Thyrotropin releasing hormone (TRH) in the brainstem: Role of Pavlov’s vagally mediated cephalic phase of gastric secretion
DOI:
https://doi.org/10.33910/2687-1270-2020-1-3-160-168Keywords:
dorsal vagal complex, cephalic phase, gastric secretion, thyrotropin releasing hormone (TRH), TRH receptor, sham feeding, vagusAbstract
Pavlov’s seminal observation that sham feeding in dogs stimulates gastric acid secretion through the vagus nerve pioneered the concept of the cephalic phase of digestion. This has been subsequently extended to a wide range of mammals including humans. In the last decades, experimental evidence in rats established that the three amino acid peptide thyrotropinreleasing hormone (TRH) expressed in the brainstem plays a key role in the vagal stimulation of digestive secretory-motor function. The dorsal motor nucleus of the vagus (DMN) neurons expresses TRH receptor subtype 1 (TRH-R1) and receives input of TRH containing fibers arising from TRH synthesizing neurons in medullary raphe nuclei. The activation of TRHTRH-R1 signaling excites the firing of DMN neurons leading to the activation of vagal efferent discharges and gastric myenteric cholinergic neurons. This results in a vagally mediated and atropine-sensitive stimulation of gastric secretory and propulsive motor function, along with duodenal and pancreatic secretion. Importantly, the blockade of TRH or TRH-R1 in the brainstem inhibits the gastric acid response to sham feeding in rats. Collectively, these convergent data support the physiological relevance of medullary TRHTRH-R1 signaling as the end effector of the vagally mediated stimulation of digestive process in the cephalic phase.
References
Barnes, M. J., Rogers, R. C., Van Meter, M. J., Hermann, G. E. (2010) Co-localization of TRHR1 and LepRb receptors on neurons in the hindbrain of the rat. Brain Research, vol. 1355, pp. 70–85. PMID: 20691166. DOI: 10.1016/j.brainres.2010.07.094 (In English)
Bayliss, D. A., Viana, F., Kanter, R. K. et al. (1994) Early postnatal development of thyrotropin-releasing hormone (TRH) expression, TRH receptor binding, and TRH responses in neurons of rat brainstem. Journal of Neurosciences, vol. 14, no 2, pp. 821–833. PMID: 8301363. DOI: 10.1523/JNEUROSCI.14-02-00821.1994 (In English)
Chen, C.-Y., Million, M., Adelson, D. W. et al. (2002) Intracisternal urocortin inhibits vagally stimulated gastric motility in rats: Role of CRF(2). British Journal of Pharmacology, vol. 136, no. 2, pp. 237–247. PMID: 12010772. DOI: 10.1038/sj.bjp.0704713 (In English)
DelParigi, A., Chen, K., Salbe, A. D. et al. (2005) Sensory experience of food and obesity: A positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast. Neuroimage, vol. 24, no. 2, pp. 436–443. PMID: 15627585. DOI: 10.1016/j.neuroimage.2004.08.035 (In English)
Feldman, M., Richardson, C. T. (1986) Role of thought, sight, smell and taste of food in the cephalic phase of gastric acid secretion in humans. Gastroenterology, vol. 90, no. 2, pp. 426–433. PMID: 3940915. DOI: 10.1016/0016-5085(86)90943-1 (In English)
Fodor, M., Pammer, C., Gorcs, T., Palkovits, M. (1994) Neuropeptides in the human dorsal vagal complex: An immunohistochemical study. Journal of Chemical Neuroanatomy, vol. 7, no. 3, pp. 141–157. PMID: 7848571. DOI: 10.1016/0891-0618(94)90025-6 (In English)
