Molecular and Circuit Mechanisms Regulating Nausea and Vomiting: Recent Advances and Future Perspectives

Abstract

Nausea and vomiting are closely related but distinct physiologic and psychological phenomena that are often experienced together. The incidence of nausea and vomiting are high but our understanding of the molecular and circuit mechanisms is limited. Currently, the drug treatments for nausea and vomiting are not very effective but are often accompanied by unpleasant side effects. Therefore, nausea and vomiting remain a crucial factor affecting early recovery of patients and urgent measures are needed to enhance prevention and treatment efforts, alleviate patient suffering, improve healthcare outcomes, and promote rapid recovery. The mechanism underlying nausea and vomiting is complex and involves multiple different receptors and neural pathways, all of which have important roles. Herein we reviewed the recent advances involving the molecular and neural circuit mechanisms regulating nausea and vomiting as well as the clinical factors and research status of postoperative nausea and vomiting (PONV). Understanding nausea and vomiting circuitry and cellular mechanisms is crucial for developing PONV prevention and treatment strategies.

Main article text

Nausea is a subjective sensation of discomfort in the stomach that is frequently accompanied by the feeling of a need to vomit [1,2]. Nausea is often described as a vague, queasy feeling that can be difficult to articulate. Vomiting, or emesis, is the forceful expulsion of the contents of the stomach through the mouth. Vomiting is a complex reflex action involving multiple body systems [3]. Nausea and vomiting are crucial protective defense mechanisms that help humans and other vomit-competent animals avoid ingesting or digesting potentially toxic substances [4]. These processes serve as an immediate response to harmful agents with nausea acting as an early warning signal and vomiting providing a means to expel harmful substances from the body. Nausea and vomiting often occur along a temporal continuum, although this is not always the case. Severe nausea can sometimes be present without vomiting, and less frequently vomiting may occur without preceding nausea. Therefore, nausea is no longer viewed merely as a precursor to vomiting [5,6].

Various stimuli can induce nausea and/or vomiting, including viruses, toxins, drug therapies, pregnancy, and motion sickness [6]. Nausea has dual aspects. While nausea can prompt vomiting to expel toxic substances, serving as an evolutionary survival mechanism, nausea can also be highly disruptive and debilitating. Severe nausea, a common side effect in treating conditions such as cancer, often results in patient non-compliance with prescribed therapies. Consequently, management of nausea and vomiting is crucial for early patient recovery, requiring urgent and effective measures to improve prevention and treatment, reduce suffering, and support rapid recovery.

In this article we have reviewed recent research progress on nausea and vomiting in both basic and clinical contexts, including neural circuit mechanisms, neurotransmitters and receptors involved, and the current state of postoperative nausea and vomiting (PONV) research.

1. NAUSEA AND VOMITING STIMULI

Accumulated research indicates that the causes of nausea and vomiting are multifaceted and complex. Key factors include the neural transmission pathways responsible for inducing these symptoms, as well as the associated neurotransmitters and receptors. The vomiting center is in the medulla oblongata, which includes the chemoreceptor trigger zone (CTZ) in the area postrema (AP) on the floor of the fourth ventricle and the nucleus tractus solitarius (NTS) in the lower part of the brainstem [7]. Multiple neurotransmitters and their receptors play crucial roles in the neural transmission pathways associated with nausea and vomiting. The primary neural transmission pathways currently implicated are as follows: visceral mechanoreceptors such as gastrointestinal distension and inflammatory injury; and chemoreceptors, such as antibiotics and endotoxins, causing changes in the gastrointestinal environment [5,8,9]. The primary neural transmission pathways stimulate the CTZ under the control of the vagus nerve, which due to the lack of a complete blood-brain barrier, receives stimuli from various chemicals or drugs and their metabolites in the blood and cerebrospinal fluid, triggering neural impulses to the NTS [10]. Additionally, changes in head position can stimulate the central nervous system to produce nausea and vomiting through input from the vestibular system in the inner ear [11]. Furthermore, stimuli, such as visual, gustatory, olfactory, pain, hypotension, hypoxia, and intracranial hypertension, can send neural input signals to the NTS via the limbic system and visual cortex system. The NTS receives inputs from the vagus nerve, vestibular and limbic systems, and stimulates nuclei, such as the nucleus ambiguous, ventral respiratory group, and dorsal motor nucleus of the vagus nerve, to trigger nausea and vomiting [12]. Therefore, the occurrence of nausea and vomiting is the result of continuous interaction between the gastrointestinal tract, including the enteric, central, and autonomic nervous systems [9,13] (Fig 1).

