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Role of medullary TRH in brain–gut interaction-mediated gastric integrity
International Congress Series 1241 (2002) 73 – 78
Role of medullary TRH in brain–gut interaction-mediated gastric integrity Hiroshi Kaneko a,*, Yvette Tache´ b a
Department of Internal Medicine, Division of General Medicine, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute, Aichi-gun, Aichi 480-1195, Japan b CURE/Digestive Diseases Research Center, VA Los Angeles Greater Health Care System, Department of Medicine, Digestive Disease Division and Brain Research Institute, University of California-Los Angeles, Bldg. #115, Rm. #203, West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
Abstract Kainic acid delivered into the raphe pallidus (Rpa) in the medulla increased gastric acid secretion and produced gastric mucosal lesions, which were completely prevented by bilateral microinjection of TRH antibody into the dorsal motor nucleus of the vagus (DMN) in rats. These findings indicated that endogenous TRH action on the DMN may contribute to gastric mucosal lesions. On the contrary, endogenous TRH at a subthreshold dose increasing gastric acid secretion alleviates gastric injury induced by intragastric administration of a strong irritant. The dual action of the medullary TRH on gastric integrity is mediated through activation of peripheral vagal-enteric nervous systems and cholinergic pathways. The outcome reflects the balance between peripheral aggressive and protective factors recruited by the level of vagal cholinergic activation. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody by itself increased gastric injury induced by a strong irritant and completely abolished the protective effect of a mild irritant pretreatment in rats. The number of c-fos protein-positive cells in the DMN increased in the process of the adaptive cytoprotection. These results suggest that vagal afferent nerves activated by gastric topical irritant act on DMN by releasing endogenous TRH to induce gastric protection against the subsequent strong irritant. Medullary TRH and gastric vagal efferent and afferent circuits may play a crucial role in the modulation of gastric integrity. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Gastric mucosal lesion; Gastric cytoprotection; Medulla; TRH; Vagus
Abbreviations: TRH, thyrotropin-releasing hormone; DMN, dorsal motor nucleus of the vagus; CRS, cold restraint stress; Rpa, raphe pallidus; GMBF, gastric mucosal blood flow; CGRP, calcitonin gene-related peptide; NO, nitric oxide; NTS, nucleus tractus solitarius of the vagus; DVC, dorsal vagal complex. * Corresponding author. Tel.: +81-561-62-3311x2179; fax: +81-561-62-1570. E-mail addresses: [email protected] (H. Kaneko), [email protected] (Y. Tache´). 0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 8 0 - 5
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H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
Since Hans Selye’s report establishing that gastric ulcer occurs under chronic stressful conditions, a plethora of investigations have been performed to unravel mechanisms underlying stress-induced gut lesions. Molecules and their receptors involved in the stress response are being characterized. On the one hand, mechanisms by which information is conveyed from the stomach to the brain have been examined in the context of viscerosensibility. In this review, the role of thyrotropin-releasing hormone (TRH) was selected among several stress-related peptides.
1. Medullary TRH-induced gastric mucosal lesions Compelling evidence indicates that medullary TRH participates in the vagal regulation of gastric function. TRH-immunoreactive nerve terminals and fibers and a high concentration of TRH receptors are localized in the dorsal vagal complex (DVC) [1]. The dense network of TRH immunoreactive fibers in the DVC arises from TRH-containing cell bodies located exclusively in the medulla, namely, the raphe pallidus (Rpa), raphe obscurus and the parapyramidal region of the ventral medulla [1]. The functional significance of these pathways was demonstrated by the fact that TRH or the stable TRH analog, RX77368, microinjected into the dorsal motor nucleus of the vagus (DMN) induces vagal cholinergicmediated stimulation of gastric secretory and motor function and hemorrhagic lesions [2]. Furthermore, activation of the Rpa neurons induced a vagal muscarinic-dependent stimulation of gastric acid secretion and