Figure 6. Schematic model of rotavirus-induced diarrhoea and vomiting.

Rotavirus non-structural protein 4 (NSP4) is released from infected enterocytes and stimulates enterochromaffin cells (ECs, one type of enteroendocrine cell) to release 5-hydroxytryptamine (5-HT)¹⁵, a neurotransmitter that regulates gastrointestinal motility and induces nausea and vomiting. 5-HT release can induce diarrhoea owing to the activation of 5-HT₃ receptors on intrinsic primary afferent nerves that compose the myenteric plexus¹⁵. The activation of nerves of the myenteric plexus increases intestinal motility and activates nerves that compose the submucosal plexus, which stimulates the release of vasoactive intestinal peptide (VIP) from nerve endings adjacent to crypt cells. These events, in turn, lead to diarrhoea by increasing cellular cAMP levels, which results in the secretion of sodium chloride (NaCl) and water into the intestinal lumen. Several lines of evidence support this model, including the attenuation of rotavirus-induced increased intestinal motility by an opioid receptor antagonist⁶⁰, the attenuation of rotavirus-induced diarrhoea by a VIP receptor antagonist in mice²¹⁶ and the secretion of water and electrolytes stimulated by VIP. In addition, enkephalins are endogenous morphine-like substances (opiates), which activate opioid receptors and therefore reduce the level of cAMP and might prevent this fluid secretion (not shown). Rotavirus infection can also activate the vomiting centre in the medulla oblongata of the brainstem, which comprises the reticular formation, nucleus tractus solitarius (NTS) and area postrema (AP). Rotavirus or NSP4 stimulates vagal afferents to the vomiting centre by release of 5-HT from ECs in the gut¹⁵, which, in turn, stimulates the vomiting reflex. Indeed, 5-HT₃ receptor antagonists are used to attenuate vomiting in children with acute gastroenteritis. ENS, enteric nervous system. Figure adapted with permission from REF. 217, Elsevier.