A few questions I had going into the International Conference on Nausea and Vomiting organized by Charles Horn and Bill Yates in Pittsburgh. It was an excellent small conference, and while I did not get all the answers I was looking for, I got plenty of questions (even better than answers!)
What is the mechanism by which glucocorticoids (still the best therapy) attenuate N&V?
Yes, dexamethasone is still one of the best therapies, alone or in combination with 5HT-3 and NK1 antagonists. No one addressed any mechanism for this, however, and a cursory literature search suggests that no-one knows the mechanism.
What is the mechanism of delayed emesis (vs. acute emesis)? Is it a form of neuronal plasticity, or a delayed manisfestion of chemotherapy toxicity?
Delayed emesis is clearly a problem. While older 5HT3 antagonists like odansetron + dex are very good at controlling acute CINV, there was considerable discussion of the efficacy of various 5HT3 antagonists and NK1 antagonists plus dex to block delayed emesis. Palonsetron, a very high affinity 5HT3 antagonist + dex was good at blocking delayed emesis, and odansetron + aprepitant (NK1 antagonist) + dex very good at blocking delayed emesis. (although better at emesis control than nausea). (Gralla; see also Rojas on cellular 5HT3-NK1 interactions). But there was no discussion of why delayed emesis is delayed.
Are women overall more susceptible to N&V, and if so why?
Overwhelmingly women seem more susceptible in almost all models (although there were a few models in which women were no more susceptible than men.) There was no discussion of why they might be more susceptible, even at the level of correlations with puberty, menstrual cycle, or menopause. There are many systems wide open for investigation at the sex steroid level, however: (e.g. 5HT3/NK1 receptor modulation by estradiol, for starters).
Do the same receptors or neural networks subserve nausea and emesis? Or are there independent sites of stimulation and processing?
Gratifyingly, convergence or independence of N vs V was recognized as a big issue, both clinically (where we have good control on emesis but not so much nausea) and neurologically (where we have some notion of the central pattern generators underlying emesis, but not so much the pathways subserving subjective experience of nausea. Distressingly, there was rampant introspection, anthropomorphism, and down-right reification of nausea throughout the conference — predictably in discussions of animals, but I think contaminatory of the human discussion as well.
Why does vestibular perturbation induce the same symptoms as GI perturbation, or at least the same outputs of N &V ?
This issue, perhaps more of evolutionary interest, was not raised, but rather just taken for granted that vestibular pertubation either by provocative motion or optokinetic stimulation, induces N&V. I still don’t see any a priori reason for a coupling of vestibular and GI perturbations. There are plenty of other interceptive stimuli which don’t induce nausea and vomiting (e.g. cold stress). Although it could be argued that N&V is a final common stress output, its hard to see why the vestibular system has a privileged access to N&V circuits.
How does vestibular stimulation lead to wakefulness?
This was not addressed, although it would be interesting (and probably someone has some data), as to how much sleep is fragmented by occurrence of nausea or urge to vomit at night. (Or is there a pronounce circadian rhythm?) Bill Yates to mention the need to address the opposite phenomenon — the influence of consciousness on susceptibilty to N&V and vestibular responses in general.
Why is nausea an oscillatory phenomenon?
This was acknowledged by some speakers, but no mechanism was suggested. Bovbjerg’s call for more Ecological Momentary Assessment was the closest thing to a discussion of the episodic bout structure of nausea and concomitant emesis. Seems wide open, though.
Is there a gold standard for measuring “nausea” in animals?
This is a trick question, of course, as we can neither confirm nor deny the subjective experience of nausea. Nonetheless, a robust model with both face and construct validity is essential. Among the physiological correlates mentioned (aside from the relentless promotion of emesis itself, no doubt the influence of Charles Horn and the Shrew People): salivation, gastric dysrhythmias, plasma vasopressin (would that be oxytocin in rodents?), skin conductance, anorexia, pica, and gaping. Of these, I was most impressed with the correlations of gastric dysrhythmias with a variety of N&V models (including pregnancy) and its treatment (Koch from Wake Forest). Unfortunately no animal work with electrogastrograms was presented, but there is probably some out there.
Best model of pica in rodents?
Given my recent difficulties getting pica in guinea pigs with either acute or chronic lithium, I really wanted to answer this question. Matt Hayes from Penn was very helpful: he suggested that it was hard to induce pica with lithium (citing Steve Woods as an authority), but he said cisplatin and exendin-4 gave very good pica. In particular, he showed data that exendin-4 causes accelerating kaolin intake in rats. Good to know (although he had no explanation for why, really). Hayes used the fact that exendin-4 induces persistent pica as evidence for nausea-induction by GLP-1 agonists, although if the classical “nausea-inducing” agents like lithium fail to induce pica I’m not sure how to conclude that. Perhaps exendin-4 reduces appetite for caloric stuff, but rodents still have an urge to gnaw and consume non-nutritive stuff?