contractility in rats. These gastric responses were blocked by bilateral microinjection of a specific TRH antibody into the DMN [3,4]. Cold restraint stress (CRS) is well-established experimental model to induce stressrelated corpus mucosal erosions with hemorrhage in rats. Aggressive factors such as increase in gastric acid, pepsin and high amplitude contractions have been reported to be responsible for gastric lesion formation. Converging evidence supports a role of medullary TRH in the gastric pathophysiology elicited by CRS exposure. First, TRH or TRH analog microinjected into the cisterna magna or DMN induced the similar gastric injury as CRS and both were prevented by the immunoneutralization with TRH antibody injected centrally [2,5]. Second, cold restraint increases TRH gene expression in the medulla and cell bodies expressing TRH as shown by Northern blot analysis in situ hybridization [6,7]. Third, cold restraint activates TRH containing cell bodies in the medulla, which was assessed by double labeling with fos and TRH preprohormone expression [7]. In addition, both cold restraint and intracisternal TRH induced a vagal nicotinic activation of gastric myenteric neurons [8,9]. The influence of excitation of the Rpa on gastric mucosal lesions was examined in urethane-anesthetized rats pretreated with indomethacin. Kainic acid (12 ng/30 nl), delivered into the Rpa, increased gastric acid secretion and produced gastric lesions of the corpus mucosa. These lesions were completely prevented by atropine and bilateral microinjection of TRH antibody into the DMN. Microinjection of the TRH antibody into the hypoglossal nucleus or control antibody into the DMN did not modify the mucosal lesions induced by kainic acid into the Rpa [10]. Taken together, these anatomical and functional data suggest a possible role of TRH contained in the Rpa – DMN projections in the vagally mediated gastric mucosal lesion induced by CRS.
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2. Medullary TRH-induced gastric protection against mucosal lesions by strong irritants The stable TRH analog injected into the cisterna magna or DMN at doses subthreshold to stimulate gastric acid secretion was protected against ethanol-induced gastric lesions in conscious or anesthetized rats. The cytoprotective effect was expressed through the vagal cholinergic release of prostaglandin E2. In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin-sensitive afferent fibers and nitric oxide (NO), both of which mediate the associated increase in gastric mucosal blood flow (GMBF) [11]. Whether endogenous medullary TRH can mimic the protective action of central injection of TRH against ethanol-induced gastric injury was investigated in urethaneanesthetized rats. Kainic acid (25 pg/30 nl), at a dose subthreshold to increase acid secretion, microinjected into Rpa inhibited by 65.8% gastric damage induced by intragastric administration of 60% ethanol. No protective effect was observed when kainic acid was injected outside of Rpa. The cytoprotective effect was completely abolished by TRH antibody microinjected bilaterally into the DMN, vagotomy, atropine, indomethacin, capsaicin deafferentation and intravenous injection of CGRP antagonist (CGRP8 – 37) and peripheral NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Kainic acid injected into the Rpa, unlike outside sites, increased basal GMBF but not acid secretion. These results show that kainic acid injected into the Rpa at a dose that did not stimulate acid secretion, due to the inhibitory effect of prostaglandins, protects against ethanolinduced gastric injury through vagal-dependent activation of CGRP contained in capsaicin-sensitive afferents and NO-mediated gastric vasodilatory mechanisms [11 –13]. Taken together, these findings support a role of TRH-containing Rpa neurons projecting to the DMN in recruiting vagal cholinergic-dependent gastric cytoprotective mechanisms.
Fig. 1. Summary of possible mechanisms involving central TRH-induced gastric mucosal lesion and cytoprotection.
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H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
The dual action of medullary TRH on gastric integrity is mediated through activation of peripheral vagal-enteric nervous systems and cholinergic mechanisms. The outcome reflects the balance between the aggressive factors such as gastric acid, and contractions and protective factors including CGRP, NO and prostaglandins (Fig. 1).