Garrick, T., Prince, M., Yang, H. et al. (1994) Raphe pallidus stimulation increases gastric contractility via TRH projections to the dorsal vagal complex in rats. Brain Research, vol. 636, no. 2, pp. 343–347. PMID: 7912160. DOI: 10.1016/0006-8993(94)91035-9 (In English)
Gershengorn, M. C., Osman, R. (1996) Molecular and cellular biology of thyrotropin-releasing hormone receptors. Physiological Reviews, vol. 76, no. 1, pp. 175–191. PMID: 8592728. DOI: 10.1152/physrev.1996.76.1.175 (In English)
Giduck, S. A., Threatte, R. M., Kare, M. R. (1987) Cephalic reflexes: Their role in digestion and possible roles in absorption and metabolism. The Journal of Nutrition, vol. 117, no. 7, pp. 1191–1196. PMID: 3302135. DOI: 10.1093/jn/117.7.1191 (In English)
Goldschmiedt, M, Redfern, J. S., Feldman, M. (1990) Food coloring and monosodium glutamate: Effects on the cephalic phase of gastric acid secretion and gastrin release in humans. American Journal of Clinical Nutrition, vol. 51, no. 5, pp. 794–797. PMID: 2333838. DOI: 10.1093/ajcn/51.5.794 (In English)
Guemes, A., Herrero, P., Bondia, J., Georgiou, P. (2019) Modeling the effect of the cephalic phase of insulin secretion on glucose metabolism. Medical & Biological Engineering & Computing, vol. 57, no. 6, pp. 1173–1186. PMID: 30685858. DOI: 10.1007/s11517-019-01950-x (In English)
Hermann, G. E., Tovar, C. A., Rogers, R. C. (1999) Induction of endogenous tumor necrosis factor-alpha: Suppression of centrally stimulated gastric motility. The American Journal of Physiology, vol. 276, no. 1, pp. R59–R68. PMID: 9887178. DOI: 10.1152/ajpregu.1999.276.1.R59 (In English)
Heuer, H., Schafer, M. K., O’Donnell, D. et al. (2000) Expression of thyrotropin-releasing hormone receptor 2 (TRH-R2) in the central nervous system of rats. The Journal of Comparative Neurology, vol. 428, no. 2, pp. 319–336. PMID: 11064370 (In English)
Heymann-Monnikes, I., Tache, Y., Trauner, M. et al. (1991) CRF microinjected into the dorsal vagal complex inhibits TRH analog- and kainic acid-stimulated gastric contractility in rats. Brain Research, vol. 554, no. 1–2, pp. 139–144. PMID: 1933296. DOI: 10.1016/0006-8993(91)90181-t (In English)
Holst, M. C., Kelly, J. B., Powley, T. L. (1997) Vagal preganglionic projections to the enteric nervous system characterized with Phaseolus vulgaris-leucoagglutinin. The Journal of Comparative Neurology, vol. 381, no. 1, pp. 81–100. PMID: 9087421. DOI: 10.1002/(sici)1096-9861(19970428)381:1<81::aid-cne7>3.0.co;2-g (In English)
Hornby, P. J., Rossiter, C. D., Kuhn, D. H. Jr. et al. Neuroactive substances in medullary nuclei that control parasympathetic outflow to the stomach. In: Y. Tache, D. L. Wingate (eds.). Brain-gut interactions. Boca Raton: CRC Press, pp. 23–43. (In English)
Hughes, J. J., Levin, A. S., Morley, J. E. et al. (1984) Intraventricular calcitonin gene-related peptide inhibits gastric acid secretion. Peptides, vol. 5, no. 4, pp. 665–667. PMID: 6436796. DOI: 10.1016/0196-9781(84)90003-2 (In English)
Iwase, M., Homma, I., Shioda, S., Nakai, Y. (1988) Thyrotropin-releasing hormone-like immunoreactive neurons in rabbit medulla oblongata. Neuroscience Letters, vol. 92, no. 1, pp. 30–33. PMID: 3141847. DOI: 10.1016/0304-3940(88)90737-9 (In English)
Kaneko, H., Kaunitz, J., Tache, Y. (1998) Vagal mechanisms underlying gastric protection induced by chemical activation of the raphe pallidus in rats. The American Journal of Physiology, vol. 275, no. 5, pp. G1056–G1062. PMID: 9815036. DOI: 10.1152/ajpgi.1998.275.5.G1056 (In English)
