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

Abstract

Abstract. 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-HT 2A agonist (DOI), but not by the preferential 5-HT 2B agonist (BW723C86) or the preferential 5-HT 2C agonist (mCPP). Selective 5-HT 2A antagonists (risperidone, spiperone, ketanserin, and MDL 11,939) dose-dependently attenuated the hyperenzymemia; and their potency order, excepting that of ketanserin which has considerable affinity at the 5-HT 2C receptor as well, paralleled their reported pK i values at the 5-HT 2A receptor. Selective 5-HT 2B (SB204741) and 5-HT 2C (SB242084) antagonists hardly affected the hyperenzymemia. Although the non-selective 5-HT 2A / 2B / 2C antagonists (metergoline, ritanserin, and methysergide) dose-dependently attenuated the hyperenzymemia, they were relatively less potent compared to their high pK i values at the 5-HT 2A 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-HT 2A receptors to aggravate cerulein-induced pancreatitis. We propose that selective 5-HT 2A antagonists may provide a new therapy for acute pancreatitis.

Impact of Muscarinic M3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients: A Case-Controlled Study

“…Another mechanism is antagonism of the 5-HT2C receptors, which can lead to weight gain and subsequent insulin resistance [16], although this effect is expected to be minor [17]. In addition, activities of 5-HT2A receptors (either agonism or antagonism) have been involved in insulin secretion and insulin resistance, but experimental studies [30–32] reported inconsistent findings. No antidepressants with 5-HT2A activation effects were used by our study population.…”

Serotonin regulates amylase secretion and acinar cell damage during murine pancreatitis

“…Specifically, lowering the endogenous 5-HT levels by temporarily inhibiting 5-HT synthesis or following depletion of platelets, the major store of circulating 5-HT, reduced the damage and inflammation of experimental AP 34 35. Moreover, administration of selective agonists and antagonists of different 5-HT receptors showed aggravating and protective effects, respectively, in the context of both acute and chronic pancreatitis, albeit discrepancies resulting from varying binding affinities and potentially undefined side effects of the used compounds were observed 34 36–39…”

Risperidone Attenuates Local and Systemic Inflammatory Responses to Ameliorate Diet-Induced Severe Necrotic Pancreatitis in Mice: It May Provide a New Therapy for Acute Pancreatitis

“…Although the 5-HT 2 receptor has now been classified into 5-HT 2A , 5-HT 2B , and 5-HT 2C subclasses, we have demonstrated recently that risperidone, spiperone, and ketanserin, which strongly block 5-HT 2A receptors (Bonhaus et al, 1995;Knight et al, 2004), attenuated the hyperenzymemia and histological alterations in the CIEP model, and their potency order paralleled their reported pK i values at the 5-HT 2A receptors but not those at 5-HT 2B and 5-HT 2C receptors (Hamada et al, 2007). Also in the present study, risperidone dose-dependently attenuated the serum IL-6 levels, plasma amylase/lipase levels, platelet counts, mortality, and histological alterations (edema, inflammatory cell infiltration, and necrosis) in the DINP model.…”

“…Because we have already shown that risperidone attenuates CIEP (Hamada et al, 2007), it may be reasonable to assume that risperidone ameliorates not only mild but also severe pancreatitis and that risperidone provides a new therapy for acute pancreatitis.…”

“…Using drugs of known selectivity at 5-HT 2 receptor subclasses, we have demonstrated that risperidone, spiperone, and ketanserin, which strongly block the 5-HT 2A receptors (Bonhaus et al, 1995;Knight et al, 2004) dose-dependently ameliorated cerulein-induced pancreatitis, and their potency order paralleled their reported pK i values at the 5-HT 2A receptors but not those at the 5-HT 2B and 5-HT 2C receptors (Hamada et al, 2007). It is interesting that metergoline, ritanserin, and methysergide, which act evenly on 5-HT 2A/2B/2C receptors (Knight et al, 2004) were less potent compared with their high pK i values at 5-HT 2A receptors.…”