3. Medullary TRH in the adaptive cytoprotection Previous studies indicate that the vagus participates in gastric adaptive cytoprotection whereby a mild irritant such as diluted alcohol into the stomach protects against gastric injury induced by subsequent exposure to a strong irritant. Data support an involvement of medullary TRH as part of brain mechanisms mediating adaptive gastric protection [14]. Injection of 0.6N and 1.0N HCl (as strong irritants) induced gastric lesions covering 23.1% and 37.8% of the corpus mucosa, respectively. Pretreatment with 0.35N HCl (as a mild irritant) resulted in 67.3% and 50.5% reductions in gastric lesions induced by 0.6N and 1.0N HCl, respectively. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody increased gastric lesions induced by 0.6N HCl to 32.2% and 42.9%, respectively, and completely abolished the protective effect of 0.35N HCl pretreatment. Control or peptide YY antibody injected intracisternally did not alter the gastric protection induced by mild acid [14]. Medullary sites activated by intragastric administration of mild and/or strong acid was investigated in conscious rats. Percentage of corpus mucosal lesions and c-fos, as a marker of activated neurons, immunoreactivity in the medulla was determined 75 min after orogastric administration of 1 ml of either vehicle or 0.35N HCl followed 15 min later by that of vehicle or 0.6N HCl. Oral 0.35N HCl significantly reduced by 99.2% the gastric mucosal injury induced by subsequent exposure to 0.6N HCl. About 1 ml of 0.35N HCl itself increased in fos positive cell count (nb/15 sections) in the nucleus tractus solitarius (NTS) (vehicle + vehicle: 253 (32); 0.35N HCl + vehicle: 803 (123), p < 0.05). Pretreatment with 0.35N HCl followed by 0.6N HCl increased in fos number in the DMN (vehicle + 0.6N HCl: 11.5 (2.8); 0.35N HCl + 0.6N HCl: 23.5 (4.4), p < 0.05), but did not affect that in the NTS. These results indicate that DVC, especially the DMN, is activated during adaptive cytoprotection [15]. These functional and neuroanatomical results suggest that vagal afferent nerves activated by gastric topical irritants influence neuronal activity in DMN neurons by releasing endogenous TRH leading to vagal-dependent gastric protection against the subsequent strong irritant.
4. Perspectives: implications of medullary TRH and stomach interactions Severe stress could lead to gastric mucosal lesions such as Cushing ulcer and Curling ulcer. It is also well known that mild stress improves the gastric resistance against subsequent stressful conditions. The experimental results described above may imply that the two aspects of stress-induced modulation of gastric mucosal integrity could be accounted for by the dual actions of endogenous medullary TRH on the stomach.
H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
77
Functional dyspepsia is defined as follows: at least 12 weeks, which need not be consecutive, within the preceding 12 months of: (1) persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen); (2) no evidence of organic disease that is likely to explain the symptoms; and (3) no evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel) [16]. Attempts to elucidate the etiology of functional dyspepsia have failed to produce consistent pathophysiological correlations even though many theories, including gastric motility dysfunction, psychological factors or neuroendocrinological disorders, have been postulated to explain the dyspeptic symptom(s). Recently, new concept has focused on the possibility that dyspepsia may develop from an altered visceral perception rather than from a primary gastric dysfunction. In particular, recent studies examined neuronal excitation in the brain stem and spinal cord after intragastric administration of HCl using in situ hybridization autoradiography for the immediate early gene c-fos. It was elegantly demonstrated that gastric challenge is signaled to the brainstem including the NTS, but not the spinal cord, through vagal afferents that are sensitive to acid but resistant to capsaicin, suggesting that the gastric acid-induced c-fos transcription in the brain stem is related to gastric chemonociception [17]. Taken together with our results, medullary TRH may play a role in nociceptive input through the vagal nerve-mediated emotion-affective component of pain. References [1] R.B. Lynn, M.S. Kreider, R.R. Miselis, Thyrotropin-releasing hormone-immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat, J. Comp. Neurol. 311 (1991) 271 – 288. [2] Y. Tache´, M. Yoneda, Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats, J. Clin. Gastroenterol. 17 (Suppl. 1) (1993) S58 – S63. [3] T. Garrick, M. Prince, H. Yang, G. Ohning, Y. Tache´, Raphe pallidus stimulation increases gastric contractility via TRH projections to the dorsal vagal complex in rats, Brain Res. 636 (1994) 343 – 347. [4] H. Yang, G. Ohning, Y. Tache´, TRH in dorsal vagal complex mediates acid response to excitation of raphe pallidus neurons in rats, Am. J. Physiol. 265 (1993) G880 – G886. [5] N. Basso, M. Bagarani, E. Pekary, A. Genco, A. Materia, Role of thyrotropin-releasing hormone in stress ulcer formation in the rats, Dig. Dis. Sci. 33 (1988) 819 – 823. [6] H. Yang, S.V. Wu, T. Ishikawa, Y. Tache´, Cold exposure elevates thyrotropin-releasing hormone gene expression in medullary raphe nuclei: relationship with vagally mediated gastric erosions, Neuroscience 61 (1994) 655 – 663. [7] H. Yang, P.