Ukr.Biochem.J. 2017; Volume 89, Issue 4, Jul-Aug, pp. 56-67


Role of peripheral dopaminergic system in the pathogenesis of experimental colitis in rats

A. I. Prysiazhniuk, M. P. Rudyk, T. M. Chervinska, T. V. Dovbynchuk,
I. V. Opeida, L. M. Skivka, G. M. Tolstanova

Taras Shevchenko National University of Kyiv, Ukraine;

Dopamine (DA) is produced and released by immune cells. Recent data pointed to DA as a key mediator between the nervous and immune systems. In the present study we tested the hypothesis that peripheral dopaminergic system plays a negative role in ulcerative colitis pathogenesis via the effect on activity of peripheral blood phagocytes. The study was conducted on male Wistar rats (170-200 g). The peripheral dopaminergic system was destroyed by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection (20 mg/kg, s.c., 4 times every 2 h). Colitis was induced by 0.1 ml 6% iodoacetamide enema. Rats were subjected to autopsy on the 18th day. We found that MPTP-treated rats had decreased levels of tyrosine hydroxylase, rate-limiting enzyme of DA synthesis, in colon but not in brain. The number and activity of colonic and peripheral blood granulocytes did not significantly differ in saline- and MPTP-treated rats with colitis. The decreased ROS production by monocytes; increased 1.8-fold the number of CD69 (an early activation marker) positive monocytes and 6-fold intensity of CD69 surface expression were observed in MPTP-treated rats vs. saline-treated rats during colitis. The CD14 (the endotoxin coreceptor of phagocytes) surface expression was 2-fold increased in MPTP-treated rats without colitis, but significantly decreased in both saline- and MPTP-treated rats with colitis. We showed for the first time that the destruction of peripheral dopaminergic neurons leads to the improvement of morphological signs of experimental colitis, which might be through the regulatory effect of dopaminergic system on monocytes phenotype and their respiratory burst activity.

