where in the brain is the vomiting center located course

Which part of the brain control vomiting?

Studies showed the existence of two areas in the brain related to emesis: one, a chemosensor for vomiting with no coordinating function, located in the fourth ventricle and two, a coordinator of vomiting with no chemosensory function, located in the lateral reticular formation of the medulla oblongata.

Why does a brain tumor induce vomiting?

Brain tumors can increase pressure in the brain, which can induce nausea and vomiting. This can occur due to primary brain tumors that form inside the brain, and metastatic brain tumors, which originate in other parts of the body and spread to the brain, such as lung, breast, and kidney cancers, as well as melanoma (a type of skin cancer).

What part of the brain controls nausea and vomiting?

The reason for this is because the parts of the brain that control nausea and vomiting are the same. In fact, these two are involuntary actions being controlled by the medulla oblongata, also called the vomiting center of the brain. Common Medical Conditions that Cause of Nausea and Vomiting

What is in the very center of the brain?

• The basal ganglia are a cluster of structures in the center of the brain. The basal ganglia coordinate messages between multiple other brain areas. • The cerebellum is at the base and the back of the brain. The cerebellum is responsible for coordination and balance.

Why do antiparkinsonian drugs cause nausea?

The high density of dopamine receptors in the area postrema makes it very sensitive to the dopamine-enhancing drugs. Stimulation of the dopamine receptors in the area postrema activates these vomiting centers of the brain; this is why nausea is one of the most common side-effects of antiparkinsonian drugs.

What triggers the vomiting reflex?

Additionally, what triggers the vomiting reflex? The vomiting centre is predominantly activated by three different mechanisms: By nervous impulses from the stomach, intestinal tract, and other portions of the body, resulting in a reflexive activation; By stimulation from the higher brain centres ; By the chemoreceptor trigger zone (CTZ) sending impulses.

Which brain centre initiates and controls the act of emesis?

…by two distinct brain centres—the vomiting centre and the chemoreceptor trigger zone—both located in the medulla oblongata. The vomiting centre initiates and controls the act of emesis, which involves a series of contractions of the smooth muscles lining the digestive tract.

What are the mechanisms of opioid induced nausea?

Though the exact physiological mechanisms underpinning opioids-induced nausea and vomiting are not fully understood, activation of opiate receptors in the area postrema, vestibular apparatus and the gastrointestinal tract are implicated [14]. It appears all three opiate receptors (µ [mu], κ [kappa] and δ [delta]) may play a role in opioid-induced nausea and vomiting, but several studies indicate that activation of µ receptors is essential in emesis [95]. Expression of µ opioid receptor has been confirmed in the area postrema, nucleus of the solitary tract, vagal afferents, and the gastrointestinal tract [96,97]. The µ opioid receptor agonist loperamide has been shown to evoke emesis in the ferret, which could not be altered by abdominal vagotomy but was abolished by ablation of the area postrema, suggesting that vagal afferent input may not be important in µ opiate receptor-mediated emesis [98]. Opiate agonists may induce vomiting via multiple mechanisms: (i) direct stimulation of opioid µ (and probably delta receptors) and subsequent signaling to the nucleus of the solitary tract primarily via dopamine D2receptors as well as 5-HT3receptors present in the area postrema. (ii) Opioid µ or κ receptor agonists can inhibit intestinal motility that can lead to gut distension and increased emptying time, resulting in stimulation of visceral mechanoreceptors and chemoreceptors, which are also associated to nausea and vomiting. These emetic signals from the gastrointestinal tract to the brainstem nucleus of the solitary tract occurs through visceral afferents, which may further stimulate the already described serotonergic signaling pathway of vagal afferents [5]. (iii) Opioids can stimulate the vestibular apparatus, which is responsible for detecting changes in equilibrium, and sensory input to the nucleus of the solitary tract occurs via histamine H1and cholinergic systems [13,14]. These inputs project to the nucleus of the solitary tract, which potentially has output pathways to the dorsal motor nucleus of the vagus to produce the vomiting reflex and projections to the mid- and forebrain for the perception of nausea [15]. Both emetic and antiemetic effects of µ opiate receptor agonists have been reported in animal studies [91,99]. There is some suggestion that, while µ opioid receptors located in the area postrema are involved in the mediation of emesis, those in the nucleus of the solitary tract provide inhibitory effects on vomiting [100], and genetic variants in the µ opioid gene also produce distinct effects on the nauseogenic and emetic potencies of opioids [92].

