Chemoreceptor trigger zone

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The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area postrema, which is on the floor of the fourth ventricle and is outside of the blood–brain barrier. [1] It is also part of the vomiting center itself. [2] The neurotransmitters implicated in the control of nausea and vomiting include acetylcholine, dopamine, histamine (H1 receptor), substance P (NK-1 receptor), and serotonin (5-HT3 receptor). There are also opioid receptors present, which may be involved in the mechanism by which opiates cause nausea and vomiting. The blood–brain barrier is not as developed here; therefore, drugs such as dopamine which cannot normally enter the CNS may still stimulate the CTZ. [3]

Contents

Evolutionary significance

The CTZ is in the medulla oblongata, which is phylogenetically the oldest part of the central nervous system.[ citation needed ] Early lifeforms developed a brainstem, or inner brain, and nothing more.[ citation needed ] This part of the brain is responsible for basic survival instincts and reactions, for example to make an organism turn its head and look where an auditory stimulus was heard. The brainstem is where the medulla is located, and therefore also the area postrema and the CTZ. Then later lifeforms developed another segment of the brain, which includes the limbic system. This area of the brain is responsible for producing emotion and emotional responses to external stimuli, and also is significantly involved in memory and reward systems. Evolutionarily, the cerebral cortex is the most recent development. This area of the brain is responsible for critical thinking and reasoning, and is actively involved in decision making. It has been discovered that a major cause of increased intelligence in species including humans is the increase in cortical neurons in the brain. [4] The emetic response was selected for protective purposes, and serves as a safeguard against poisoning of the body. This response gets toxins and drugs out of the body by summoning control over motor neurons which stimulate muscles in the chest and thoracic diaphragm to expel contents from the stomach.

Chemoreception

Since the CTZ is located in the area postrema, a sensory circumventricular organ, it does not have a blood–brain barrier. [3] This means that large polar molecules, such as emetic toxins, can diffuse through to and reach the CTZ quite easily. This is because the medulla oblongata is located in the area of the brain, the most inferior portion, which does not have a robust and highly developed blood-brain barrier. Without this barrier, emetic drugs and toxins are free to interact with a receptor (biochemistry), or multiple receptors located in the CTZ. These receptors in the CTZ are called chemoreceptors because they interact with different types of chemicals which are usually referred to as neurotransmitters. These neurotransmitters implement their effects on the CTZ receptors by binding to them which sets off a chain of events which produces an action potential. Studies have shown that neurons in the CTZ increase their rate of firing when exposed to emetic substances. [3]

The CTZ has many different types of receptors, which are specific to different types of toxins or drugs that might be present in the bloodstream and thus that can affect the CTZ. Types of CTZ receptors include dopamine, serotonin, histamine, substance P, opioid, and acetylcholine receptors. It has been discovered that the cholinergic neurons are actually nicotinic. [5] These receptors are meant to monitor the amount of associated neurotransmitter of these receptors in the blood. For instance, the CTZ has opioid receptors that monitor the level of opioids in the blood, and when the amount of opioids in the blood reach a certain level, the opioid receptors in the CTZ will signal to the rest of the vomiting center to initiate vomiting. This is because the CTZ sends the "vomit" command through action potentials, and these specific action potentials that trigger emesis are only produced when a certain amount of opioids bind to a certain amount of opioid receptors in the CTZ. Neurons in the CTZ, and area postrema in general, actually have two types of receptors: those at the surface of the neuron and those that are located deeper down in the dendrites. [5]

The receptors on the surface of the neuron are chemoreceptors that are activated from direct contact of emetic substances in the blood, whereas the receptors that are deeper down on the dendrites are receptors that are activated in response to the activated chemoreceptors on the surface. [5]

Communication

The vomiting center of the brain refers to the groups of loosely organized neurons in the medulla that include the CTZ within the area postrema and the nucleus tractus solitarii. [2] One of the ways the chemoreceptor trigger zone implements its effects on the vomiting center is by activation of the opioid mu receptors and delta receptors. [6] The activation of these opioid receptors in the CTZ are especially important for patients who take opioid based pain medications on a regular basis. However, opioids do not play a role in communication to the vomiting center of the brain, they only induce communication. [6] Dopamine and serotonin have been found to play the biggest role in communication from the CTZ to the remainder of the vomiting center, as well as histamine. [6] Chemoreceptors in the CTZ relay information about the presence of emetic agents in the blood to the adjacent nucleus tractus solitarii (NTS). [7] The relaying happens by the initiation of an action potential, which is caused by the chemoreceptor causing a change in electric potential in the neuron it is embedded in, which then subsequently causes an action potential. This happens constantly, so the chemoreceptors in the CTZ are continually sending information about how much emetic agents are in the blood, even when emesis is not signaled for. The NTS is organized into subnuclei that direct many different functions relating to swallowing, gastric sensation, laryngeal and pharyngeal sensation, baroreceptor function, and respiration. [7] The NTS directs signals about these functions to a central pattern generator (CPG). This CPG actually coordinates the sequences of physical movements during emesis. The main neurotransmitters involved in communication between the CTZ and remaining vomiting center are serotonin, dopamine, histamine, and endogenous opioids which include endorphins, enkephalins, dynorphin.