Kaneko, H., Yang, H., Ohning, G., Tache, Y. (1995) Medullary TRH is involved in gastric protection induced by low dose of kainic acid into the raphe pallidus. The American Journal of Physiology, vol. 268, no. 4, pp. G548–G552. PMID: 7733282. DOI: 10.1152/ajpgi.1995.268.4.G548 (In English)
Katschinski, M. (2000) Nutritional implications of cephalic phase gastrointestinal responses. Appetite, vol. 34, no. 2, pp. 189–196. PMID: 10744909. DOI: 10.1006/appe.1999.0280 (In English)
Katschinski, M., Dahmen, G., Reinshagen, M. et al. (1992) Cephalic stimulation of gastrointestinal secretory and motor responses in humans. Gastroenterology, vol. 103, no. 2, pp. 383–391. PMID: 1634057. DOI: 10.1016/0016-5085(92)90825-j (In English)
Kiraly, A., Suto, G., Guth, P. H., Tache, Y. (1998) Peripheral mediators involved in gastric hyperemia to vagal activation by central TRH analog in rats. The American Journal of Physiology, vol. 274, no. 1, pp. G170–G177. PMID: 9458786. DOI: 10.1152/ajpgi.1998.274.1.G170 (In English)
Kovacs, T. O., Lloyd, K. C., Lawson, D. C. et al. (1997) Inhibition of sham feeding-stimulated acid secretion in dogs by immunoneutralization of gastrin. The American Journal of Physiology, vol. 273, no. 2, pp. G399–G403. PMID: 9277419. DOI: 10.1152/ajpgi.1997.273.2.G399 (In English)
Krammer, H. J., Karahan, S. T., Rumpel, E. et al. (1993) Immunohistochemical visualization of the enteric nervous system using antibodies against protein gene product (PGP) 9.5. Anatomischer Anzeiger, vol. 175, no. 4, pp. 321–325. PMID: 8363037. DOI: 10.1016/s0940-9602(11)80029-4 (In English)
Livingston, C. A., Berger, A. J. (1993) Response of neurons in the dorsal motor nucleus of the vagus to thyrotropinreleasing hormone. Brain Research, vol. 621, no. 1, pp. 97–105. PMID: 8221078. DOI: 10.1016/0006-8993(93)90302-4 (In English)
Lynn, R. B., Kreider, M. S., Miselis, R. R. (1991) Thyrotropin-releasing hormone-immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat. The Journal of Comparative Neurology, vol. 311, no. 2, pp. 271–288. PMID: 1753019. DOI: 10.1002/cne.903110208 (In English)
Manaker, S., Rizio, G. (1989) Autoradiographic localization of thyrotropin-releasing hormone and substance P receptors in the rat dorsal vagal complex. The Journal of Comparative Neurology, vol. 290, no. 4, pp. 516–526. PMID: 2559109. DOI: 10.1002/cne.902900406 (In English)
Martinez, V., Barrachina, M. D., Ohning, G., Tache, Y. (2002) Cephalic phase of acid secretion involves activation of medullary TRH receptor subtype 1 in rats. American Journal of Physiology, vol. 283, no. 6, pp. G1310–G1319. PMID: 12388176. DOI: 10.1152/ajpgi.00222.2002 (In English)
Martinez, V., Tache, Y. (2000) Bombesin and the brain-gut axis. Peptides, vol. 21, no. 11, pp. 1617–1625. PMID: 11090915. DOI: 10.1016/s0196-9781(00)00293-x (In English)
Mattes, R. D. (1997) Physiologic responses to sensory stimulation by food: Nutritional implications. Journal of American Dietetic Association, vol. 97, no. 4, pp. 406–413. DOI: 10.1016/S0002-8223(97)00101-6 (In English)
McCann, M. J., Hermann, G. E., Rogers, R. C. (1989) Thyrotropin-releasing hormone: Effects on identified neurons of the dorsal vagal complex. Journal of Autonomic Nervous System, vol. 26, no. 2, pp. 107–112. PMID: 2498419. DOI: 10.1016/0165-1838(89)90158-6 (In English)
