Physiology, Chemoreceptor Trigger Zone

Article Author:
Megan MacDougall
Article Editor:
Sandeep Sharma
Updated:
2/3/2019 11:45:17 PM
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Physiology, Chemoreceptor Trigger Zone

Introduction

The chemoreceptor trigger zone (CTZ) for emesis, also commonly known as the area postrema (AP), is located within the dorsal surface of the medulla oblongata, on the floor the fourth ventricle of the brain. The CTZ contains receptors that detect emetic agents in the blood and relays that information to the vomiting center which is responsible for inducing the vomiting reflex.[1]

Cellular

The chemoreceptor trigger zone is a circumventricular organ (CVO), in that it serves as a link between the brain parenchyma and the cerebrospinal fluid (CSF) containing ventricles. It is made of glia and neurons, covered by a thin ependymal cover and penetrated with convoluted capillaries lacking tight endothelial junctions. This specialized structure means the CTZ within the AP forms a permeable blood-brain barrier and therefore can detect emetic toxins in both the blood and the CSF.[2][1]

Blood flow velocity in the capillaries of the chemoreceptor trigger zone is slow, extending the length of time blood, circulating messengers, and toxins are moving through this zone. This allows increased contact time for blood and its contents to penetrate the permeable capillaries and interact with receptors for various substances involved in homeostasis and body fluids.[1]

Receptors of the CTZ that have been identified to induce emesis include opioid mu, kappa, dopamine-type 2 (D2), neurokinin-1 (NK-1), and serotonin-type 3 (5-HT3).[3] Animal studies with dogs have also shown the role of enkephalin and histamine-1 (H1) and histamine-2 (H2) receptors in the emetic reflex of the CTZ.[4][5]

Development

The autonomic nervous system (ANS) of mammals has not completed development at birth, resulting in a dysfunctional ANS. While an ANS framework is present in the early embryo, the development of the AP delays. For example, a study on ANS development in mice revealed that during postnatal days 0 to 7, there was no significant change in the AP volume or synaptic input from PHOX2B-derived neurons, but by day 7 to 20, there was an increase in volume and synaptic input from these same neurons. The study concluded that key ANS structures undergo dynamic developmental changes in the post-natal period. This finding can provide a basis for the future understanding of ANS dysfunction and disease predisposition in premature and term humans.[6]

Mechanism

The chemoreceptor trigger zone in the AP plays a crucial role in emesis and is one of four principal areas that can induce emesis. The other sites besides the CTZ that relay information to the vomiting center to induce emesis include the GI tract, the vestibular system, and the higher centers in the cortex and thalamus.[3] 

Vomiting that is triggered by the CTZ begins when its receptors detect emetogenic toxins in the blood and CSF and relay this information to the neighboring nucleus tractus solitarius (NTS). Abdominal vagal afferents that identify potentially emetogenic substances in the lumen also terminate here.[7] The NTS is the beginning of a final common pathway by which all the emetic inputs induce vomiting.[1] Results from lesion experiments suggest that the NTS connects to the emetic central pattern generator (CPG). The CPG is located in the retrofacial nucleus of the reticular formation and organizes the progression of various actions to induce emesis. It controls respiratory groups that coordinate the muscular movements involved in retching and vomiting. Therefore, there is no segregated "vomiting center" but instead, pools of loosely organized neurons in the medulla that can be activated in a specific sequence by a CPG.[8][7]

Clinical Significance

Chemotherapy Induced Nausea and Vomiting. Nausea and vomiting affect between 50% and 70% of patients with advanced cancer. Chemotherapy-induced nausea and vomiting (CINV) gets triggered by radiation and other chemotherapeutic agents that induce the release of serotonin from the GI wall and thus, stimulates the 5HT-3 receptors in the CTZ.[9][3] Therefore, pharmacological antagonists of 5HT-3 receptors in the chemoreceptor trigger zone have been developed to combat and prevent CINV. One such agent is ondansetron, a selective serotonin receptor antagonist, one of the four FDA approved drugs of its class used to treat nausea and vomiting. It acts centrally on the CTZ in the AP, and peripherally.[10]

Post-Operative Nausea and Vomiting.  In addition to CINV, the CTZ plays a significant role in opiate-induced post-operative nausea and vomiting (PONV), two of the most unpleasant side effects following surgery.[11] The mechanism of PONV is due to the administration of opioids that stimulate the D2 receptors in the CTZ, such as fentanyl and morphine commonly used to treat post-operative pain.[9][12] Phenothiazines, act by directly antagonizing the D2 receptors on the CTZ and are considered the most effective class of drugs for treating opioid-induced PONV.[11]

In addition to stimulating D2 receptors, opioids can stimulate their own receptor sites. Within the CTZ, opioid stimulation at the mu receptor induces emesis, while on mu receptors within the BBB, specifically the NTS, stimulation inhibits emesis. The separation of mu receptors by the BBB, and the opposing effects they have on emesis explains the dose-dependent effects opioids have on nausea and vomiting, such that that low doses of opioids induce emesis, but high doses inhibit it.

