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Replacing animals in the study of multi-system reflexes, such as nausea and emesis (vomiting), cough and gastro-oesophageal reflux disease (GORD) represents a substantial challenge. Multi-system reflexes have no single target tissue or organ and thus it has always been considered unfeasible to use anything other than conscious whole animals for studying these.
Nausea and emesis are common symptoms encountered in medicine either as symptoms of disease or side effects of treatments. They are also components of the body's defensive response to toxins ingested accidentally .
Nausea and emesis are complicated responses involving many central and peripheral nervous system inputs and pathways that often interact with each other. Integrating these inputs occurs within the brainstem and results in a number of effects including salivation, sweating, muscle contraction, retching and vomiting. Further activation of the cerebral hemispheres in humans leads to the sensation of nausea.
The past 25 years have seen a resurging interest in the basic and applied neuropharmacology of nausea and emesis in order to:
Due to the number of systems involved and remaining knowledge gaps regarding the neurophysiology/pharmacology of nausea and emesis, recreating these interactions without animals is extremely difficult.
Current research relies on a wide variety of mammalian species including cats, dogs, primates, ferrets, rodents and shrews. Not all species have a similar range of sensitivities to emetogenic agents to humans, so choosing the most appropriate species is complicated, and interpreting results is extremely difficult.
There are other concerns too: rats, the animals most commonly used in nausea and emesis studies, do not possess an emetic reflex. Research using these animals are based upon behavioural changes in response to emetogens such as ingesting non-nutritious substances (pica) and conditioned taste/flavour aversion/avoidance. However the specificity of these behaviours to nausea and emesis is questionable as they have also been reported in animals suffering pain.
While animal models of emesis have led to the development of some efficacious anti-emetic drugs, nausea still remains an untreated problem. Nausea is a subjective human sensation and there is considerable debate over what sensory experience an animal may have compared with humans when exposed to the same stimulus.
In July 2007, the NC3Rs hosted a workshop to explore opportunities to reduce and replace animals in nausea and emesis research. The workshop attracted international delegates from academia, industry, regulatory authorities and funding bodies. A review of the meeting, including recommendations for research priorities, has been published in the British Journal of Pharmacology, and is the subject of an accompanying Commentary article.
Further work is currently underway to explore the full potential of these solutions to reduce animal use, increase knowledge of nausea and emesis, and provide faster and enhanced development of medicines. This initiative may also have implications for the 3Rs in other areas such as coughing and gastro-oesophageal reflux disease.
For a printable PDF of the publications mentioned above, please contact Dr Anthony Holmes directly.
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