Keywords: , , , , ,


  1. Pacheco R, Contreras F, Zouali M. The dopaminergic system in autoimmune diseases. Proceedings of ICI Milan. 2013; 2014: 132.
  2. Eisenhofer G, Aneman A, Friberg P, Hooper D, Fåndriks L, Lonroth H, Hunyady B, Mezey E. Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab. 1997 Nov;82(11):3864-71. PubMed, CrossRef
  3. Eaker EY, Bixler GB, Dunn AJ, Moreshead WV, Mathias JR. Dopamine and norepinephrine in the gastrointestinal tract of mice and the effects of neurotoxins. J Pharmacol Exp Ther. 1988 Feb;244(2):438-42. PubMed
  4. Eldrup E, Richter EA, Christensen NJ. DOPA, norepinephrine, and dopamine in rat tissues: no effect of sympathectomy on muscle DOPA. Am J Physiol. 1989 Feb;256(2 Pt 1):E284-7. PubMed
  5. Li ZS, Schmauss C, Cuenca A, Ratcliffe E, Gershon MD. Physiological modulation of intestinal motility by enteric dopaminergic neurons and the D2 receptor: analysis of dopamine receptor expression, location, development, and function in wild-type and knock-out mice. J Neurosci. 2006 Mar 8;26(10):2798-807. PubMed, CrossRef
  6. Seol IW, Kuo NY, Kim KM. Effects of dopaminergic drugs on the mast cell degranulation and nitric oxide generation in RAW 264.7 cells. Arch Pharm Res. 2004 Jan;27(1):94-8. PubMed, CrossRef
  7.  Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, Manseau EJ, Dasgupta PS, Dvorak HF, Mukhopadhyay D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med. 2001 May;7(5):569-74. PubMed, CrossRef
  8. Basu S, Sarkar C, Chakroborty D, Nagy J, Mitra RB, Dasgupta PS, Mukhopadhyay D. Ablation of peripheral dopaminergic nerves stimulates malignant tumor growth by inducing vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis. Cancer Res. 2004 Aug 15;64(16):5551-5. PubMed, CrossRef
  9. Chakroborty D, Sarkar C, Yu H, Wang J, Liu Z, Dasgupta PS, Basu S. Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Kruppel-like factor-2 expression in tumor endothelial cells. Proc Natl Acad Sci USA. 2011 Dec 20;108(51):20730-5. PubMed, PubMedCentral, CrossRef
  10. Gomez R, Gonzalez-Izquierdo M, Zimmermann RC, Novella-Maestre E, Alonso-Muriel I, Sanchez-Criado J, Remohi J, Simon C, Pellicer A. Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model. Endocrinology. 2006 Nov;147(11):5400-11. PubMedCrossRef
  11. Magro F, Vieira-Coelho MA, Fraga S, Serrão MP, Veloso FT, Ribeiro T, Soares-da-Silva P. Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci. 2002 Jan;47(1):216-24. PubMed
  12. Magro F, Fraga S, Ribeiro T, Soares-da-Silva P. Decreased availability of intestinal dopamine in transmural colitis may relate to inhibitory effects of interferon-gamma upon L-DOPA uptake. Acta Physiol Scand. 2004 Apr;180(4):379-86. PubMed, CrossRef
  13. Magro F, Cunha E, Araujo F, Meireles E, Pereira P, Dinis-Ribeiro M, Veloso FT, Medeiros R, Soares-da-Silva P. Dopamine D2 receptor polymorphisms in inflammatory bowel disease and the refractory response to treatment. Dig Dis Sci. 2006 Nov;51(11):2039-44. PubMed, CrossRef
  14. Tolstanova G, Deng X, Ahluwalia A, Paunovic B, Prysiazhniuk A, Ostapchenko L, Tarnawski A, Sandor Z, Szabo S. Role of Dopamine and D2 Dopamine Receptor in the Pathogenesis of Inflammatory Bowel Disease. Dig Dis Sci. 2015 Oct;60(10):2963-75.  PubMed, CrossRef
  15. Szabo S, Horner HC, Maull H, Schnoor J, Chiueh CC, Palkovits M. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat. J Pharmacol Exp Ther. 1987 Mar;240(3):871-8. PubMed
  16. Prysiazhniuk A., Dovbynchuk T., Kopiyak B., Kompanets I., Tolstanova G. The role of central and peripheral D2R receptors in the mechanism of colonic vascular permeability during experimental colitis in rats. Bull Taras Shevchenko Nat Univ Kyiv, Series: Probl Physiol Funct Regul. 2017; 1(22): 44-48.
  17. Anderson G, Noorian AR, Taylor G, Anitha M, Bernhard D, Srinivasan S, Greene JG. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp Neurol. 2007 Sep;207(1):4-12. PubMed, PubMedCentral, CrossRef