The CTZ communicates with the other parts of the vomiting center through neurons that contain 5-HT3, D2, H1 and H2 receptors. [6] It has been seen that intraventricular administration of histamine in dogs causes an emetic response. [8] This shows that histamine plays a significant role in signaling for emetic action in the CTZ. Some classes of molecules have been shown to inhibit the emetic response due to histamine, these include mepyramine, burimamide and metiamide. [8]

Phosphodiesterases

Recent studies have found that phosphodiesterase 4 (PDE4) inhibitors, such as Rolipram, cause emesis as one of their side effects. [9] It has been found that these PDE4 isoforms are expressed in the CTZ and in the brainstem in general. [9] The mRNA products from genes that code for these PDE4 isoforms are plentiful in the CTZ, and not only located in CTZ neurons, but also in glial cells and blood vessels associated with the CTZ neurons. [9] PDE4 mRNAs are transcribed more in the area postrema and the CTZ than anywhere else in the brainstem. [9] The PDE4 degrades the phosphodiester bonds in the second messenger molecule cyclic adenosine monophosphate (cAMP), which is one of the ways the brain relays information. By modifying cAMP signaling in the CTZ, it is thought that this could mediate the emetic effects of PDE4 inhibitors in the CTZ. [9]

H-channels

Most of the neurons located in the CTZ express hyperpolarization-activated cation channels (H-channels). [10] Since the neurons in the CTZ convey information relating to emesis to the other parts of the vomiting center, it was thought that these H-channels might play a role in nausea and the emetic response. Recently, evidence of this notion that H-channels in CTZ neurons play a role in emesis has come to light. It has been found that ZD7288, which is a H-channel inhibitor, inhibited the acquisition of conditioned taste aversion (CTA) in rats and reduced apomorphine-induced c-Fos expression in the area postrema where the CTZ is located. [10] This suggests that the neurons that express H-channels in the CTZ and area postrema are involved in nausea and the emetic response. [10]

The vomiting center of the brain

This integrates the emetic response. This is the area in which "a final decision is made" about whether to evoke an emetic response. This decision is based heavily on the information which the CTZ relays to the rest of the vomiting center, but also the chemoreceptors in the GI tract, the information sent to the vomiting center by the vestibular system, and higher order centers located in the cortex. [6] The vomiting center is not a discrete or specific place in the brain, but rather an area consisting of many nuclei, axons, and receptors that together cause the physical changes necessary to induce vomiting. [6] Also, emesis can occur by direct neural stimulation of the vomiting center. [11]

Damage to the CTZ

Damage to the CTZ can come via stroke, physical injury, or over-excitation resulting in neuron death. Once the damage has occurred, the effects can cause the emetic response to disappear, or cause the emetic response to heighten, in some cases causing intractable vomiting that leave patients in severe distress. In cases such as these, if the damage is severe enough, little can be done to inhibit an intractable vomiting response because the chemoreceptors in the CTZ are physically damaged or hindered in some way. Recently, it has been discovered that physical changes in the area postrema and CTZ do cause or inhibit emesis. [12] Specifically, compression of blood vessels which are physically located near in or around the CTZ, and that result in physical compression of the area postrema as a whole, have been found to be the cause of chronic medically intractable emesis and weight loss. [12] Surgical microvascular decompression resulted in postoperative and long-term resolution of emesis. [12]

Antiemetic medications

Antiemetic medications often target the CTZ to completely inhibit or greatly reduce vomiting. Most of these work by not allowing certain blood-borne drugs (usually pain killers or stimulants) to bind to their respective receptors located in the CTZ. The antiemetic medications can block the binding site on a chemoreceptor in the CTZ, so that the emetic agent cannot bind to it to cause its emetic effects. [6] Another way that antiemetic medications can work is by binding to a chemoreceptor in the CTZ, but instead of initiate vomiting, the medication can cause the receptors to send signals to the other parts of the vomiting center that inhibit emesis. [6] Also, some anti-emetic medications work by lowering the amount of dopamine levels in the brain, which in turn effects how much dopamine comes in contact with dopamine receptors in the CTZ. Other antiemetic medications work similarly by lowering a different substance in the brain that is known to interact with chemoreceptors in the CTZ that cause emesis.

Antiemetic drugs coupled with pain relieving medications

Oftentimes, doctors will "pre-treat" patients who might exhibit emetic responses due to drugs they prescribe them. Usually pain relieving drugs such as opioids are co-prescribed with anti-emetic drugs to stop the emetic response due to the pain reliever before it can even mediate its effects on the CTZ. This way, the patient does not have to worry about the doctors prescription to treat their pain causing them to be in severe discomfort via vomiting.

Chemotherapy

Chemotherapy is a major cause of emesis, and often can cause severe and frequent emetic responses. This is because chemotherapy agents circulating in the blood activate the CTZ in such a way as to cause emesis. [13] Patients receiving chemotherapy are often prescribed antiemetic medications.