-Q. Yuan, L. Wang, Y. Tache´, Activation of parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats, Neuroscience 95 (2000) 773 – 779. [8] M. Miampamba, H. Yang, K.A. Sharkey, Y. Tache´, Intracisternal TRH analog induces fos expression in gastric myenteric neurons and glia in conscious rats, Am. J. Physiol. 280 (2001) G979 – G991. [9] P.-Q. Yuan, Y. Tache´, M. Miampamba, H. Yang, Acute cold exposure induces vagally mediated fos expression in gastric myenteric neurons in conscious rats, Am. J. Physiol. 281 (2001) G560 – G568. [10] H. Kaneko, Y. Tache´, TRH in the dorsal motor nucleus of vagus is involved in gastric erosion induced by excitation of raphe pallidus in rats, Brain Res. 699 (1995) 97 – 102. [11] Y. Tache´, M. Yoneda, K. Kato, A. Kiraly, G. Suto, H. Kaneko, Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: central and peripheral mechanisms, J. Gastroenterol. Hepatol. 9 (1994) S29 – S35. [12] H. Kaneko, H. Yang, G. Ohning, Y. Tache´, Medullary TRH is involved in gastric protection induced by low dose of kainic acid into the raphe pallidus, Am. J. Physiol. 268 (1995) G548 – G552. [13] H. Kaneko, J. Kaunitz, Y. Tache´, Vagal mechanisms underlying gastric protection induced by chemical activation of raphe pallidus in rats, Am. J. Physiol. 275 (1998) G1056 – G1062.
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[14] H. Kaneko, K. Kato, G. Ohning, Y. Tache´, Medullary thyrotropin-releasing hormone mediates vagaldependent adaptive gastric protection induced by mild acid in rats, Gastroenterology 109 (1995) 861 – 865. [15] H. Kaneko, L. Wang, K. Kato, Y. Tache´, Role of medullary thyrotropin-releasing hormone (TRH) in vagally-mediated adaptive cytoprotection in rats, Gastroenterology 108 (1995) A980. [16] N.J. Tally, V. Stanghellini, R.C. Heading, K.L. Koch, J.R. Malagelada, G.N. Tytgat, Functional gastroduodenal disorders, Gut 45 (Suppl. II) (1999) II34 – II42. [17] R. Schuligoi, M. Jocic, A. Heinemann, E. Schoninkle, M.A. Pabst, P. Holzer, Gastric acid-evoked c-fos messenger RNA expression in rat brainstem is signaled by capsaicin-resistant vagal afferents, Gastroenterology 115 (1998) 649 – 660.
Role of medullary TRH in brain–gut interaction-mediated gastric integrity Hiroshi Kaneko a,*, Yvette Tache´ b a
Department of Internal Medicine, Division of General Medicine, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute, Aichi-gun, Aichi 480-1195, Japan b CURE/Digestive Diseases Research Center, VA Los Angeles Greater Health Care System, Department of Medicine, Digestive Disease Division and Brain Research Institute, University of California-Los Angeles, Bldg. #115, Rm. #203, West Los Angeles VA Medical Center, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA
Abstract Kainic acid delivered into the raphe pallidus (Rpa) in the medulla increased gastric acid secretion and produced gastric mucosal lesions, which were completely prevented by bilateral microinjection of TRH antibody into the dorsal motor nucleus of the vagus (DMN) in rats. These findings indicated that endogenous TRH action on the DMN may contribute to gastric mucosal lesions. On the contrary, endogenous TRH at a subthreshold dose increasing gastric acid secretion alleviates gastric injury induced by intragastric administration of a strong irritant. The dual action of the medullary TRH on gastric integrity is mediated through activation of peripheral vagal-enteric nervous systems and cholinergic pathways. The outcome reflects the balance between peripheral aggressive and protective factors recruited by the level of vagal cholinergic activation. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody by itself increased gastric injury induced by a strong irritant and completely abolished the protective effect of a mild irritant pretreatment in rats. The number of c-fos protein-positive cells in the DMN increased in the process of the adaptive cytoprotection. These results suggest that vagal afferent nerves activated by gastric topical irritant act on DMN by releasing endogenous TRH to induce gastric protection against the subsequent strong irritant. Medullary TRH and gastric vagal efferent and afferent circuits may play a crucial role in the modulation of gastric integrity. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Gastric mucosal lesion; Gastric cytoprotection; Medulla; TRH; Vagus
Abbreviations: TRH, thyrotropin-releasing hormone; DMN, dorsal motor nucleus of the vagus; CRS, cold restraint stress; Rpa, raphe pallidus; GMBF, gastric mucosal blood flow; CGRP, calcitonin gene-related peptide; NO, nitric oxide; NTS, nucleus tractus solitarius of the vagus; DVC, dorsal vagal complex. * Corresponding author. Tel.: +81-561-62-3311x2179; fax: +81-561-62-1570. E-mail addresses: [email protected] (H. Kaneko), [email protected] (Y. Tache´). 0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 6 8 0 - 5
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H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
Since Hans Selye’s report establishing that gastric ulcer occurs under chronic stressful conditions, a plethora of investigations have been performed to unravel mechanisms underlying stress-induced gut lesions. Molecules and their receptors involved in the stress response are being characterized. On the one hand, mechanisms by which information is conveyed from the stomach to the brain have been examined in the context of viscerosensibility. In this review, the role of thyrotropin-releasing hormone (TRH) was selected among several stress-related peptides.
