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Effects of Selective Blockade of 5-HT3 Receptors on Physiological Markers of Abdominal Pain in Conscious Dogs

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Experiments on conscious dogs addressed the effects of blockade of type 3 serotonin receptors on visceromotor reactions and changes in heart rate (HR) initiated by nociceptive distension of the rectum. Distension of the rectal walls with pressures of 20–60 mmHg were found not to produce significant changes in the electromyographic activity of the abdominal muscles or HR. Distension of the intestine with a pressure of 80 mmHg and greater produced marked visceromotor reactions (contractions of the abdominal muscles) and increases in HR (tachycardia), which are regarded as markers for the occurrence of pain sensations. Use of these indicators allowed the first demonstration in conscious dogs of the dose-dependent antinociceptive effect of blockade of 5-HT3 receptors with granisetron. Administration of granisetron at doses of 0.25, 0.5, and 1.0 mg/kg was accompanied by prolonged (at least 90 min) decreases in visceromotor reactions to nociceptive rectal distension by 33.6 ± 9.2%, 58.0 ± 8.6%, and 76.7 ± 5.5% of baseline, respectively. In turn, the inhibitory effect of granisetron on tachycardia induced by painful rectal stimulation was seen only immediately after administration. Thus, studies on conscious dogs demonstrated the antinociceptive effect of granisetron in relation to abdominal pain, which may be relevant in the development of pharmacological agents to treat pain in patients with irritable bowel syndrome.

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References

  1. V. Andresen and M. Camilleri, “Irritable bowel syndrome: recent and novel therapeutic approaches,” Drug, 66, 1073–1078 (2006).

    Article  CAS  Google Scholar 

  2. F. Azpiroz, M. Bouin, M. Camilleri, et al., “Mechanisms of hypersensitivity in IBS and functional disorders,” Neurogastroenterol. Motil., 19, Suppl. 1, 62–88 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. S. E. Banner and G. J. Sanger, “Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity,” Br. J. Pharmacol., 114, 558–562 (1995).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. S. E. Banner, M. Carter, and G. J. Sanger, “5-Hydroxytryptamine 3 receptor antagonists modulate a noxious visceral pseudoaffective reflex,” Neuropharmacology, 34, 263–267 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. S. C. Boike, B. Ilson, N. Zariffa, and D. K. Jorkasky, “Cardiovascular effects of i.v. granisetron at two administration rates and of ondansetron in healthy adults,” Am. J. Health Syst. Pharm., 54, 1172–1176 (1997).

    CAS  PubMed  Google Scholar 

  6. M. Bouin, V. Plourde, M. Boivin, et al., “Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds,” Gastroenterology, 122, No. 2, 1771–1777 (2002).

    Article  PubMed  Google Scholar 

  7. S. Bradesi, L. Lao, P. G. McLean, et al., “Dual role of 5-HT3 receptors in a rat model of delayed stress-induced visceral hyperalgesia,” Pain, 13, No. 1–2, 56–65 (2007).

    Article  Google Scholar 

  8. C. Brock, L. Arendt-Nelson, O. Wilder-Smith, and A. M. Drewes, “Sensory testing of the human gastrointestinal tract,” World J. Gastroenterol., 15, No. 2, 151–159 (2009).

    Article  PubMed Central  PubMed  Google Scholar 

  9. L. Bueno, F. De Ponti, M. Fried, et al., “Serotonergic and non-serotonergic targets in the pharmacotherapy of visceral hypersensitivity,” Neurogastroenterol. Motil., 19, Suppl. 1, 89–119 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. M. Buyukavci, H. Olgun, and N. Ceviz, “The effects of ondansetron and granisetron on electrocardiography in children receiving chemotherapy for acute leukemia,” Am. J. Clin. Oncol., 28, 201–204 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. F. B. Cakir, O. Yapar, C. Canpolat, et al., “Cardiac effects of granisetron in a prospective crossover randomized dose comparison trial support,” Care Cancer, 20, 2451–2457 (2012).

    Article  CAS  Google Scholar 

  12. M. Camilleri, “Serotonergic modulation of visceral sensation: lower gut,” Gut, 51, Suppl. I, i81–i86 (2002).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. R. M. Danzebrink and G. F. Gebhart, “Evidence that spinal 5-HT1, 5-HT2, and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat,” Brain Res., 538, No. 1, 64–75 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. M. Fayyaz and J. M. Lackner, “Serotonin receptor modulators in the treatment of irritable bowel syndrome,” Ther. Clin. Risk. Manag., 4, 41–48 (2008).

    PubMed Central  CAS  PubMed  Google Scholar 

  15. H. Gregersen, A. M. Drewes, B. P. McMahon, and D. Liao, “Balloon-distension studies in the gastrointestinal tract: Current role,” Dig. Dis., 24, 286–296 (2006).

    Article  PubMed  Google Scholar 

  16. J. Huang, A. D. Spier, and V. M. Pickil, “5-HT3a receptor subunits in the rat medial nucleus of the solitary tract: subcellular distribution and relation to the serotonin transporter,” Brain Res., 1028, 156–169 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. V. Jain, J. K. Mitra, G. P. Rath, et al., “A randomized, double-blinded comparison of ondansetron, granisetron, and placebo for prevention of postoperative nausea and vomiting after supratentorial craniotomy,” J. Neurosurg. Anesthesiol., 21, 226–230 (2009).

