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Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea

¹ Department of Virology, Swedish Institute for infectious Disease Control, 172 82 Solna, Sweden, and Department of Physiology, Box 432, S-405 30 Göteborg University, Göteborg, Sweden
² Department of Physiology, Box 432, S-405 30 Göteborg University, Göteborg, Sweden
³ Department of Virology, Swedish Institute for Infectious Disease Control, 172 82 Solna, Sweden, and Department of Molecular and Clinical Medicine, University of Linköping, Linköping, Sweden

Correspondence to:
Correspondence to:
Dr S Kordasti
Department of Molecular and Clinical Medicine, University of Linköping, 581 85 Linköping, Sweden; shirin.kordasti{at}nll.se

Background and aims: The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT₃) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea.

Methods: Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus.

Results: While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04–3.56), the 5-HT₃ receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe⁶,Leu¹⁷)-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31–2.9) (p<0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days; p<0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice.

Conclusions: Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea; observations that could imply new principles for treatment of this disease with significant global impact.

Abbreviations: CT, cholera toxin; ENS, enteric nervous system; NK-1, neurokinin 1; NK-1R–/–, neurokinin 1 receptor knockout mouse; NDD, total number of days with diarrhoea; RRV, rhesus rotavirus; 5-HT₃, serotonin 3; SP, substance P; VIP, vasoactive intestinal peptide

Keywords: rotavirus; enteric nervous system; diarrhoea; vasoactive intestinal peptide; serotonin

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