Possible Involvement of Endogenous 5-HT in Aggravation of Cerulein-Induced Acute Pancreatitis in Mice

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  • Hamada Kentaro
    UMN Pharma, Inc., Department of Pharmacology, Japan
  • Yoshida Masanori
    Department of Pharmacology, Graduate School of Medicine, Osaka City University, Japan Department of Neuroscience, Osaka Bioscience Institute, Japan
  • Isayama Hiroyuki
    Department of Gastroenterology, Faculty of Medicine, The University of Tokyo, Japan
  • Yagi Yoshiki
    UMN Pharma, Inc., Department of Pharmacology, Japan
  • Kanazashi Shuichi
    UMN Pharma, Inc., Department of Pharmacology, Japan
  • Kashihara Yasunari
    UMN Pharma, Inc., Department of Pharmacology, Japan
  • Takeuchi Koji
    Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Japan
  • Yamaguchi Isamu
    UMN Pharma, Inc., Department of Pharmacology, Japan

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The aim of the present study was to elucidate the pathogenic role of endogenous 5-HT in pancreatitis. Injections of cerulein at hourly intervals caused edematous pancreatitis in mice characterized by hyperenzymemia and histological alterations. While the cerulein-induced hyperenzymemia was attenuated in mice pretreated with p-CPA, a 5-HT depletor, it was exaggerated by the preferential 5-HT2A agonist (DOI), but not by the preferential 5-HT2B agonist (BW723C86) or the preferential 5-HT2C agonist (mCPP). Selective 5-HT2A antagonists (risperidone, spiperone, ketanserin, AMI-193, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT2C receptor as well, paralleled their reported pKi values at the 5-HT2A receptor. Selective 5-HT2B (SB204741) and 5-HT2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT2A/2B/2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pKi values at the 5-HT2A receptor. In another set of experiments, risperidone, but not SB204741 and SB242084, dose-dependently reversed the cerulein-induced histological alteration of the pancreas (inflammatory cell infiltration). These results suggest that endogenously released 5-HT activates 5-HT2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT2A antagonists may provide a new therapy for acute pancreatitis.<br>

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