The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

Abstract

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.

Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases

“…human, Cynomologousmonkey, marmoset), Carnivora (dog, cat, ferret), Cetartiodactyla (e.g. pig, sperm whale), and Insectivora (e.g., house musk shrew, Suncus murinus), and it is also present throughout the Vertebrates, being demonstrated in prototypical fish, amphibia, reptiles and birds (Andrews et al, 1990King, 1990;Sims et al, 2000;Tanihata et al, 2004). A discussion of the vomiting mechanisms in these non-mammalian species is beyond the scope of the current paper.…”

“…It should also be noted that although rats do not vomit to intragastric stimuli that evoke emesis in susceptible species (e.g. ferret) (Andrews et al, 1990), rats do respond to stimuli such as veratridine and high concentrations of KCl and NaCl by markedly delaying gastric emptying (see Fig. 1).…”

Chemotherapy-Induced Nausea and Vomiting: The Importance of Acute Antiemetic Control

“…All three agents licensed for use in the U.S. are available in both injectable and oral formulations; however, only granisetron and ondansetron are indicated for use with highly emetogenic chemotherapy by the oral route. Data from animal studies have shown that the oral formulation reaches the gut directly, is absorbed across the proximal gut mucosa, and is immediately available to bind with 5-HT 3 receptors on the vagal afferent neurons [37,38]. Oral antiemetics can be more convenient for patients and may allow reductions in nursing time, in contrast with intravenous administration of the same agents [39].…”

Effects of Fractionated Abdominal Irradiation on Small Intestinal MotilityStudies in a Novel In Vitro Animal Model

“…In common with dogs, the gastrointestinal tract of the ferret shows many similarities with humans. In addition, ferrets are robust and have previously been used to investigate the effects of ionising radiation (16). During the current study, the animals showed a high tolerance to repeated anaesthesia and although they developed diarrhoea and lost weight consistent with radiation enteritis, no animal required euthanasia.…”

“…Until recently acute radiation enteritis has been considered to be due entirely to mucosal injury, but recent studies in humans have demonstrated that abnormally rapid small intestinal transit occurs frequently following therapeutic irradiation and that this correlates with changes in small intestinal absorptive function (5,6,16). Studies in animals following single doses of radiation have shown that this is also associated with rapid intestinal transit (7).…”