Area postrema

Two AT-II receptors, AT and AT2 are known and show wide distribution (27). The AT receptor has been cloned and predominates ia regions iavolved ia the regulation of blood pressure and water and sodium retention, eg, the aorta, Hver, adrenal cortex, and ia the CNS ia the paraventricular nucleus, area postrema, and nucleus of the soHtary tract. AT2 receptors are found primarily ia the adrenal medulla, utems, and ia the brain ia the locus coeruleus and the medial geniculate nucleus. AT receptors are GCPRs inhibiting adenylate cyclase activity and stimulating phosphoHpases C, A2, and D. AT2 receptors use phosphotyrosiae phosphatase as a transduction system. 

The area postrema is a circumventricular brain region positioned on the dorsal surface of the medulla on the floor of the fourth ventricle. The blood-brain barrier and the cerebrospinal fluid-brain barrier are absent in this region and consequently many substances that do not pass across capillaries in other regions of the brain can do so in the area postrema. The chemoreceptor trigger zone (CTZ), located in the lateral area postrema is sensitive to blood-borne emetogens. Nerves from the CTZ connect with the vomiting centre. 

NTS) in the medulla. The area postrema lacks a blood-brain barrier and is accessible to emetogens in the bloodstream. Neurons pass from the CTZ to the NTS and the vomiting centre. 

Dopamine D2 receptors are involved in some emetic responses but studies have also suggested that activation of D3 receptors in the area postrema may either produce vomiting or enhance that elicited by D2 receptor activation. 

Cytotoxics cause an elevation of dopamine levels in the area postrema in animal studies and may release prostaglandins and inhibit enzymes such as enkepha-linases to allow increased levels of enkephalins to activate opioid receptors on dopaminergic nerves. 

Opioids act on the area postrema and/or the NTS via p or 8 receptors to produce emesis. Also, ambulatory patients receiving opioids are more affected than those confined to bed, suggesting a vestibular component in the effect. The emetic action of opioids is complicated by an antiemetic action, possibly involving two receptors at the NTS or the vomiting centre. 

Substance P is a member of a group of polypeptides known as neurokinins or tachykinins. It is thought to be the primary neurotransmitter for the transfer of sensory information from the periphery to the spinal cord and brain. Substance P as well as neurokinin NKX receptors has been detected in vagal afferent neurons in the area postrema, nucleus tractus solitarius and dorsal motor nucleus of the vagus. Substance P has been shown to increase the firing rate of neurons in the area postrema and nucleus tractus solitarius and to produce retching when applied directly to these areas in animal studies. 

Similar to alcohol (Lovinger and White 1991) and volatile anesthetics (Machu and Harris 1994), trichoroethane, trichloroethylene, and toluene enhance 5-HT3 receptor function. All three inhalants significantly and reversibly potentiated, in a dose-dependent manner, 5-HT-activated currents, mediated by mouse 5-HT3 receptors expressed in Xenopus oocytes. Another feature common to these drugs is that the acute use of inhalants, as well as alcohol and volatile anesthetics, can produce nausea and vomiting (Meredith et al. 1989). It is believed that 5-HT3 receptors located in the area postrema mediate this action of alcohol and the volatile anesthetics (Aapro 1991). 

B9 Nucleus prosupralemniscus B1 and B3 Neurons of the lateral paragigantocellular nucleus and the intermediate reticular nuclei Cells in the area postrema... 

These receptors are quite different from any other monoamine reeeptor in that they are not coupled to G proteins. Instead, they eomprise a pentamerie eomplex of subunits that ineorporates an ion ehannel. This is seleetive for the eations Na+ and K+ whieh, when opened, leads to depolarisation of the host eell. 5-HT3 reeeptors are found at high eoneentrations in the brainstem and area postrema. However, they are also found elsewhere in lower eoneentrations, notably in the eortex, amygdala and hippoeampus, where they are thought to be assoeiated mainly with GABAergie neurons. 

Chemoreceptor trigger zone Located in the area postrema of the fourth ventricle of the brain, it is exposed to cerebrospinal fluid and blood and is easily stimulated by circulating toxins to induce nausea and vomiting. 

Hippocampus, entorhinal cortex, amygdala, nucleus, accumbens, solitary tract nerve, trigeminal nerve, motor nucleus of the dorsal vagal nerve, area postrema, spinal cord... 

Dey, M.S., R.I. Krieger, and R.C. Ritter. 1987. Paraquat-induced, dose-dependent conditioned taste aversions and weight loss mediated by the area postrema. Toxicol. Appl. Pharmacol. 87 212-221. 

Divalent mercury in rats has been reported to poorly penetrate the blood-brain barrier [23], However, there is an impairment of the blood-brain barrier within hours after mercury treatment [24, 25], By means of autoradiographic techniques, it was demonstrated [26] that after a single intravenous injection of labelled mercuric chloride, large portions of the radioactive mercury were detected in the cerebellar grey matter, area postrema, hypothalamus and areas near the lateral ventricle of mice. 

The reader is referred to comprehensive reviews and monographs on the subject matter neuroanatomy and functions of the area postrema [36], nausea and vomiting mechanisms and treatment [37] and a recent multidisciplinary symposium on vomiting [38],... 

The abdominal vagus and sympathetic nerves are the most important afferent inputs involved in vomiting induced by chemotherapy and radiation [31]. The input from vestibular nerves and the cerebellum plays an important role in the motion disease [52]. The afferent inputs from vagal, trigeminal and glossopharyngeal nerves terminate eventually in the nucleus solitarius tract located in the medulla oblongata which has neuronal connections with other medullary areas involved in emesis, for example, area postrema [53]. 

In view of the universal role of the area postrema (AP) in emesis among animal species, including man [54], an analysis of this structure in terms of receptors, neurotransmitters and neurophysiological responses is indicated. The AP has also been implicated in several other functions (cardiovascular, caloric intake, osmotic water balance) unrelated to emesis [55], The reader is referred to general and comprehensive references on this neuronal structure [36, 37, 56],... 

Sympathectomy and vagotomy alone or combined did not have any effect on radiation-induced emesis in dogs, while ablation of the AP abolished it [65-67], On the other hand, a triple intervention (ablation of area postrema and nerve sectionings) was required to prevent delayed emesis [65]. The rhesus monkey was similar to the dog, that is, the radiation-induced emesis was prevented by ablation of the area postrema [41]. 

There are a few reports on possible sites of action of 5-HT3 antagonists. Low doses of zacopride administered directly into the fourth ventricle (i.c.v.) antagonized cisplatin (i.v.[-induced emesis in the cat [108]. A similar antagonism was demonstrated when routes of drug administration were interchanged. Similarly, GR 38032F, GR 65630 and MDL 72222, administered i.c.v. onto the area postrema at very low doses, antagonized cisplatin-induced... 

It can be concluded that direct evidence linking endogenous 5-HT to emesis is not convincing. On the other hand, selective effectiveness of 5-HT3 antagonists as antiemetic agents and presence of 5-HT3 receptors in the area postrema and vagus nerve do implicate 5-HT mechanisms. 

Morphine also causes nausea and vomiting by stimulation of the area postrema. Nausea is a common reaction to intravenous injection, but tolerance develops to this effect over repeated use. 

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