See also

Related Research Articles

Neurotransmitter Chemical substance that enables neurotransmission

Neurotransmitters are chemical messengers that transmit a signal from a neuron across the synapse to a target cell, which can be a different neuron, muscle cell, or gland cell. Neurotransmitters are chemical substances made by the neuron specifically to transmit a message.

Dopamine Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neurotransmitter that plays several important roles in the brain and body. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

Chlorpromazine Antipsychotic medication

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given by mouth, by injection into a muscle, or into a vein.

An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be used for severe cases of gastroenteritis, especially if the patient is dehydrated.

Substance P Chemical compound

Substance P (SP) is an undecapeptide member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

A chemoreceptor, also known as chemosensor, is a specialized sensory receptor cell which transduces a chemical substance to generate a biological signal. This signal may be in the form of an action potential, if the chemoreceptor is a neuron, or in the form of a neurotransmitter that can activate a nerve fiber if the chemoreceptor is a specialized cell, such as taste receptors, or an internal peripheral chemoreceptor, such as the carotid bodies. In physiology, a chemoreceptor detects changes in the normal environment, such as an increase in blood levels of carbon dioxide (hypercapnia) or a decrease in blood levels of oxygen (hypoxia), and transmits that information to the central nervous system which engages body responses to restore homeostasis.

The control of ventilation refers to the physiological mechanisms involved in the control of breathing, which is the movement of air into and out of the lungs. Ventilation facilitates respiration. Respiration refers to the utilization of oxygen and balancing of carbon dioxide by the body as a whole, or by individual cells in cellular respiration.

Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomiting, or retching experienced by a patient in the postanesthesia care unit (PACU) or within 24 hours following a surgical procedure. PONV affects about 10% of the population undergoing general anaesthesia each year. PONV can be unpleasant and lead to a delay in mobilization and food, fluid, and medication intake following surgery.

Dolasetron

Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata. It does not have much antiemetic effect when symptoms are due to motion sickness. This drug does not have any effect on dopamine receptors or muscarinic receptors.

Apomorphine

Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non-selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the -morphine suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo- prefix relates to it being a morphine derivative ("[comes] from morphine").

Trimethobenzamide

Trimethobenzamide is an antiemetic used to prevent nausea and vomiting.

Area postrema Medullary structure in the brain that controls vomiting

The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and transduce them into neural signals and networks. Its position adjacent to the bilateral nuclei of the solitary tract and role as a sensory transducer allow it to integrate blood-to-brain autonomic functions. Such roles of the area postrema include its detection of circulating hormones involved in vomiting, thirst, hunger, and blood pressure control.

Lateral hypothalamus

The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity, and eating disorders.

Vomiting Involuntary, forceful expulsion of stomach contents, typically via the mouth

Vomiting is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.

5-HT<sub>3</sub> antagonist

The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With the notable exceptions of alosetron and cilansetron, which are used in the treatment of irritable bowel syndrome, all 5-HT3 antagonists are antiemetics, used in the prevention and treatment of nausea and vomiting. They are particularly effective in controlling the nausea and vomiting produced by cancer chemotherapy and are considered the gold standard for this purpose.

Respiratory center brain region controlling respiration

The respiratory center is located in the medulla oblongata and pons, in the brainstem. The respiratory center is made up of three major respiratory groups of neurons, two in the medulla and one in the pons. In the medulla they are the dorsal respiratory group, and the ventral respiratory group. In the pons, the pontine respiratory group includes two areas known as the pneumotaxic centre and the apneustic centre.

Nausea Medical symptom or condition

Nausea is a diffuse sensation of unease and discomfort, often perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, upper abdomen, or back of the throat.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes crippling symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

Cancer and nausea

Cancer and nausea are associated in about fifty percent of people affected by cancer. This may be as a result of the cancer itself, or as an effect of the treatment such as chemotherapy, radiation therapy, or other medication such as opiates used for pain relief. About 70 to 80% of people undergoing chemotherapy experience nausea or vomiting. Nausea and vomiting may also occur in people not receiving treatment, often as a result of the disease involving the gastrointestinal tract, electrolyte imbalance, or as a result of anxiety. Nausea and vomiting may be experienced as the most unpleasant side effects of cytotoxic drugs and may result in patients delaying or refusing further radiotherapy or chemotherapy.

Netupitant

Netupitant is an antiemetic drug. In the United States, the combination drug netupitant/palonosetron is approved by the Food and Drug Administration for prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin. In Europe, it is approved by the European Medicines Agency (EMA) for the same indication.

References

  1. ↑ editors, Ansgar M. Brambrink, Jeffrey R. Kirsch (2012). Essentials of neurosurgical anesthesia & critical care : strategies for prevention, early detection, and successful management of perioperative complications (2012 ed.). New York: Springer. p. 716. ISBN   978-0387095615 . Retrieved 16 August 2014.CS1 maint: extra text: authors list (link)
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  11. ↑ Encarnacion, H. J. et al. (2009). Vomiting. Compendium-Continuing Education for Veterinarians. 31(3): 122-+.
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