1. Medullary TRH-induced gastric mucosal lesions Compelling evidence indicates that medullary TRH participates in the vagal regulation of gastric function. TRH-immunoreactive nerve terminals and fibers and a high concentration of TRH receptors are localized in the dorsal vagal complex (DVC) [1]. The dense network of TRH immunoreactive fibers in the DVC arises from TRH-containing cell bodies located exclusively in the medulla, namely, the raphe pallidus (Rpa), raphe obscurus and the parapyramidal region of the ventral medulla [1]. The functional significance of these pathways was demonstrated by the fact that TRH or the stable TRH analog, RX77368, microinjected into the dorsal motor nucleus of the vagus (DMN) induces vagal cholinergicmediated stimulation of gastric secretory and motor function and hemorrhagic lesions [2]. Furthermore, activation of the Rpa neurons induced a vagal muscarinic-dependent stimulation of gastric acid secretion and contractility in rats. These gastric responses were blocked by bilateral microinjection of a specific TRH antibody into the DMN [3,4]. Cold restraint stress (CRS) is well-established experimental model to induce stressrelated corpus mucosal erosions with hemorrhage in rats. Aggressive factors such as increase in gastric acid, pepsin and high amplitude contractions have been reported to be responsible for gastric lesion formation. Converging evidence supports a role of medullary TRH in the gastric pathophysiology elicited by CRS exposure. First, TRH or TRH analog microinjected into the cisterna magna or DMN induced the similar gastric injury as CRS and both were prevented by the immunoneutralization with TRH antibody injected centrally [2,5]. Second, cold restraint increases TRH gene expression in the medulla and cell bodies expressing TRH as shown by Northern blot analysis in situ hybridization [6,7]. Third, cold restraint activates TRH containing cell bodies in the medulla, which was assessed by double labeling with fos and TRH preprohormone expression [7]. In addition, both cold restraint and intracisternal TRH induced a vagal nicotinic activation of gastric myenteric neurons [8,9]. The influence of excitation of the Rpa on gastric mucosal lesions was examined in urethane-anesthetized rats pretreated with indomethacin. Kainic acid (12 ng/30 nl), delivered into the Rpa, increased gastric acid secretion and produced gastric lesions of the corpus mucosa. These lesions were completely prevented by atropine and bilateral microinjection of TRH antibody into the DMN. Microinjection of the TRH antibody into the hypoglossal nucleus or control antibody into the DMN did not modify the mucosal lesions induced by kainic acid into the Rpa [10]. Taken together, these anatomical and functional data suggest a possible role of TRH contained in the Rpa – DMN projections in the vagally mediated gastric mucosal lesion induced by CRS.