Figure1 |

Schematic diagram of stimulus information of nausea and vomiting (modified according to reference [14]). The main afferent pathways capable of inducing nausea and vomiting converging on the nucleus tractus solitarius (NTS) are as follows: Vestibular system (semicircular canals and otoliths via cranial nerve VIII and the vestibular nucleus); and area postrema and the abdominal vagal afferents (vagal afferent mechanoreceptors, vagal afferent mucosal chemoreceptors, nodose ganglion). The NTS sends outputs to the major motor nuclei, which are located in the more ventral parts of the brainstem. Motor nuclei, such as the ventral respiratory group (VRG), and presympathetic neurons are responsible for the mechanical events of retching and vomiting (e.g., abdominal vagus nerve from the dorsal motor vagal nucleus mediating upper/lower esophageal sphincter relaxation, gastric relaxation, and giant retrograde contraction of the small intestine, the phrenic nerve with nuclei in C3–C5 driven from VRG, and spinal motor neurons). The prodromata of vomiting is associated with nausea (mediated by sympathetic and parasympathetic nerves) and the rostral projections (predominantly via the parabrachial nucleus) leading to vasopressin secretion (hypothalamus–posterior pituitary) and the more complex responses requiring cerebral cortical involvement, including genesis of the sensation of nausea itself. See figure for details.

2. NEURAL CIRCUITS ASSOCIATED WITH NAUSEA AND VOMITING

The neural pathways underlying the occurrence of nausea and vomiting are not completely understood. Existing studies have indicated that several types of neuronal pathways may transmit signals to the brain, including input via the vagus nerve, neurons in the AP, the vestibular system, and potentially other cell types [15]. Brainstem nuclei are highly critical for energy balance, vomiting, nausea, malaise, and food aversions. The AP, located around the brain ventricles, is associated with nausea and vomiting. The AP is typically considered a sensory structure within the brain that is closely associated with interoception. Electrical stimulation of the AP induces nausea and vomiting. Damage to the AP abolishes nausea-related responses to specific intravenous toxins but not motion sickness [16]. While mice and other rodents cannot vomit, some stimuli that induce nausea and vomiting in humans can elicit strong behavioral aversions in rodents by acting on the AP [17]. These findings suggest that neural circuits mediated by the brainstem AP may have a critical role in nausea and vomiting. The AP has also been proposed to have additional functions in feeding, metabolism, cardiovascular regulation, and fluid/cerebrospinal fluid homeostasis [18].