What is the substance P?

Substance P is one member of structurally related mammalian family of tachykinin peptides, including neurokinin A, neurokinin B, and the N-terminally extended forms of neurokinin A such as neuropeptide K and neurokinin g [53]. Mammalian tachykinins activate three specific membrane-associated neurokinin receptors known as NK1, NK2, and NK3, which belong to the superfamily of G protein-coupled receptors. These receptors are recognized with moderate selectivity by endogenous substance P, neurokinin A, and neurokinin B, with respective preferential selectivity for NK1, NK2, and NK3receptors. Although their affinity differences are not large and cross-interaction can occur across neurokinin receptors, substance P appears to be the endogenous ligand for NK1receptors and has a major role in the induction of vomiting, particularly during the delayed phase of cancer chemotherapy-evoked emesis [17,18]. In fact, low doses of substance P (0.03–0.2 mg/kg) can evoke vomiting in dogs when administered intravenously [54] but not when injected intraperitoneally [55]. In fact, very large doses of intraperitoneally (i.p.) administered substance P (e.g., 50–100 mg/kg) are required to evoke vomiting in least shrews [29]. This is probably due to rapid metabolism of substance P following its intraperitoneal administration. In fact, administration of low doses of the selective NK1receptor agonist GR73632 (1–5 mg/kg, i.p.) causes vomiting in least shrews in a dose-dependent fashion [29]. Both neurokinin NK1Rs and substance P are expressed in central and peripheral emetic loci, including the brainstem dorsal vagal complex emetic nuclei, as well as vagal afferents, enteric neurons, and enterochromaffin cells of the gastrointestinal tract [17,56]. Moreover, stimulation of NK1Rs by substance P excites neurons in the area postrema of dogs and subsequently evokes vomiting [57], whereas specific ablation of either intestinal or brainstem NK1Rs leads to blockade of vomiting evoked by the NK1R selective agonist GR73632 in the least shrew [29]. In fact, GR73632 is a potent emetogen in the least shrews, where central NK1Rs play a major role, and peripheral NK1Rs play a minor role, in the induction of vomiting [58]. In the clinic, NK1R antagonists (such as Aprepitant, netupitant and rolapitant) are recommended for the suppression of the second phase of vomiting evoked by highly emetogenic cancer chemotherapeutics [59]. In fact, they are one major component of the so-called “triple prophylactic antiemetic therapy”, along with one of the above-described 5-HT3receptor antagonists plus dexamethasone [50,51,52,60]. Basic studies have indicated that NK1R antagonists behave as broad-spectrum antiemetic [61] and are also effective against postoperative nausea and vomiting in the clinic [62,63]; however, they are not recommended in patients on birth control medications, since aprepitant reduces the effectiveness of oral contraceptives [59].

What are the central and peripheral anatomical sites involved in nausea and vomiting?

