Search tips
Search criteria 


Logo of neuroscibullNeuroscience Bulletin
Neurosci Bull. 2007 March; 23(2): 75–82.
Published online 2008 February 1. doi:  10.1007/s12264-007-0011-4
PMCID: PMC5550590

Language: English | Chinese

Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats




To investigate the expression of motilin-immunoreactive neurons in the hypothalamus and the effect of central administration of erythromycin (EM) on the regulation of gastric motility in diabetic rats.


The motilin immunoreactive neurons in the hypothalamus and the hippocampus were detected by immunohistochemistry with rabbit anti-motilin polyclonal antibody. To measure the gastric motility, force transducers were surgically affixed to the gastric serosa. A microinjection syringe was connected via a plastic tube to an injection cannula, which was connected with a stainless steel guide cannula. The syringe was inserted into the right lateral cerebral ventricle for microinjecting the chemicals.


Diabetic mellitus was successfully induced in cohorts of rats. Motilin-immunoreactive neurons significantly increased in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in the diabetic rats. Intracerebroventricular (i.c.v.) administration of EM, a motilin receptor agonist, stimulated the gastric motility of diabetic rats. EM (91.56 nmol, i.c.v.) dose-dependently increased the amplitude by (174.82±48.62)% (P < 0.05), and increased the frequency by (70.43±27.11)% (P < 0.05) in 5 min. The stimulatory effect lasted more than 15 min to the end of the measurement, and can be blocked partially by the prior treatment of motilin receptor antagonist GM-109.


Motilin-immunoreactive neurons are increased in the PVN and SON of the hypothalamus in diabetic rats. Centrally administered EM may regulate gastric motility by binding to the central motilin receptors, and central motilin might be involved in regulation of gastric motility in diabetic rats.

Keywords: motilin, hypothalamus, erythromycin, gastrointestinal motility, diabetes mellitus, rats



以往的研究表明胃动素存在于大鼠的中枢神经系统, 在中枢注射胃动素具有促进清醒大鼠胃运动的作用。 但糖尿病大鼠中枢胃动素表达含量及中枢注射胃动素对糖尿病大鼠胃运动的潜在作用目前尚未报导。 本研究探索糖尿病大鼠胃动素免疫阳性神经元在下丘脑的表达, 观察侧脑室微量注射胃动素受体激动剂红霉素(erythromycin, EM)对正常和糖尿病大鼠胃运动的作用。


采用免疫组织化学方法测定下丘脑胃动素免疫阳性神经元的分布特征。 在胃窦浆膜层植入应力传感器, 测定清醒大鼠胃运动的幅度和频率。


糖尿病大鼠下丘脑室旁核和视上核胃动素免疫阳性神经元数量明显高于正常对照大鼠(P < 0.05)。 脑室内微量注射EM可以明显促进糖尿病大鼠的胃运动。 注射91.56 nmol的EM五分钟后, 大鼠胃窦运动幅度升高(174.82 ± 48.62)% (P < 0.05), 运动频率加快(70.43 ± 27.11)% (P < 0.05)。 在脑室内微量注射胃动素拮抗剂GM-109后, 再注射EM, 其促胃运动效应可被部分阻断。


