We have all suffered from nausea and vomiting. In the midst of severe nausea, our world view changes to the extent that nausea becomes our dominant experience. Perhaps that is why in English the expression to be sick is synonymous with nausea and vomiting. Nausea and vomiting often arise secondarily to other common diseases and as side effects of medical therapy. Despite the totality of suffering engendered by the experience of nausea and vomiting, relatively little attention has been paid to diagnosis and treatment. Most clinicians prescribe medications such as prochlorperazine (Compazine) or promethazine (Phenergan) for nausea of any etiology with a "one size fits all" mentality. In fact, as more is learned about the pathophysiology of nausea and vomiting, the better therapy can be tailored to a specific cause. So doing will allow better palliation and avoid unwanted side effects.

Why Do We Experience Nausea and Vomiting?

Most animal research on nausea is performed on ferrets, apparently one step up the evolutionary tree from rodents, which do not vomit.

Nausea and vomiting, unpleasant as they are, serve important purposes. They protect us from ingesting toxic substances, an evolutionary advantage. Our senses of sight, smell, and taste can serve to protect us from eating substances that might be bad for us. A useful rule of thumb is that if something looks gross or smells or tastes awful, it probably is. Unfortunately, looks, smell, and taste can sometimes be deceiving, so we may still eat something poisonous. If ingested, a toxic substance may irritate the stomach or intestine, stimulate special chemoreceptors, and cause vomiting, thus limiting absorption of the poison, but even this is not adequate protection. Some toxins may get through these safeguards. The brain has a variety of receptors that test for potential toxins. Stimulation of these receptors triggers nausea and vomiting, preferably in time to limit further ingestion of poison. Memory also serves as a protective mechanism. If eating something made you sick before, it probably will do so again. The memory of nausea and vomiting associated with that substance would itself be a potent stimulus for nausea, overcoming hunger. In this sense nausea and vomiting helped our species survive over millennia.

Unfortunately, nausea arises with certain illnesses and secondarily to certain therapies in ways that offer no survival advantage. Indeed, nausea and vomiting in such cases may increase the morbidity and mortality of illness through dehydration, electrolyte imbalance, and limitation of food intake.

Pathophysiology of Nausea and Vomiting

Good evidence exists that various stimuli that affect nausea and vomiting come together in an area in the brain known as the vomit (or emetic) center in the medulla. This "center" is not a discrete nucleus, but a complex array of neurons coordinated by a "central pattern generator."1 Still, for our purpose, it is useful to think of a final pathway that gives rise to vomiting. The vomit center receives input from four major areas: the GI tract, the chemoreceptor trigger zone, the vestibular apparatus, and the cerebral cortex. (The center also has intrinsic chemoreceptors that can modulate, stimulate, and repress nausea.)2,3 Each of these four areas responds to certain types of stimuli, modulated by specific neurotransmitters that bind specific receptors. Understanding how these areas modulate nausea and vomiting helps us tailor specific therapies for specific problems.

The GI tract

As the primary source of toxin absorption is the gut, the effect of the GI tract on the vomit center is complex. Stimulation of the gut chemoreceptors and stretch receptors triggers nausea and vomiting via vagal nerve afferents and afferent fibers associated with the sympathetic nervous system. Serotonin, acetylcholine, histamine, and substance P are major neurotransmitters involved in stimulating these receptors. Chemoreceptors in the gut appear to be major mediators of the toxic effect of certain chemotherapeutic agents, such as cisplatin, even when such drugs are given intravenously via binding to 5HT 3 receptors. In addition to being a neurotransmitter that stimulates nausea, acetylcholine also increases gut motility and gut secretion. Histamine mediates transmission of nausea via the vagus nerve. Substance P binds neurokinin 1 receptors in the gut (and directly in the vomit center in the brain).4,5

The chemoreceptor trigger zone (CTZ)

The CTZ senses chemicals in the blood. The CTZ is particularly sensitive to increasing blood levels of potentially toxic substances. If a toxic substance is detected, nausea is experienced and the vomit reflex initiated - hopefully before more toxin is absorbed. It is easy to understand the evolutionary advantage of such a failsafe. The brain detects an "alien" chemical. By itself, this is not so unusual - we have lots of peculiar non-self chemicals floating around in our bloodstreams. However, if the concentration of a chemical is rapidly rising, this could constitute a threat to our health - better to expel any residual substance in the stomach; better safe than dead. Two major neurotransmitters are involved - dopamine, acting on D 2 receptors, and serotonin, acting on 5HT 3 receptors. Different toxin responses are mediated through different neurotransmitters. Opioid-related nausea appears to be most related to stimulation of D 2 receptors. Understanding this has helped with selective blockage of specific receptors in specific disorders.

The vestibular apparatus

Motion and body position are sensed through the vestibular apparatus. Motion sickness, such as car sickness and seasickness, are mediated through the vestibular apparatus, as are inner-ear diseases, such as Meniere's disease. The vestibular apparatus may once have served as a sensor for certain neurotoxins (such as alcohol) that can produce disequilibrium. Stimulation of the vestibular apparatus by alcohol may provide a survival advantage in keeping our species from, literally, drinking ourselves to death. Stimulus of the vestibular apparatus is mediated largely through histamine and acetylcholine receptors.

The cerebral cortex

The cerebral cortex and associated structures in the limbic system modulate complex experiences such as taste, sight, and smell as well as memory (involved in anticipatory nausea) and emotion. Discrete neuropathways are less well understood. However, higher cortical effects are still important and can be extremely powerful in stimulating and suppressing nausea and vomiting.

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