H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
75
2. Medullary TRH-induced gastric protection against mucosal lesions by strong irritants The stable TRH analog injected into the cisterna magna or DMN at doses subthreshold to stimulate gastric acid secretion was protected against ethanol-induced gastric lesions in conscious or anesthetized rats. The cytoprotective effect was expressed through the vagal cholinergic release of prostaglandin E2. In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin-sensitive afferent fibers and nitric oxide (NO), both of which mediate the associated increase in gastric mucosal blood flow (GMBF) [11]. Whether endogenous medullary TRH can mimic the protective action of central injection of TRH against ethanol-induced gastric injury was investigated in urethaneanesthetized rats. Kainic acid (25 pg/30 nl), at a dose subthreshold to increase acid secretion, microinjected into Rpa inhibited by 65.8% gastric damage induced by intragastric administration of 60% ethanol. No protective effect was observed when kainic acid was injected outside of Rpa. The cytoprotective effect was completely abolished by TRH antibody microinjected bilaterally into the DMN, vagotomy, atropine, indomethacin, capsaicin deafferentation and intravenous injection of CGRP antagonist (CGRP8 – 37) and peripheral NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Kainic acid injected into the Rpa, unlike outside sites, increased basal GMBF but not acid secretion. These results show that kainic acid injected into the Rpa at a dose that did not stimulate acid secretion, due to the inhibitory effect of prostaglandins, protects against ethanolinduced gastric injury through vagal-dependent activation of CGRP contained in capsaicin-sensitive afferents and NO-mediated gastric vasodilatory mechanisms [11 –13]. Taken together, these findings support a role of TRH-containing Rpa neurons projecting to the DMN in recruiting vagal cholinergic-dependent gastric cytoprotective mechanisms.
Fig. 1. Summary of possible mechanisms involving central TRH-induced gastric mucosal lesion and cytoprotection.
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H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
The dual action of medullary TRH on gastric integrity is mediated through activation of peripheral vagal-enteric nervous systems and cholinergic mechanisms. The outcome reflects the balance between the aggressive factors such as gastric acid, and contractions and protective factors including CGRP, NO and prostaglandins (Fig. 1).
3. Medullary TRH in the adaptive cytoprotection Previous studies indicate that the vagus participates in gastric adaptive cytoprotection whereby a mild irritant such as diluted alcohol into the stomach protects against gastric injury induced by subsequent exposure to a strong irritant. Data support an involvement of medullary TRH as part of brain mechanisms mediating adaptive gastric protection [14]. Injection of 0.6N and 1.0N HCl (as strong irritants) induced gastric lesions covering 23.1% and 37.8% of the corpus mucosa, respectively. Pretreatment with 0.35N HCl (as a mild irritant) resulted in 67.3% and 50.5% reductions in gastric lesions induced by 0.6N and 1.0N HCl, respectively. Subdiaphragmatic vagotomy or intracisternal injection of TRH antibody increased gastric lesions induced by 0.6N HCl to 32.2% and 42.9%, respectively, and completely abolished the protective effect of 0.35N HCl pretreatment. Control or peptide YY antibody injected intracisternally did not alter the gastric protection induced by mild acid [14]. Medullary sites activated by intragastric administration of mild and/or strong acid was investigated in conscious rats. Percentage of corpus mucosal lesions and c-fos, as a marker of activated neurons, immunoreactivity in the medulla was determined 75 min after orogastric administration of 1 ml of either vehicle or 0.35N HCl followed 15 min later by that of vehicle or 0.6N HCl. Oral 0.35N HCl significantly reduced by 99.2% the gastric mucosal injury induced by subsequent exposure to 0.6N HCl. About 1 ml of 0.35N HCl itself increased in fos positive cell count (nb/15 sections) in the nucleus tractus solitarius (NTS) (vehicle + vehicle: 253 (32); 0.35N HCl + vehicle: 803 (123), p < 0.05). Pretreatment with 0.35N HCl followed by 0.6N HCl increased in fos number in the DMN (vehicle + 0.6N HCl: 11.5 (2.8); 0.35N HCl + 0.6N HCl: 23.5 (4.4), p < 0.05), but did not affect that in the NTS. These results indicate that DVC, especially the DMN, is activated during adaptive cytoprotection [15]. These functional and neuroanatomical results suggest that vagal afferent nerves activated by gastric topical irritants influence neuronal activity in DMN neurons by releasing endogenous TRH leading to vagal-dependent gastric protection against the subsequent strong irritant.
4. Perspectives: implications of medullary TRH and stomach interactions Severe stress could lead to gastric mucosal lesions such as Cushing ulcer and Curling ulcer. It is also well known that mild stress improves the gastric resistance against subsequent stressful conditions. The experimental results described above may imply that the two aspects of stress-induced modulation of gastric mucosal integrity could be accounted for by the dual actions of endogenous medullary TRH on the stomach.