糖尿病大鼠中枢胃动素对胃运动有一定的调制作用, 而且脑室内微量注射的EM是通过脑内的胃动素受体介导而发挥其促胃动力效应。

关键词: 胃动素, 下丘核, 红霉素, 胃运动, 糖尿病大鼠


[1] Itoh Z. Motilin and clinical application. Peptides. 1997;18:593–608. doi: 10.1016/S0196-9781(96)00333-6. [PubMed] [Cross Ref]
[2] Xu L., Depoortere I., Tang M., Peeters T.L. Identification and expression of the motilin precursor in the guinea pig. FEBS Lett. 2001;490:7–10. doi: 10.1016/S0014-5793(01)02125-1. [PubMed] [Cross Ref]
[3] Depoortere I., Van Assche G., Peeters T.L. Distribution and subcellular localization of motilin binding sites in the rabbit brain. Brain Res. 1997;777:103–109. doi: 10.1016/S0006-8993(97)01094-9. [PubMed] [Cross Ref]
[4] Feldman M., Schiller L.R. Disorders of gastrointestinal motility associated with diabetes mellitus. Ann Intern Med. 1983;98:378–384. [PubMed]
[5] Horowitz M., Maddox A.F., Wishart J.M., Harding P.E., Chatterton B.E., Shearman D.J. Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur J Nucl Med. 1991;18:229–234. doi: 10.1007/BF00186645. [PubMed] [Cross Ref]
[6] Chen J., McCallum R.W. Gastric slow wave abnormalities in patients with gastroparesis. Am J Gastroenterol. 1992;87:477–482. [PubMed]
[7] Peeters T.L. Erythromycin and other macrolides as prokinetic agents. Gastroenterology. 1993;105:1886–1899. [PubMed]
[8] Ueno N., Inui A., Asakawa A., Takao F., Tani S., Komatsu Y., et al. Erythromycin improves glycaemic control in patients with Type II diabetes mellitus. Diabetologia. 2000;43:411–415. doi: 10.1007/s001250051323. [PubMed] [Cross Ref]
[9] Peeters T.L. New motilin agonists: a long and winding road. Neurogastroenterol Motil. 2006;18:1–5. doi: 10.1111/j.1365-2982.2005.00749.x. [PubMed] [Cross Ref]
[10] Janssens J., Peeters T.L., Vantrappen G., Tack J., Urbain J.L., De Roo M., et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies. N Engl J Med. 1990;322:1028–1031. doi: 10.1056/NEJM199004123221502. [PubMed] [Cross Ref]
[11] Lin L., Ji M., Zhang H.J., Lin Z., Zhao Z.Q. Effect of erythromycin on gastric dysmotility and neuroendocrine peptides in rats with diabetes mellitus. Chin Med Sci J. 2005;20:176–180. [PubMed]
[12] Schmid R., Schusdziarra V., Allescher H.D., Bofilias I., Buttermann G., Classen M. Effect of motilin on gastric emptying in patients with diabetic gastroparesis. Diabetes Care. 1991;14:65–68. doi: 10.2337/diacare.14.1.65. [PubMed] [Cross Ref]
[13] Asakawa A., Inui A., Momose K., Ueno N., Fujino M.A., Kasuga M. Motilin increases food intake in mice. Peptides. 1998;19:987–990. doi: 10.1016/S0196-9781(97)00477-4. [PubMed] [Cross Ref]
[14] Tang M., Zhang H.Y., Jiang Z.Y., Xu L., Peeters T.L. Effect of central administration of motilin on the activity of gastricrelated neurons in brain stem and gastric motility of rats. Acta Physiol Sinica. 2000;52:416–420. [PubMed]
[15] Zhang A.J., Tang M., Jiang Z.Y. Administration of motilin into the lateral hypothalamus increases gastric antrum motility and activates the dorsal vagal complex in rats. Acta Physiol Sinica. 2002;54:417–421. [PubMed]
[16] Guan Y., Tang M., Jiang Z., Peeters T.L. Excitatory effects of motilin in the hippocampus on gastric motility in rats. Brain Res. 2003;984:33–41. doi: 10.1016/S0006-8993(03)03016-6. [PubMed] [Cross Ref]
[17] Bahnak B.R., Gold A.H. Effects of alloxan diabetes on the turnover of rat liver glycogen synthase. Comparison with liver phosphorylase. J Biol Chem. 1982;257:8775–8780. [PubMed]
