Date: April 4th, 2007

Speaker's Name and Affiliation:
Charles Horn, Ph.D.
Monell Chemical Senses

Title: "Why is the neurobiology of nausea and vomiting so important?"

Presiding Chair: Harry R. Kissileff, Ph.D.

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Harry Kissileff	Columbia/Obesity Research Center
Debra Zellner	Montclair State University
Janell Mensinger	SUNY Downstate
Ilene Bernstein	University of Washington
Laurence Nolan	Wagner College
Karen Acroff	Brooklyn College
Allan Geliebter	St. Luke's
Joe Vasselli	St. Luke's
Tony Sclafani	Brooklyn College
Chris Ochner	St. Luke's

Summary: (Provided by Speaker)

Nausea and vomiting are important as biological systems for drug side effects, disease co-morbidities, and defenses against food poisoning. Vomiting can serve the function of emptying a noxious chemical from the gut, and nausea appears to play a role in a conditioned response to avoid ingestion of offending substances. The sensory pathways for nausea and vomiting, such as gut and vestibular inputs, are generally defined but the problem of determining the brain's final common pathway and central pattern generator for nausea and vomiting is largely unsolved. A neurophysiological analysis of brain pathways provides an opportunity to more closely determine the neurobiology of nausea and vomiting and its prodromal signs (e.g., cold sweating, salivation).

Nausea and vomiting are commonly studied at pharmacological, behavioral, and psychological levels of analysis. These approaches are represented by a large literature of human clinical research highlighting the efficacy of various anti-emetic agents. Extensive work has also been conducted to demonstrate that treatments for disease do not have negative effects, such as nausea and vomiting, that might limit their clinical application. The current scarcity of research on the neurobiological basis of nausea and vomiting is striking considering its clinical importance

Discussion:

Q. You have lactose in your list under food "intolerances." I thought the story with lactose was that it affected the lower gut, and people who are lactose intolerant avoid foods with lactose because of the negative side effects. I was not aware that it resulted in nausea and vomiting.
A. I don't know the full story with lactose but the NIDDK claims that nausea is an important side effect of this condition.

Q. I notice that you do not have shock on your list of situations that might result in vomiting.
A. Yes, that could go up there as well. There are anecdotal reports of intense emotional stress causing emesis.

Q.Regarding the issue of motion and nausea, do you mean that the neural pathways aren't understood, or are you talking about a teleological explanation?
A. The reason (adaptive) advantages are not understood, but the neural pathways are known.

Q. Can the vagus nerve still mediate some of the vomiting responses when it is severed?
A. It is possible that the severed end might still be retain sensitive to emetogenic agents. This might explain the partial recovery of chemotherapy-induced emesis in animal models following vagotomy.

Q. Are those mostly central or peripheral receptors (those that play a role in emesis, CB1 & CB2 receptors in the cannabinoid system)?
A. The evidence supports a role for CB1 and CB2 in the hindbrain.

Q. Where does dexamethasone work?
A. It works on steroid receptors, but it is not known where. This could be central or peripheral. Few studies have investigated the sole action of steroids on nausea and emesis. It's quite possible that their potency has been grossly underestimates since they are usually combined with other treatments.

Q. Which drugs do people commonly take for motion sickness?
A. The histamine (H1) blockers and mucarinic (M) receptor blockers.

Q. What guides the development of anti-nausea or anti-emetic medications? How are these drugs developed?
A. Much of what is known came out of the basic animal physiology, and some of these medications were discovered by accident.

Q. What are some of the side effects of these medications?
A. Delirium is one side effect. Scopolamine has this problem.

Q. Will they prescribe them to pregnant women?
A. Sometimes yes, but only if there is intense nausea and vomiting.

Q. Is there any evolutionary theory why some animals have emetic reflexes while others do not?
A. No, but there seem to be large classes of animals that don't have these reflexes. However, rats and other animals in this class might have more highly evolved first order defenses, e.g., sensitivity to learning conditioned flavor aversions.

Q. Comment: There seem to be a lot of differences across humans and the correlation between motion and nausea and vomiting?
A. Yes, that's true. There are some racial and ethnic differences related to susceptibility to nausea and vomiting. Also, there are genetic variances in the neurotransmitter receptors involved in these responses, for example the 5-HT3 receptor.

Q. How do you distinguish regurgitation from emesis?
A. That's a good question, and it hasn't been investigated. Causal observation suggests that emesis is a more intense response.

Q. What about rodents. Do they have an emetic reflex?
A. No, but they might have a degenerative "emetic" response. They have a gagging reflex, and they will retch (or gag) upon administration of some medications, but this does not result in expulsion of gastric contents. However, please note that relatively few strains of rats, mice, guinea pigs, or hamsters (or rabbits) have been evaluated and with a limited set of emetogenic stimuli.

Q. Have studies been done with animals to study which types of substances they choose to consume when they are exhibiting pica?
A. Yes, one study compared clay, pebbles, and dirt and found that clay was the most consumed. This seems to make sense because clay can absorb toxins very well and therefore is the most beneficial response.

Q. How do you measure the intensity of emesis?
A. By the frequency of emetic and retching responses.

Q. If you repeated this experiment with the rat, would they sensitize over time (with repeated injections of kaolin)?
A. A recent study by Vera et al. showed heightened pica responses to cisplatin (a chemotherapy agent) injection with repeat doses.

Q. Does vomiting reduce the formation of a conditioned taste aversion?
A. I'm not sure how you would test that. But perhaps one could reason that if vomiting is a positive outcome perhaps a strong stimulus, producing emesis, might function less effectively as a US for the formation of CTA than a sub-threshold stimulus.

Q. What do you feed the suncus murinus?
A. We feed them cat chow and mink pellets.

Q. Are you looking for a hormonal response in the suncus that regulations the emetic response? Is oxytocin a good marker?
A. We don't know but we are currently considering these measures.