Using single-cell sequencing technology, a recent study established a cellular atlas of AP and identified four excitatory and three inhibitory neuronal types [16]. Chemogenetics and conditioned flavor avoidance (CFA) experiments found that selectively activating GFRAL or SLAC6A2 neurons in the AP (both of which belong to GLP1R-expressing excitatory neurons) is sufficient to induce nausea-related malaise. Furthermore, circuit tracing revealed that excitatory neurons in the AP possess long-distance information transmission capabilities, conveying information to calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN), thereby eliciting nausea-associated behaviors in mice. In a subsequent study, it was shown that inhibitory neurons in the AP form a connected dense network with nearby excitatory neurons [19]. Activation of these inhibitory neurons significantly inhibit nausea induced by excitatory neurons. Further investigation revealed that one type of inhibitory neuron expresses glucose-dependent insulinotropic polypeptide receptor (GIPR), which is activated by GIP, a small protein released by the digestive system to control blood glucose levels. Activation of these inhibitory neurons by GIP leads to the inhibition of nearby excitatory neurons through GABA-mediated inhibitory currents, thereby reducing their activity. At the behavioral level, administering GIP to activate these inhibitory neurons alleviated nausea. However, when inhibitory neurons are disrupted, mice still exhibit signs of nausea even after GIP administration. Further research revealed that GIPR-positive neurons in the AP also co-express neuropeptide Y receptor type 2 (NPY2R) [20]. Administration of PYY analogs induce anorexia and nausea reactions in mice, while peripheral or central administration of GIPR agonists significantly reduce nausea in mice without affecting the anorexigenic effects of PYY. Whole-brain c-Fos labeling results demonstrated that PYY administration significantly increase activation of AP and PBN dorsomedial nucleus neurons, while GIPR agonists significantly decreased neuronal activation (Fig 2). Therefore, there are actually various types of neuronal cell clusters in the AP with a few specific neuronal clusters being crucial for the generation of nausea and vomiting, while the functions of other types of neurons still require further investigation.

Figure2 |

Schematic diagram of projection circuits in AP related to nausea (modified according to references [19,20]). Selectively activating GFRAL+ neurons in the AP is sufficient to induce nausea-related malaise. Neurons in the AP possess long-distance information transmission capabilities, conveying information to CGRP+ neurons in the PBN and thereby eliciting nausea-associated behaviors. The GIPR+ inhibitory neurons in the AP, which co-express NPY2R, can be activated by GIP to alleviate nausea. This activation leads to inhibition of nearby excitatory neurons through GABA-mediated inhibitory currents, thereby reducing their activity. PYY analogs increased activation of AP and PBN dorsomedial nucleus neurons, which induced anorexia and nausea reactions. GFRAL: glial-derived neurotrophic factor receptor alpha-like receptors; CGRP: calcitonin gene-related peptide; GIPR: glucose-dependent insulinotropic polypeptide receptor; NPY2R: neuropeptide Y receptor type 2; PBN: parabrachial nucleus.

Appropriate animal models and research paradigms are extremely important for studying the mechanisms underlying nausea and vomiting. Another study established a new research paradigm of mouse model using staphylococcal enterotoxin A (SEA) to investigate the neural mechanisms underlying nausea and retching [21]. This study confirmed that inhibiting the Tac1⁺ neurons in the dorsal vagal complex (DVC) prevent conditioned flavor avoidance and retching in mice. DVC ^Tac1+ neuron labeling and patch-clamp recording confirmed that DVC ^Tac1+ neurons release glutamate and neuropeptides encoded by Tac1. Retrograde circuit tracing localized the brain-gut axis circuitry that innervates DVC ^Tac1+ neurons. The GCAMP signal associated with retching is transmitted from gut-innervating sensory neurons to DVC ^Tac1+ neurons. Activation of DVC ^Tac1+ neurons using optogenetics is sufficient to induce retching and CFA in mice. Dual labeling of DVC ^Tac1+ neurons using circuit tracing revealed that neurons projecting to the rostral part of the ventral respiratory group (rVRG) and lateral parabrachial nucleus (LPB) are spatially separate. Selective activation of DVC ^Tac1+ neurons projecting to rVRG and LPB induced retching behavior and CFA, respectively [21]. Additionally, DVC ^Tac1+ neurons also have a critical role in chemotherapy-induced defensive responses in mice (Fig 3). Further research demonstrated that activation of a class of neurons in NTS mediates toxin-induced retching [22]. Transcriptomic sequencing combined with opto/chemogenetic techniques showed that Calb1⁺ neurons in the NTS are crucial neurons inducing retching. Retrograde circuit tracing revealed that NTS Calb1⁺ neurons project to the external lateral subdivision of the parabrachial nucleus (PBNel) and nucleus ambiguous/rostral ventrolateral medulla (Amb/RVLM). The Calb1 NTS-Amb/RVLM pathway induces retching by regulating diaphragm contractions to increase gastric pressure, while the Calb1 NTS-PBNel pathway has a role in inducing nausea and establishing CFA. Additionally, external emetic toxins induce retching behavior by directly stimulating 5-HT3-positive neurons in the jugular ganglion to transmit emetic signals to NTS Calb1⁺ neurons, thus inducing retching behaviors (Fig 3). Another study exploring sickness behaviors (manifested as reduced food and water intake and decreased locomotor activity) induced by LPS showed that peak activity occurred in a group of neurons expressing neuropeptide ADCYAP1 in the DVC brainstem region [23]. Activation of ADCYAP1⁺ neurons promotes feeding and drinking, and decreases locomotor activity in mice, while inactivation of ADCYAP1⁺ neurons significantly attenuates the effects of LPS on these behaviors. These findings illustrate the complex regulation of nausea and vomiting, which the AP and other brainstem regions interact through a finely tuned neural circuit network to modulate the body’s response to internal and external stimuli. Therefore, targeting the local and long-distance projections mediated by the AP and other brainstem regions may be crucial for the development of antiemetic drugs or therapeutic strategy for nausea and vomiting.