[18] Nerurkar M.A., Satav J.G., Katyare S.S. Insulin-dependent changes in lysosomal cathepsin D activity in rat liver, kidney, brain and heart. Diabetologia. 1988;31:119–122. doi: 10.1007/BF00395559. [PubMed] [Cross Ref]
[19] Paxinos G., Watson C. The rat brain in stereotaxic coordinates. 4. New York: Academic Press; 1998.
[20] Federiuk I.F., Casey H.M., Quinn M.J., Wood M.D., Ward W.K. Induction of type-1 diabetes mellitus in laboratory rats by use of alloxan: route of administration, pitfalls, and insulin treatment. Comp Med. 2004;54:252–257. [PubMed]
[21] Momose K., Inui A., Asakawa A., Ueno N., Nakajima M., Kasuga M. Anxiolytic effect of motilin and reversal with GM-109, a motilin antagonist, in mice. Peptides. 1998;19:1739–1742. doi: 10.1016/S0196-9781(98)00131-4. [PubMed] [Cross Ref]
[22] Plotsky P.M. Hypothalamic secretion of somatostatin and growth hormone-releasing factor into the hypophysial-portal circulation is reduced in streptozotocin diabetic male rats. Neuroendocrinology. 1991;53:433–438. [PubMed]
[23] Leidy J.W., Jr, Cugini C.D., Jr, Driscoll H.K., Chertow B.S. Time course of hypothalamic growth hormone-releasing hormone and somatostatin content in streptozocin diabetic rats: evidence for early changes in hypothalamic regulation. Brain Res. 1995;681:84–90. doi: 10.1016/0006-8993(95)00288-2. [PubMed] [Cross Ref]
[24] Fu M., Li X., Zhang M., Xian Y. Increased expression of neuropeptide Y and its mRNA in STZ-diabetic rats. Chin Med J (Engl) 2002;115:690–695. [PubMed]
[25] Morris M.J., Pavia J.M. Increased endogenous noradrenaline and neuropeptide Y release from the hypothalamus of streptozotocin diabetic rats. Brain Res. 2004;1006:100–106. doi: 10.1016/j.brainres.2004.02.002. [PubMed] [Cross Ref]
[26] Poitras P., Trudel L., Lahaie R.G., Pomier-Layrargue G. Motilinlike-immunoreactivity in intestine and brain of dog. Life Sci. 1987;40:1391–1395. doi: 10.1016/0024-3205(87)90329-8. [PubMed] [Cross Ref]
[27] Xu L., Depoortere I., Thielemans L., Huang Z., Tang M., Peeters T.L. Sequence, distribution and quantification of the motilin precursor in the cat. Peptides. 2003;24:1387–1395. doi: 10.1016/j.peptides.2003.09.005. [PubMed] [Cross Ref]
[28] Nagase H., Nakajima A., Sekihara H., York D.A., Bray G.A. Regulation of feeding behavior, gastric emptying, and sympathetic nerve activity to interscapular brown adipose tissue by galanin and enterostatin: the involvement of vagal-central nervous system interactions. J Gastroenterol. 2002;37(Suppl14):118–127. [PubMed]
[29] Makarenko I.G., Meguid M.M., Gatto L., Chen C., Ugrumov M.V. Decreased NPY innervation of the hypothalamic nuclei in rats with cancer anorexia. Brain Res. 2003;961:100–108. doi: 10.1016/S0006-8993(02)03850-7. [PubMed] [Cross Ref]
[30] Rowland N.E., Farnbauch L.J., Robertson K.L. Brain muscarinic receptor subtypes mediating water intake and Fos following cerebroventricular administration of bethanecol in rats. Psychopharmacology (Berl) 2003;167:174–179. [PubMed]
[31] Xu L., Depoortere I., Vertongen P., Waelbroeck M., Robberecht P., Peeters T.L. Motilin and erythromycin-A share a common binding site in the third transmembrane segment of the motilin receptor. Biochem Pharmacol. 2005;70:879–887. doi: 10.1016/j.bcp.2005.06.022. [PubMed] [Cross Ref]

Articles from Neuroscience Bulletin are provided here courtesy of Springer