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The chemoreceptor trigger zone (CTZ) is an area of the medulla that receives inputs from blood-borne drugs or hormones, and communicates with the vomiting center to initiate vomiting. The CTZ is close to the area postrema on the floor of the fourth ventricle and is outside of the blood–brain barrier. The neurotransmitters implicated in the control of nausea and vomiting include acetylcholine, dopamine, histamine (H-1 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, and drugs such as dopamine which can normally not enter the CNS may still stimulate the CTZ.[1]
Evolutionary significance of the CTZ
[edit]The CTZ is in the medulla oblongata, which is phylogenetically the oldest part of the nervous system. Early lifeforms developed a brainstem, or inner brain, and nothing more. This part of the brain is responsible for basic survival instincs 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 postrea 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 simuli, and also is significantly involved in memory and reward systems. Now, the most advanced lifeforms to date have developed the cerebral cortex, which is the most recent part of the nervous system. 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.[2] The emetic response was selected for, 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. The hope here is that whatever poison or toxin that is mediating its effects in the stomach will be inhibited. This is why the CTZ is located in the brain stem, outside of the blood-brain barrier: because your body needs to get rid of toxins and drugs even if you are unconscious and cannot consciously produce the emetic response.
Chemoreception
[edit]Since the CTZ is located in the medulla oblongata, it therefore does not have a specific blood-brain barrier.[1] This means that large polar molecules, such as emetic toxins, can diffuse through to and reach the CTZ quite easily. This is because the medula oblangata 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.[1] 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.[3] 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 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 postrea 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.[3] 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.[3]
Communication
[edit]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.[4] 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.[4] Dopamine and serotonin have been found to play the biggest role in communication from the CTZ to the vomiting center, as well as histamine.[4] Chemoreceptors in the CTZ relay information about there being emetic agents in the blood to the adjacent nucleus tractus solitarius (NTS).[5] 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.[5] 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 vomiting center of the brain refers to the groups of loosely organized neurons in the medulla that are activated in sequence by the CPG.[5] The main neurotransmitters involved in communication between the CTZ and the vomiting center are serotonin, dopamine, histamine, and endogenous opioids which include endorphins, enkephalins, dynorphin.
Serotonin
[edit]The CTZ signals the vomiting center of the brain with Serotonin (5-HT3) receptors.[4] The neurotransmitter serotonin binds to the (5-HT3) receptors, which triggers action potentials that are sent from the neurons that the receptors are attached to in the CTZ, to neurons which reside in the nearby vomiting center. New antiemetic medications are currently being developed based on these serotonin receptors.[4] These drugs are serotonin antagonists. This insinuates that an excess of serotonin in the bloodstream is known to cause an emetic response.
Dopamine
[edit]The CTZ also signals the vomiting center of the brain with dopamine (D2) receptors.[4] The neurotransmitter dopamine binds to the (D2) receptors and initiates an action potential that is sent from the neuron the receptor is attached to in the CTZ to neurons that reside in the vomiting center. There are also many antiemetic drugs which inhibit (D2) receptors in the CTZ. This is because uncontrollable emesis has also been shown to be a result of excess amounts of dopamine in the bloodstream.
Histamine
[edit]The CTZ signals the vomiting center of the brain with Histamine H1 and H2 receptors.[4] The neurotransmitter histamine binds to the either the H1 receptor or the H2 or both, and initiates an action potential that is sent from the neuron the receptor is attached to in the CTZ to neurons that reside in the vomiting center. The CTZ is very rich in biogenic amines like histamine.[6] It has been seen that intraventricular administration of histamine in dogs causes an emetic response.[6] 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.[6]
Phosphodiesterases
[edit]Recent studies have found that phosphodiesterase 4 (PDE4) inhibitors, such as Rolipram, cause emesis as one of their side effects.[7] It has been found that these PDE4 inhibitors are numerous in the CTZ and in the brainstem in general.[7] The mRNA products from genes that code for these PDE4 inhibitors are plentiful in the CTZ, and not only located in CTZ neurons, but also in glial cells and blood vessles associated with with the CTZ neurons.[7] Also, the hydridization signals from the PDE4 mRNAs are stronger in the area postrema and the CTZ than anywhere in the brainstem.[7] 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.[7]
H-Channels
[edit]Most of the neurons located in the CTZ express hyperpolarization-activated cation channels (H-channels).[8] Since the neurons in the CTZ convey information relating to emesis to 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.[8] This suggests that the neurons that express H-channels in the CTZ and area postrema are involved in nausea and the emetic response.[8]
The vomiting center of the brain
[edit]This integrates the emetic response. This is the area in which "a final decision is made" about whether to evoke an emetic response or not. This decision is based heavily on the information which the CTZ relays to 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.[4] 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.[4] Also, emesis can occur by direct neural stimulation of the vomiting center.[9]
Damage to the CTZ
[edit]Damage to the CTZ can either benefit or severely hurt someone. Damage 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 dissapear, 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 in fact cause emesis or inhibit it.[10] 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.[10] Surgical microvascular decompression resulted in postoperative and long-term resolution of emesis.[10]
Antiemetic medications
[edit]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.[4] 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 vomiting center that inhibit emesis.[4] 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. Some examples of antiemetic medications include Dolasetron, Olanzapine, Aprepitant, Cyclizine, and Hyoscine.
Antiemetic drugs coupled with pain relieving medications
[edit]Often times, doctors will "pre-treat" patients who he/she believes 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
[edit]Radiation via chemotherapy is a big 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.[11] Patients receiving chemotherapy are often prescribed antiemetic medications.
References
[edit]- ^ a b c Miller AD, Leslie RA. The area postrema and vomiting. Frontiers in Neuroendocrinology. 1994 Dec;15(4):301-20. PMID 7895890
- ^ Roth, G. and Dicke, U. (2005). Evolution of the brain and intelligence. Trends in Cognitive Sciences. 9(5): 250-257.
- ^ a b c Hori,N. et al. (2000). Brainstem slice studies of receptor activation in the mouse area postrema. Society for Neuroscience Abstracts. 26(1-2) Abstract No.-716.13.
- ^ a b c d e f g h i j k Porreca, F., & Ossipov, M. H. (2009). Nausea and Vomiting Side Effects with Opioid Analgesics during Treatment of Chronic Pain: Mechanisms, Implications, and Management Options. Pain Medicine, 10(4), 654-662. doi: 10.1111/j.1526-4637.2009.00583.x
- ^ a b c Hornby, P. J. (2001). Central Neurocircuitry Associated With Emesis. American Journal of Medicine. 111(8a), 106S-112S.
- ^ a b c Bhargava, K.P. (1968). Role Of Chemoreceptor Trigger Zone In Histamine-induced Emesis. British Journal of Pharmacology. 34(3): 508-&
- ^ a b c d e Mori, F. et al. (2010). The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D. Journal of Chemical Neuroanatomy. 40(1): 36-42.
- ^ a b c Shinpo, K. et al. (2012). The role of area postrema neurons expressing H-channels in the induction mechanism of nausea and vomiting. Physiology and Behavior. 107(1): 98-103
- ^ Encarnacion, H. J. et al. (2009). Vomiting. Compendium-Continuing Education for Veterinarians. 31(3): 122-+.
- ^ a b c Mortazavi, M. M. (2010). Chronic emesis due to compression of the area postrema by the posterior inferior cerebellar artery resolution following microvascular decompression. Journal of Neurosurgery-Pediatrics. 6(6): 583-585
- ^ Edwards, C.M. (1988). Chemotherapy induced emesis -mechanisms and treatment: a review. Journal of the Royal Society of Medicine. 81(11): 658-662.