Miampamba, M., Million, M., Tache, Y. (2011) Brain-gut interactions between central vagal activation and abdominal surgery to influence gastric myenteric ganglia Fos expression in rats. Peptides, vol. 32, no. 5, pp. 1078–1082. PMID: 21376096. DOI: 10.1016/j.peptides.2011.02.018 (In English)
Miampamba, M., Yang, H., Sharkey, K. A., Tache, Y. (2001) Intracisternal TRH analog induces Fos expression in gastric myenteric neurons and glia in conscious rats. American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 280, no. 5, pp. G979–G991. PMID: 11292608. DOI: 10.1152/ajpgi.2001.280.5.G979 (In English)
Morrow, N. S., Quinonez, G., Weiner, H. et al. (1995) Interleukin-1 beta in the dorsal vagal complex inhibits TRH analogue-induced stimulation of gastric contractility. The American Journal of Physiology, vol. 269, no. 2, pp. G196–G202. PMID: 7653558. DOI: 10.1152/ajpgi.1995.269.2.G196 (In English)
O’Dowd, B. F., Lee, D. K., Huang, W. et al. (2000) TRH-R2 exhibits similar binding and acute signaling but distinct regulation and anatomic distribution compared with TRH-R1. Molecular Endocrinology, vol. 14, no. 1, pp. 183–193. PMID: 10628757. DOI: 10.1210/mend.14.1.0407 (In English)
Ohara, I., Otsuka, S., Yugari, Y. (1988) Cephalic phase response of pancreatic exocrine secretion in conscious dogs. The American Journal of Physiology, vol. 254, no. 3, pp. G424–G428. PMID: 3348407. DOI: 10.1152/ajpgi.1988.254.3.G424 (In English)
Okumura, T., Taylor, I. L., Pappas, T. N. (1995) Microinjection of TRH analogue into the dorsal vagal complex stimulates pancreatic secretion in rats. American Journal of Physiology, vol. 269, no. 3, pp. G328–G334. DOI: 10.1152/ajpgi.1995.269.3.G328 (In English)
O-Lee, T. J., Wei, J. Y., Tache, Y. (1997) Intracisternal TRH and RX 77368 potently activate vagal efferent discharge in rats. Peptides, vol. 18, no. 2, pp. 213–219. PMID: 9149293. DOI: 10.1016/s0196-9781(96)00281-1 (In English)
Pavlov, I. P. (1910) The work of the digestive glands. 2nd ed. London: C. Griffin & Company limited, 266 p. (In English)
Power, M. L., Schulkin, J. (2008) Anticipatory physiological regulation in feeding biology: Cephalic phase responses. Appetite, vol. 50, no. 2–3, pp. 194–206. PMID: 18045735. DOI: 10.1016/j.appet.2007.10.006 (In English)
Powley, T. L. (2000) Vagal circuitry mediating cephalic-phase responses to food. Appetite, vol. 34, no. 2, pp. 184–188. PMID: 10744908. DOI: 10.1006/appe.1999.0279 (In English)
Powley, T. L., Berthou, H.-R., Prechtl, J. C., Fox, A. E. (1991) Fibers of the vagus regulating gastrointestinal function. In: Y. Tache, D. Wingate (eds.). Brain-gut interactions. Boca Raton: CRC Press, pp. 73–82. (In English)
Raggenbass, M., Vozzi, C., Tribollet, E. et al. (1990) Thyrotropin-releasing hormone causes direct excitation of dorsal vagal and solitary tract neurones in rat brainstem slices. Brain Research, vol. 530, no. 1, pp. 85–90. PMID: 2125519. DOI: 10.1016/0006-8993(90)90659-y (In English)
Rinaman, L., Miselis, R. R. (1990) Thyrotropin-releasing hormone-immunoreactive nerve terminals synapse on the dentrites of gastric vagal motoneurons in the rat. The Journal of Comparative Neurology, vol. 294, no. 2, pp. 235–251. PMID: 2110196. DOI: 10.1002/cne.902940208 (In English)
Rinaman, L., Miselis, R. R., Kreider, M. S. (1989) Ultrastructural localization of thyrotropin-releasing hormone immunoreactivity in the dorsal vagal complex in rat. Neuroscience Letters, vol. 104, no. 1–2, pp. 7–12. PMID: 2510095. DOI: 10.1016/0304-3940(89)90320-0 (In English)