Figure3 |

Schematic diagram of the neural circuitry mediating toxin-induced nausea and vomiting via the gut-brain axis (modified according to references [21,22]). Circuit tracing localized the brain-gut axis circuitry that innervates DVC Tac1+ neurons. The GCAMP signal associated with retching is transmitted from gut-innervating Htr3a+ sensory neurons in Nodose Ganglion to DVC Tac1+ neurons. Selective activation of DVC Tac1+ neurons projecting to rVRG and LPB induced retching behavior and nausea, respectively. Furthermore, external emetic toxins directly stimulate 5-HT3-positive neurons in the jugular ganglion to transmit emetic signals to NTS Calb1+ neurons. NTS Calb1+ neurons project to the PBNel and Amb/RVLM. The Calb1 NTS-Amb/RVLM pathway induces retching by regulating diaphragm contractions to increase gastric pressure, while the Calb1 NTS-PBNel pathway plays a role in inducing nausea. SEA: staphylococcal enterotoxin A; DOX: doxorubicin; EC cell: enterochromaffin cell; DVC: dorsal vagal complex; NTS: nucleus tractus solitarius; LPB: lateral parabrachial nucleus; rVRG: the rostral part of the ventral respiratory group; PBNel: the external lateral subdivision of the parabrachial nucleus; Amb/RVLM: nucleus ambiguous/rostral ventrolateral medulla.

3. RECEPTORS ASSOCIATED WITH NAUSEA AND VOMITING

A number of studies have shown that some exogenous stimuli induce nausea and vomiting by releasing emetic neurotransmitters/mediators to activate corresponding emetic receptors [6], including 5-hydroxytryptamine (5-HT), neurokinin-1 (NK-1R), dopamine D2 and D3, mu and kappa opioid, muscarinic M1, and histamine H1 receptors (Table 1). Most of these receptors are expressed peripherally, such as in the gastrointestinal tract and vagus, glossopharyngeal, phrenic, trigeminal, and lingual nerves, and in the brainstem dorsal vagal complex, such as the AP, and have crucial roles in the generation of nausea and vomiting.

Table1 |

Receptors and the ligands related to nausea and vomiting.