Central and peripheral anatomical sites involved in nausea and vomiting induced by various stimuli. Nausea and vomiting can be generated by diverse stimuli and are mediated by the bidirectional interaction between brain and gut. In brief: (1) The brainstem area postrema in the floor of the fourth ventricle lacks blood brain barrier and thus serves as direct central receptor sites for circulating and systemic emetic stimuli in the cerebrospinal fluid and the blood [11]. (2) Systemically administered drugs can activate corresponding receptors present on vagal afferents, which project sensory signals to the nucleus of the solitary tract [11,12]. (3) Peripheral stimuli such as toxic drugs and microbials (e.g., bacteria, viruses, fungi) that enter the lumen of the gastrointestinal tract (GIT) and pathologies in the GIT cause release of local emetic neurotransmitters/modulators, which subsequently act on the corresponding receptors present on vagal afferents and/or stimulate the brainstem area postrema via circulating blood [9,10]. Besides the area postrema and the sensory vagal afferents, the nucleus of the solitary tract is also the recipient of: (i) direct neural inputs from the splanchnic nerves carrying sensation caused by diseases of visceral organs (e.g., cardiac, kidney); (ii) brainstem vestibular nuclei collecting signals from vestibular apparatus in inner ear and/or cerebellum, caused by stimuli related to motion sickness and opioid analgesics [13,14]; and (iii) the cerebral cortex and limbic system, which accept and process emotional and cognitive stimuli [3,4,5,6,7,8]. The nucleus of the solitary tract has output pathways to the dorsal motor nucleus of the vagus, which further project to the upper gastrointestinal tract to produce the vomiting reflex [11]. In addition, the nucleus of the solitary tract has projections to the mid- and forebrain for the perception of nausea [15].

How does histamine affect the brain?

Significant preclinical evidence indicates that vestibular hyperactivity triggers activation of histaminergic neuronal system during motion sickness, which ultimately stimulates histamine H1receptors in the brainstem to evoke vomiting [83]. In fact, intracerebroventricular injections of histamine causes vomiting, which was abolished by bilateral ablation of area postrema or pretreatment with antihistamines [84]. In addition, inhibition of histamine N-methyltransferase (HNMT), the enzyme responsible for metabolism of histamine with tacrine, increases endogenous histamine and exacerbates motion sickness in dogs, as well as susceptibility to condition taste aversion (an index of motion sickness) in rats [83]. Concomitantly, conditioned taste aversion was associated with histamine N-methyltransferase expression. Moreover, the latter authors have also demonstrated that, in rats: (i) microinjection of the H1receptor antagonist promethazine to their dorsal vagal complex reduced condition taste aversion; (ii) repeated exposure to rotary stimulation habituated animals to motion sickness and elevated histamine N-methyltransferase expression in their brainstem; and (iii) elevation of histamine N-methyltransferase gene expression in the dorsal vagal complex inhibited the motion sickness, whereas introduction of recombinant lentiviral vectors expressing rat histamine N-methyltransferase-shRNA into the DVC to reduce the expression of histamine N-methyltransferase promoted motion sickness. Additionally, increased histamine tissue levels in the hypothalamus and brainstem nuclei such as the vestibular nucleus and the dorsal vagal complex are considered the primary reason for induction of motion sickness [83,85,86,87,88,89]. Although, like rats, mice do not vomit, motion sickness experience evokes increased levels of histamine, histamine H1receptor mRNA, and H1receptor protein expression in their hypothalamus and brainstem, which can be significantly reduced by pretreatment with hesperidin [83], a bioflavonoid that inhibits the synthesis and release of histamine from mast cells [90]. Histamine H1receptor blockers such as dimenhydrinate and diphenhydramine are commonly used antiemetic agents against nausea and vomiting secondary to motion sickness [91,92,93]. It is important to note that many H1receptor blockers have anticholinergic properties that block muscarinic receptors, which may also contribute to their antiemetic effects [81]. Histamine also has a peripheral emetic component, since its release from intestinal mast cells contributes to emesis in house musk shrews in response to food poisoning caused by Staphylococcal enterotoxins, to be discussed later (Section 4.6.1). Staphylococcal enterotoxins bind to jejunal submucosal mast cells and induce mast cell degranulation as well as the histamine release, which evokes vomiting through stimulating the vagal afferents and transmission to the brainstem emetic nuclei [94].

What are the receptors of dopamine?