H. Kaneko, Y. Tache´ / International Congress Series 1241 (2002) 73–78
77
Functional dyspepsia is defined as follows: at least 12 weeks, which need not be consecutive, within the preceding 12 months of: (1) persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen); (2) no evidence of organic disease that is likely to explain the symptoms; and (3) no evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel) [16]. Attempts to elucidate the etiology of functional dyspepsia have failed to produce consistent pathophysiological correlations even though many theories, including gastric motility dysfunction, psychological factors or neuroendocrinological disorders, have been postulated to explain the dyspeptic symptom(s). Recently, new concept has focused on the possibility that dyspepsia may develop from an altered visceral perception rather than from a primary gastric dysfunction. In particular, recent studies examined neuronal excitation in the brain stem and spinal cord after intragastric administration of HCl using in situ hybridization autoradiography for the immediate early gene c-fos. It was elegantly demonstrated that gastric challenge is signaled to the brainstem including the NTS, but not the spinal cord, through vagal afferents that are sensitive to acid but resistant to capsaicin, suggesting that the gastric acid-induced c-fos transcription in the brain stem is related to gastric chemonociception [17]. Taken together with our results, medullary TRH may play a role in nociceptive input through the vagal nerve-mediated emotion-affective component of pain. References [1] R.B. Lynn, M.S. Kreider, R.R. Miselis, Thyrotropin-releasing hormone-immunoreactive projections to the dorsal motor nucleus and the nucleus of the solitary tract of the rat, J. Comp. Neurol. 311 (1991) 271 – 288. [2] Y. Tache´, M. Yoneda, Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats, J. Clin. Gastroenterol. 17 (Suppl. 1) (1993) S58 – S63. [3] T. Garrick, M. Prince, H. Yang, G. Ohning, Y. Tache´, Raphe pallidus stimulation increases gastric contractility via TRH projections to the dorsal vagal complex in rats, Brain Res. 636 (1994) 343 – 347. [4] H. Yang, G. Ohning, Y. Tache´, TRH in dorsal vagal complex mediates acid response to excitation of raphe pallidus neurons in rats, Am. J. Physiol. 265 (1993) G880 – G886. [5] N. Basso, M. Bagarani, E. Pekary, A. Genco, A. Materia, Role of thyrotropin-releasing hormone in stress ulcer formation in the rats, Dig. Dis. Sci. 33 (1988) 819 – 823. [6] H. Yang, S.V. Wu, T. Ishikawa, Y. Tache´, Cold exposure elevates thyrotropin-releasing hormone gene expression in medullary raphe nuclei: relationship with vagally mediated gastric erosions, Neuroscience 61 (1994) 655 – 663. [7] H. Yang, P.-Q. Yuan, L. Wang, Y. Tache´, Activation of parapyramidal region in the ventral medulla stimulates gastric acid secretion through vagal pathways in rats, Neuroscience 95 (2000) 773 – 779. [8] M. Miampamba, H. Yang, K.A. Sharkey, Y. Tache´, Intracisternal TRH analog induces fos expression in gastric myenteric neurons and glia in conscious rats, Am. J. Physiol. 280 (2001) G979 – G991. [9] P.-Q. Yuan, Y. Tache´, M. Miampamba, H. Yang, Acute cold exposure induces vagally mediated fos expression in gastric myenteric neurons in conscious rats, Am. J. Physiol. 281 (2001) G560 – G568. [10] H. Kaneko, Y. Tache´, TRH in the dorsal motor nucleus of vagus is involved in gastric erosion induced by excitation of raphe pallidus in rats, Brain Res. 699 (1995) 97 – 102. [11] Y. Tache´, M. Yoneda, K. Kato, A. Kiraly, G. Suto, H. Kaneko, Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: central and peripheral mechanisms, J. Gastroenterol. Hepatol. 9 (1994) S29 – S35. [12] H. Kaneko, H. Yang, G. Ohning, Y. Tache´, Medullary TRH is involved in gastric protection induced by low dose of kainic acid into the raphe pallidus, Am. J. Physiol. 268 (1995) G548 – G552. [13] H. Kaneko, J. Kaunitz, Y. Tache´, Vagal mechanisms underlying gastric protection induced by chemical activation of raphe pallidus in rats, Am. J. Physiol. 275 (1998) G1056 – G1062.
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