  18. Beregovyi SM, Chervinska TM, Dranitsina AS, Szabo S, Tolstanova GM. Redox-sensitive transcription factors Egr-1 and Sp1 in the pathogenesis of experimental gastric ulcer. Ukr Biochem J. 2015 Jul-Aug;87(4):70-7. PubMed, CrossRef
  19. Skivka LM, Fedorchuk OG, Rudyk MP, Pozur VV, Khranovska NM, Grom MY, Nowicky JW. Antineoplastic drug NSC631570 modulates functions of hypoxic macrophages. Tsitol Genet. 2013 Sep-Oct;47(5):70-82. PubMed
  20. Skivka LM, Fedorchuk OG, Susak YM, Susak MY, Malanchuk OM, Rudyk MP, Nowicky YW. Physical activity interferes with the immunomodulatory effect of the antineoplastic drug NSC631570. Curr Pharm Biotechnol. 2015;16(1):49-59. PubMed, CrossRef
  21. Shapiro H, Lutaty A, Ariel A. Macrophages, meta-inflammation, and immuno-metabolism. Sci World J. 2011;11:2509-29.  PubMed, PubMedCentral, CrossRef
  22. Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011 Mar;63(1):182-217.  PubMed, CrossRef
  23. Mezey E, Eisenhofer G, Hansson S, Harta G, Hoffman BJ, Gallatz K, Palkovits M, Hunyady B. Non-neuronal dopamine in the gastrointestinal system. Clin Exp Pharmacol Physiol Suppl. 1999 Apr;26:S14-22. PubMed
  24. Yamamoto C, Kawana E. Immunohistochemical detection of GABA in rat striatum by intraperitoneal injection of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Okajimas Folia Anat Jpn. 1991 Dec;68(5):271-82. PubMed, CrossRef
  25. Natale G, Kastsiushenka O, Fulceri F, Ruggieri S, Paparelli A, Fornai F. MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res. 2010 Oct 8;1355:195-206.  PubMed, CrossRef
  26. Ampe B, Anissa EA, Michotte Y, Sarre S. Dopaminergic Control of the Neurotransmitter Release in the Subthalamic Nucleus: Implications for Parkinson’s Disease Treatment Strategies. Etiology and Pathophysiology of Parkinson’s Disease. Ed. Prof. Abdul Qqyyum Rana. InTech, 2011. P. 421-433. CrossRef
  27. Kmieć Z, Cyman M, Ślebioda TJ. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci. 2017 Mar;62(1):1-16.  PubMed, CrossRef
  28. de Lange KM, Barrett JC. Understanding inflammatory bowel disease via immunogenetics. J Autoimmun. 2015 Nov;64:91-100.  PubMed, CrossRef
  29. Katsanos KH, Papadakis KA. Inflammatory Bowel Disease: Updates on Molecular Targets for Biologics. Gut Liver. 2017 Jul 15;11(4):455-463. PubMed, CrossRef
  30. Pinoli M, Marino F, Cosentino M. Dopaminergic Regulation of Innate Immunity: a Review. J Neuroimmune Pharmacol. 2017 Jun 3: 1-22. PubMed, CrossRef
  31. Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S. The immunoregulatory role of dopamine: an update. Brain Behav Immun. 2010 May;24(4):525-8.  PubMed, PubMedCentral, CrossRef
  32. Kumar V, Sharma A. Neutrophils: Cinderella of innate immune system. Int Immunopharmacol. 2010 Nov;10(11):1325-34. PubMed, CrossRef
  33. Yamazaki M, Matsuoka T, Yasui K, Komiyama A, Akabane T. Dopamine inhibition of superoxide anion production by polymorphonuclear leukocytes. J Allergy Clin Immunol. 1989 May;83(5):967-72. PubMed, CrossRef
  34. Trabold B, Gruber M, Fröhlich D. Functional and phenotypic changes in polymorphonuclear neutrophils induced by catecholamines. Scand Cardiovasc J. 2007 Jan;41(1):59-64. PubMed, CrossRef
  35. Radulovic K, Niess JH. CD69 is the crucial regulator of intestinal inflammation: a new target molecule for IBD treatment? J Immunol Res. 2015;2015:497056. PubMed, PubMedCentral, CrossRef
  36. Yamauchi K, Kasuya Y, Kuroda F, Tanaka K, Tsuyusaki J, Ishizaki S, Matsunaga H, Iwamura C, Nakayama T, Tatsumi K. Attenuation of lung inflammation and fibrosis in CD69-deficient mice after intratracheal bleomycin. Respir Res. 2011 Oct 5;12:131.  PubMed, PubMedCentral, CrossRef
  37. Bergquist J, Ohlsson B, Tarkowski A. Nuclear factor-kappa B is involved in the catecholaminergic suppression of immunocompetent cells. Ann N Y Acad Sci. 2000;917:281-9. PubMed, CrossRef
  38. Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell. 2015 Jan 15;160(1-2):62-73. PubMed, CrossRef

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