Rindi, G., Leiter, A. B., Kopin, A. S. et al. (2004) The “normal” endocrine cell of the gut: Changing concepts and new evidences. Annals of the New York Academy of Sciences, vol. 1014, pp. 1–12. PMID: 15153415. DOI: 10.1196/annals.1294.001 (In English)
Rogers, J., Raimundo, A. H., Misiewicz, J. J. (1993) Cephalic phase of colonic pressure response to food. Gut, vol. 34, no. 4, pp. 537–543. PMID: 8491403. DOI: 10.1136/gut.34.4.537 (In English)
Simonian, H. P., Kresge, K. M., Boden, G. H., Parkman, H. P. (2005) Differential effects of sham feeding and meal ingestion on ghrelin and pancreatic polypeptide levels: Evidence for vagal efferent stimulation mediating ghrelin release. Neurogastroenteroly and Motility, vol. 17, no. 3, pp. 348–354. PMID: 15916622. DOI: 10.1111/j.1365-2982.2004.00634.x (In English)
Sivarao, D. V., Krowicki, Z. K., Abrahams, T. P., Hornby, P. J. (1997) Intracisternal antisense oligonucleotides to TRH receptor abolish TRH-evoked gastric motor excitation. The American Journal of Physiology, vol. 272, no. 6, pp. G1372–G1381. PMID: 9227472. DOI: 10.1152/ajpgi.1997.272.6.G1372 (In English)
Smeets, P. A. M., Erkner, A., de Graaf, C. (2010) Cephalic phase responses and appetite. Nutrition Reviews, vol. 68, no. 11, pp. 643–655. PMID: 20961295. DOI: 10.1111/j.1753-4887.2010.00334.x (In English)
Sobhani, I., Buyse, M., Goiot, H. et al. (2002) Vagal stimulation rapidly increases leptin secretion in human stomach. Gastroenterology, vol. 122, no. 2, pp. 259–263. PMID: 11832440. DOI: 10.1053/gast.2002.31385 (In English)
Somiya, H., Tonoue, T. (1984) Neuropeptides as central integrators of autonomic nerve activity: Effects of TRH, SRIF, VIP and bombesin on gastric and adrenal nerves. Regulatory Peptides, vol. 9, no. 1–2, pp. 47–52. PMID: 6150518. DOI: 10.1016/0167-0115(84)90006-5 (In English)
Tache, Y., Adelson, D., Yang, H. (2014) TRH/TRH-R1 receptor signaling in the brain medulla as a pathway of vagally mediated gut responses during the cephalic phase. Current Pharmaceutical Design, vol. 20, no. 16, pp. 2725–2730. PMID: 23886382. DOI: 10.2174/13816128113199990578 (In English)
Tache, Y., Bonaz, B. (2007) Corticotropin-releasing factor receptors and stress-related alterations of gut motor function. The Journal of Clinical Investigation, vol. 117, no. 1, pp. 33–40. PMID: 17200704. DOI: 10.1172/JCI30085 (In English)
Tache, Y., Goto, Y., Hamel, D. et al. (1985) Mechanisms underlying intracisternal TRH-induced stimulation of gastric acid secretion in rats. Regulatory Peptides, vol. 13, no. 1, pp. 21–30. PMID: 3937184. DOI: 10.1016/0167-0115(85)90083-7 (In English)
Tache, Y., Goto, Y., Lauffenburger, M., Lesiege, D. (1984) Potent central nervous system action of p-Glu-His-(3,3’-dimethyl)-Pro NH2, a stabilized analog of TRH, to stimulate gastric secretion in rats. Regulatory Peptides, vol. 8, no. 1, pp. 71–78. DOI: 10.1016/0167-0115(84)90030-2 (In English)
Tache, Y., Stephens, R. L., Ishikawa, T. (1989) Central nervous system action of TRH to influence gastrointestinal function and ulceration. Annals of the New York Academy of Sciences, vol. 553, pp. 269–285. PMID: 2497674. DOI: 10.1111/j.1749-6632.1989.tb46649.x (In English)
Tache, Y., Vale, W., Brown, M. (1980) Thyrotropin-releasing hormone-CNS action to stimulate gastric acid secretion. Nature, vol. 287, no. 5778, pp. 149–151. PMID: 6776408. DOI: 10.1038/287149a0 (In English)
