requires higher doses. Although fewer investigations have been carried out in other species, evidence from the available data clearly indicates that TRH acts in the brain to increase gastric secretion and motility in the rabbit, sheep, and cat. Lack of stimulation of gastric acid secretion after third ventricle injection in the dog may be related to species difference or to rapid degradation of the peptide before it reaches its site of action. TRH acts centrally to stimulate gastric function and also intestinal secretion, motility, and transit as reported mostly in rabbits (TABLE 3). TRH produces enteropooling and release of serotonin in portal blood, increases duodenal and intestinal contractility and colonic transit, and elicits diarrhea. All these effects were shown to be vagally mediated. Stimulation of intestinal motility and transit by central injection of TRH has been observed in rats and sheep. The biological activity of centrally injected TRH is well correlated with the presence of TRH immunoreactivity and receptors in the dorsal vagal complex containing afferent and efferent connections to the stomach. Moreover, endogenous release of brain TRH in rats mimics the stimulatory effect of centrally injected TRH on gastric function. Although the lack of a specific TRH antagonist has hampered assessment of the physiological role of TRH, converging neuropharmacological, neuroanatomical, and physiological findings support the concept that TRH in the dorsal vagal complex may play a physiological role in the vagal regulation of gastrointestinal function.(ABSTRACT TRUNCATED AT 400 WORDS)

Central nervous system action of TRH to influence gastrointestinal function and ulceration

https://www.gastrojournal.org/article/S0016-5085(88)80065-9/pdf

Medullary sites of action of the TRH analogue, RX 77368, for stimulation of gastric acid secretion in the rat.

Cyclo(His-Pro), or cHP, is a putative metabolite of thyrotropin-releasing hormone (TRH), and, like TRH, can inhibit food intake but requires higher doses. In attempts to improve the anorectic effects of cHP through modification of its structure, a number of its analogs were synthesized. These analogs or cHP itself were administered to rats either by intracerebroventricular (ICV) infusion or systemic injection, and their effects on food intake were measured. None of the synthetic analogs was more potent than cHP, although several analogs demonstrated comparable potencies to the parent compound. Interestingly, one cHP analog reversed the suppressive effect and stimulated feeding. This reversal, as well as the preservation of the anorectic effect by some but not all the analogs, suggests that the cHP effect on feeding does require specific structural features.

W.K. Engel

Papers

Analog specificity of the thyrotropin-releasing hormone receptor in the central nervous system: possible clinical implications.