    Article  PubMed  Google Scholar 

  18. M. Kanazawa, M. Hongo, and S. Fukudo, “Visceral hypersensitivity in irritable bowel syndrome,” J. Gastroenterol. Hepatol., 26, Suppl. 3, 119–121 (2011).

    Article  PubMed  Google Scholar 

  19. D. Y. Kim and M. Camilleri, “Serotonin: a mediator of the brain-gut connection,” Am. J. Gastroenterol., 95, No. 10, 2698–2709 (2000).

    CAS  PubMed  Google Scholar 

  20. C. M. Kozlowski, A. Green, D. Grundy, et al., “The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat,” Gut, 46, 474–480 (2000).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. S. D. Kuiken, G. N. Tytgat, and G. F. Boeckxstaens, “Review article: drugs interfering with visceral sensitivity for the treatment of functional gastrointestinal disorders – the clinical evidence,” Aliment. Pharmacol. Ther., 21, No. 6, 633–651 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. A. Langlois, X. Pascaud, J. L. Junien, et al., “Response heterogeneity of 5-HT3 receptor antagonists in a rat visceral hypersensitivity model,” Eur. J. Pharmacol., 318, No. 1, 141–144 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. H. Mertz, B. Naliboff, J. Munakata, et al., “Altered rectal perception is a biological marker of patients with irritable bowel syndrome,” Gastroenterology, 109, No. 1, 40–52 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. A. Miranda, S. Peles, P. G. McLean, and J. N. Sengupta, “Effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia,” Pain, 126, No. 1–3, 54–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. M. Miura, D. C. Lawson, E. M. Clary, et al., “Central modulation of rectal distension induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist,” Dig. Dis. Sci., 44, 20–24 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. H. Monnikes, J. Ruter, M. Konig, et al., “Differential induction of c-fos expression in brain nuclei by noxious and non-noxious colonic distention: role of afferent C-fibers and 5-HT3 receptors,” Brain Res., 966, 252–264 (2003).

    Article  Google Scholar 

  27. M. Morales, E. Battenburg, and F. E. Bloom, “Distribution of neurons expressing immunoreactivity for the 5-HT3 receptor subtype in the rat brain and spinal cord,” J. Comp. Neurol., 402, 385–401 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. O. Morteau, V. Lulia, C. Eeckhout, and L. Bueno, “Influence of 5-HT3 receptor antagonists in visceromotor and nociceptive responses to rectal distension before and during experimental colitis in rats,” Fundam. Clin. Pharmacol., 8, 553–562 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. H. E. Moss and G. J. Sanger, “The effects of granisetron, ICS 205–930 and ondansetron on the visceral pain reflex induced by duodenal distension,” Br. J. Pharmacol., 100, 497–501 (1990).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. R. M. Navari and J. M. Koeller, “Electrocardiographic and cardiovascular effects of the 5-hydroxytryptamine3 receptor antagonists,” Ann. Pharmacother., 37, 1276–1286 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. T. J. Ness and G. F. Gebhart, “Colorectal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudoaffective reflexes in the rat,” Brain Res., 450, 153–169 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. F. G. Pinarli, M. Elli, A. Dagdemir, et al., “Electrocardiographic findings after 5-HT3 receptor antagonists and chemotherapy in children with cancer,” Pediatr. Blood Cancer, 47, 567–571 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. A. Prior and N. W. Read, “Reduction of rectal sensitivity and postprandial motility by granisetron, a 5-HT3-receptor antagonist, in patients with irritable bowel syndrome,” Aliment. Pharmacol. Ther., 7, 175–180 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. J. Ritchie, “Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome,” Gut, 14, No. 2, 125–132 (1973).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. D. R. Robinson and G. F. Gebhart, “Animal models of visceral pain,” in: Chronic Visceral and Abdominal Pain, Informa Healthcare USA Inc., New York (2007), pp. 107–125.

    Google Scholar 

  36. M. I. Smith, S. E. Banner, and G. J. Sanger, “5-HT4 receptor antagonism potentiates inhibition of intestinal allodynia by 5-HT3 receptor antagonism in conscious rats,” Neurosci. Lett., 271, 61–64 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. R. Spiller, “Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease,” Neurogastroenterol. Motil., 19, Supplement 2, 25–31 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. M. Thumshirn, B. Coulie, M. Camilleri, et al., “Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome,” Aliment. Pharmacol. Ther., 14, No. 7, 869–878 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. K. Tsukamoto, T. Kurihara, N. Nakayama, et al., “Pressor responses to serotonin injected into the nucleus tractus solitarius of Sprague–Dawley rats and spontaneously hypertensive rats,” Clin. Exp. Hypertens., 22, 63–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Y. Wang, A. Ramage, and D. Jordan, “Presynaptic 5-HT3 receptors evoke an excitatory response in dorsal preganglionic neurons in anaesthetized rats,” J. Physiol., 509, 683–694 (1998).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia

    S. S. Panteleev, I. I. Busygina & O. A. Lyubashina

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  1. S. S. Panteleev
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  2. I. I. Busygina
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  3. O. A. Lyubashina
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Correspondence to S. S. Panteleev.

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Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 99, No. 4, pp. 471–483, April, 2013.

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Panteleev, S.S., Busygina, I.I. & Lyubashina, O.A. Effects of Selective Blockade of 5-HT3 Receptors on Physiological Markers of Abdominal Pain in Conscious Dogs. Neurosci Behav Physi 45, 263–270 (2015). https://doi.org/10.1007/s11055-015-0066-z

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  • DOI: https://doi.org/10.1007/s11055-015-0066-z

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