For example, with higher concentrations of opioids in the systemic circulation, or with a more lipophilic agent like fentanyl, there will be greater penetration of opioids within the blood-brain barrier, inducing the antiemetic effect of mu receptors at the NTS and thus counteracting the emetic effect of opioids on the mu receptors in the AP.[12]

Studies have shown that female gender is a risk for PONV. PONV increases during menstruation and the follicular phase of the menstrual cycle from sensitization of the CTZ to follicle stimulating hormone (FSH) and estrogen. However, this gender difference does not appear to be present in pediatric or elderly age groups.[11]

Area Postrema (AP) Syndrome. The CTZ, as part of the AP, is the pathologic target in AP Syndrome, frequently occurring in both the onset and course of neuromyelitis optica (NMO).[13] NMO is an autoimmune, demyelinating disease that involves recurring attacks of the optic nerves, spinal cord, and aquaporin-4 (AQP4)-enriched periventricular brain regions. The area postrema has a dense expression of AQP4 and therefore is a frequent target for NMO demyelinating lesions. Given the role of the AP in inducing emesis, clinical manifestations of NMO include intractable nausea, vomiting, and hiccups.[2]


References

[1] Miller AD,Leslie RA, The area postrema and vomiting. Frontiers in neuroendocrinology. 1994 Dec;     [PubMed PMID: 7895890]
[2] Popescu BF,Lennon VA,Parisi JE,Howe CL,Weigand SD,Cabrera-Gómez JA,Newell K,Mandler RN,Pittock SJ,Weinshenker BG,Lucchinetti CF, Neuromyelitis optica unique area postrema lesions: nausea, vomiting, and pathogenic implications. Neurology. 2011 Apr 5;     [PubMed PMID: 21368286]
[3] Becker DE, Nausea, vomiting, and hiccups: a review of mechanisms and treatment. Anesthesia progress. 2010 Winter;     [PubMed PMID: 21174569]
[4] Bhargava KP,Dixit KS, Role of the chemoreceptor trigger zone in histamine-induced emesis. British journal of pharmacology. 1968 Nov;     [PubMed PMID: 4387255]
[5] Bhargava KP,Dixit KS,Gupta YK, Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog. British journal of pharmacology. 1981 Mar;     [PubMed PMID: 6266566]
[6] Gokozan HN,Baig F,Corcoran S,Catacutan FP,Gygli PE,Takakura AC,Moreira TS,Czeisler C,Otero JJ, Area postrema undergoes dynamic postnatal changes in mice and humans. The Journal of comparative neurology. 2016 Apr 15;     [PubMed PMID: 26400711]
[7] Hornby PJ, Central neurocircuitry associated with emesis. The American journal of medicine. 2001 Dec 3;     [PubMed PMID: 11749934]
[8] Horn CC, Why is the neurobiology of nausea and vomiting so important? Appetite. 2008 Mar-May;     [PubMed PMID: 17996982]
[9] O'Brien C, Nausea and vomiting. Canadian family physician Medecin de famille canadien. 2008 Jun;     [PubMed PMID: 18556493]
[10] Griddine A,Bush JS, Ondansetron 2018 Jan;     [PubMed PMID: 29763014]
[11] Chatterjee S,Rudra A,Sengupta S, Current concepts in the management of postoperative nausea and vomiting. Anesthesiology research and practice. 2011;     [PubMed PMID: 22110499]
[12] Horn CC,Wallisch WJ,Homanics GE,Williams JP, Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. European journal of pharmacology. 2014 Jan 5;     [PubMed PMID: 24495419]
[13] Shosha E,Dubey D,Palace J,Nakashima I,Jacob A,Fujihara K,Takahashi T,Whittam D,Leite MI,Misu T,Yoshiki T,Messina S,Elsone L,Majed M,Flanagan E,Gadoth A,Huebert C,Sagen J,Greenberg BM,Levy M,Banerjee A,Weinshenker B,Pittock SJ, Area postrema syndrome: Frequency, criteria, and severity in AQP4-IgG-positive NMOSD. Neurology. 2018 Oct 23;     [PubMed PMID: 30258024]