Tache, Y., Vale, W., Rivier J., Brown, M. (1981) Brain regulation of gastric acid secretion in rats by neurogastrointestinal peptides. Peptides, vol. 2, suppl. 2, pp. 51–55. PMID: 6123991. DOI: 10.1016/0196-9781(81)90010-3 (In English)
Tache, Y., Yang, H., Kaneko, H. (1995) Caudal raphe-dorsal vagal complex peptidergic projections: Role in gastric vagal control. Peptides, vol. 16, no. 3, pp. 431–435. PMID: 7544464. DOI: 10.1016/0196-9781(94)00212-o (In English)
Tache, Y., Yang, H., Miampamba, M. et al. (2006) Role of brainstem TRH/TRH-R1 receptors in the vagal gastric cholinergic response to various stimuli including sham-feeding. Autonomic Neurosciences: Basic and Clinical, vol. 125, no. 1–2, pp. 42–52. PMID: 16520096. DOI: 10.1016/j.autneu.2006.01.014 (In English)
Tache, Y., Yang, H., Yoneda, M. (1993) Vagal regulation of gastric function involves thyrotropin-releasing hormone in the medullary raphe nuclei and dorsal vagal complex. Digestion, vol. 54, no. 2, pp. 65–72. PMID: 8319841. DOI: 10.1159/000201015 (In English)
Travagli, R. A., Gillis, R. A., Vicini, S. (1992) Effects of thyrotropin-releasing hormone on neurons in the rat dorsal motor nucleus of the vagus, in vitro. The American Journal of Physiology, vol. 263, no. 4, pp. G508–G517. PMID: 1329553. DOI: 10.1152/ajpgi.1992.263.4.G508 (In English)
Van der Kooy, D., Koda, L. Y., McGinty, J. F. et al. (1984) The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. The Journal of Comparative Neurology, vol. 224, no. 1, pp. 1–24. PMID: 6715573. DOI: 10.1002/cne.902240102 (In English)
White, R. L. Jr., Rossiter, C. D., Hornby, P. J. et al. (1991) Excitation of neurons in the medullary raphe increases gastric acid and pepsin production in cats. The American Journal of Physiology, vol. 260, no. 1, pp. G91–G96. PMID: 1899009. DOI: 10.1152/ajpgi.1991.260.1.G91 (In English)
Yang, H., Ohning, G., Tache, Y. (1993) TRH in dorsal vagal complex mediates acid response to excitation of raphe pallidus neurons in rats. The American Journal of Physiology, vol. 265, no. 5, pp. G880–G886. PMID: 8238517. DOI: 10.1152/ajpgi.1993.265.5.G880 (In English)
Yang, H., Tache, Y., Ohning, G., Go, V. L. W. (2002) Activation of raphe pallidus neurons increases insulin through medullary thyrotropin-releasing hormone (TRH)-vagal pathways. Pancreas, vol. 25, no. 3, pp. 301–307. PMID: 12370543. DOI: 10.1097/00006676-200210000-00014 (In English)
Yang, H., Yuan, P.-Q., Wang, L., Tache, Y. (2000) Activation of the parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats. Neuroscience, vol. 95, no. 3, pp. 773–779. PMID: 10670444. DOI: 10.1016/s0306-4522(99)00490-x (In English)
Yoneda, M., Goto, M., Nakamura, K. et al. (2005) Thyrotropin-releasing hormone in the dorsal vagal complex stimulates pancreatic blood flow in rat. Regulatory Peptides, vol. 131, no. 1–3, pp. 74–81. PMID: 16040141. DOI: 10.1016/j.regpep.2005.06.010 (In English)
Yuan, P.-Q., Kimura, H., Million, M. et al. (2005) Central vagal stimulation activates enteric cholinergic neurons in the stomach and VIP neurons in the duodenum in conscious rats. Peptides, vol. 26, no. 4, pp. 653–664. PMID: 15752581. DOI: 10.1016/j.peptides.2004.11.015 (In English)
Zafra, M. A., Molina, F., Puerto, A. (2006) The neural/cephalic phase reflexes in the physiology of nutrition. Neuroscience & Biobehavioral Reviews, vol. 30, no. 7, pp. 1032–1044. PMID: 16678262. DOI: 10.1016/j.neubiorev.2006.03.005 (In English)
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