Dopamine, its proemetic receptors (dopamine D2/3), and/or their mRNA are well distributed in the emetic reflex arc, including the dorsal vagal complex (area postrema, nucleus of the solitary tract, dorsal motor nucleus of the vagus), vagal nerves, gastrointestinal tract, and the enteric nervous system [65]. In fact, dopamine tissue levels and turnover increase in the least shrew brainstem and jejunum during peak early and delayed phases of vomiting following cisplatin administration in the least shrew model of emesis [71]. Currently, several classes of dopamine D2-like receptor antagonists such as phenothiazines (e.g., chlorpromazine), butyrophenones (e.g., haloperidol), and benzamides (e.g., metoclopramide, which also blocks 5-HT3receptors) are employed in the clinic for prevention of vomiting caused by diverse emetic stimuli, including: uremia, radiation sickness, viral gastroenteritis, postoperative nausea, and vomiting, as well as prophylaxis for cancer patients receiving chemotherapy with low emetogenic potential, or as a recue antiemetic in patients who have breakthrough emesis [65,72].

What receptors are involved in vomiting?

The notion that 5-hydroxytryptamine (5-HT; serotonin) is involved in vomiting was deduced from drugs that interfere with its synthesis, storage, release, and metabolism long before the discovery of selective tools that modulate specific serotonergic receptor subtypes [47]. Serotonergic receptors can be classified into seven major families (5-HT1–7), which are trans-membrane G-protein-coupled receptors, except for the 5-HT3receptor, belonging to the cys-loop ligand-gated ion channel family. The 7 families are divided further into subfamilies, and to date a total of 14 5-HT receptor subtypes have been described. Although basic evidence indicate that serotonin 5-HT1–4receptors could be involved in the modulation of the emetic reflex, to date application of clinical evidence support a major emetic role for 5-HT3receptors [47]. Being an ion channel, 5-HT3receptor activation induces fast excitatory postsynaptic potentials and rapid depolarization of serotonergic neurons [48], leading to augmentation of intracellular Ca2+concentration that causes the release of different emetic neurotransmitters and/or peptides (e.g., dopamine, cholecystokinin, glutamate, acetylcholine, substance P, or 5-HT, itself [49]. Significant clinical evidence indicates that both the first (e.g., ondansetron, Granisetron, dolasetron) and second (e.g., palonosetron) generation 5-HT3receptor antagonists attenuate the first phase of cancer chemotherapy-evoked vomiting where serotonin is a major emetic player [50,51]. In fact, combination of a 5-HT3receptor antagonist with a substance P neurokinin NK1receptor antagonist plus dexamethasone is required to prevent both phases of highly emetogenic chemotherapy-evoked vomiting in approximately 90% of cancer patients. Although 5-HT3receptor antagonists are generally considered as narrow-spectrum antiemetics, they are also useful for the suppression of postoperative nausea and vomiting, as well as pregnancy-induced emesis [50,51,52].

What is the gut brain axis?

The gut–brain axis is a continuous, bidirectional neural and endocrine communication network between the gastrointestinal tract and the brain that is crucial to gastrointestinal regulation [16]. The gut–brain axis includes the gastrointestinal tract and the afferent and efferent vagal nerves and spinal cord, the brainstem, limbic and interoceptive regions, and autonomous system and motor outputs [11]. This axis plays an important role in the initiation and maintenance of nausea and vomiting caused by diverse emetic stimuli. The central and peripheral compartments [17,18] of the emetic reflex arc are shown in Figure 1. The key sites in the mediation of vomiting are: (i) the brainstem dorsal vagal complex emetic nuclei such as the area postrema (AP), the nucleus of the solitary tract, and the dorsal motor nucleus of the vagus (DMNV) and (ii) the peripheral sites, including the sentinel epithelial enterochromaffin cells, which are present in the mucosa of gastrointestinal tract; the enteric nervous system embedded in the wall of gastrointestinal tract; and the vagus and splanchnic nerves. These peripheral emetic loci transfer emetic signals between the gastrointestinal tract as well as other internal organs, to the dorsal vagal complex emetic nuclei in the brainstem [5].