Receptor types	Location distribution	Species	Agonists	Inhibitors
5-HT3 receptor [24–26]	Gastrointestinal tract, the brainstem dorsal vagal complex emetic nuclei, vagus nerve	Human	Serotonin	Ondansetron, granisetron, dolasetron, palonosetron
NK1 receptor [27–29]	The brainstem dorsal vagal complex emetic nuclei, vagal afferent neurons, enteric neurons, and enterochromaffin cells of the gastrointestinal tract	Dogs, ferrets, least shrews	Substance P, GR73632	Aprepitant, netupitant, rolapitant
D2/3 receptors [4,30–32]	The brainstem dorsal vagal complex emetic nuclei, vagus nerve,	Ferrets, dogs, least shrews	Apomorphine, quinpirole, PNU95666E, 7-OH-DPAT	Chlorpromazine, haloperidol, metoclopramide
Muscarinic M1 receptor [30,33]	The brainstem dorsal vagal complex	Cats, least shrews	McN-A-343, Pilocarpine	Scopolamine, atropine
Histamine H1 Receptor [34–36]	Vestibular system, brainstem nucleus	Rats, mice, human	Histamine	Promethazine, dimenhydrinate, diphenhydramine
μ opioid receptor [37–40]	Area postrema, solitary tract nucleus, vagal afferent neurons, gastrointestinal tract	Rats, ferrets	Loperamide, morphine	Naloxone, naldemedine
Neuropeptide Y2 receptor [69–71]	Area postrema, vagal afferent neurons, extrinsic enteric neurons, submucosal neurons	Mice, dogs, ferrets, human	PYY (3-36)	JNJ-31020028
GFRAL receptor [69,73]	Area postrema	Mice, rats, musk shrews	GDF15	—
TP receptor [81–83]	Brainstem, cortex, cerebellum	Ferrets, least shrews	U46619	—
EP3/1 receptor [85]	The brainstem dorsal vagal complex	Ferrets	Sulprostone	—
CysLT1 receptor [90,91]	The brainstem dorsal vagal complex, intestinal nervous system	Least shrews, rats	LTC4, LTD4, LTE4	Pranlukast, montelukast
TRPV1 receptor [41,92–94]	The brainstem dorsal vagal complex	Least shrews, ferrets, dogs	RTX, arvanil, arachidonamide, N-arachidonoyl-dopamine	—
Glucagon-like peptide 1 receptor [98]	Septal nucleus, hypothalamus, brain stem	Mice, rats, musk shrews	GLP-140	—
Ghrelin receptor [100,101]	Hypothalamus, ventromedial nucleus, arcuate nucleus, ventral tegmental area, hippocampus	Mice, ferrets, human	Ghrelin, relamorelin	—

3.1 5-hydroxytryptamine receptors

The 5-HT receptors are classified into seven families (5-HT_1–7), with 5-HT₃ being an exception because 5-HT₃ is a voltage-gated ion channel rather than a metabotropic receptor. The other subtypes of 5-HT receptors are all G protein-coupled receptors. While evidence suggests that 5-HT_1–4 receptors may be involved in regulation of the vomiting reflex, clinical evidence thus far supports a primary role for 5-HT₃ receptor in the vomiting process [24]. Activation of the 5-HT₃ receptor results in rapid excitatory postsynaptic potentials and rapid depolarization of 5-HTergic neurons, leading to an increased intracellular Ca²⁺ concentration and subsequent release of various vomiting neurotransmitters and peptides, such as dopamine, cholecystokinin, glutamate, acetylcholine, substance P, or 5-HT [41]. Clinical studies have indicated that first-generation (e.g., ondansetron, granisetron, and dolasetron) and second-generation (e.g., palonosetron) 5-HT₃ receptor antagonists alleviate acute-phase chemotherapy-induced vomiting, with serotonin being a major vomiting mediator [25,26]. Although 5-HT₃ receptor antagonists are generally considered narrow-spectrum antiemetic drugs and are used to suppress postoperative nausea and vomiting as well as pregnancy-induced vomiting [25,26,42].

3.2 Neurokinin NK₁ receptor

Substance P is a member of the tachykinin family in mammals. Tachykinins in mammals activate three specific membrane receptors (NK₁, NK₂, and NK₃) all of which belong to the G protein-coupled receptor superfamily. These receptors are selectively recognized by endogenous Substance P, Neurokinin A, and Neurokinin B, respectively, with preferential selectivity for NK₁, NK₂, and NK₃ receptors, respectively. Current research suggests that the NK₁ receptor has a major role in inducing vomiting [43], especially in the delayed phase of vomiting induced by chemotherapy for cancer. Systemic administration of Substance P induces vomiting in dogs, while surgical removal of the AP do not exhibit vomiting to Substance P. Similar findings have been observed in ferrets [27]. Additionally, administration of the selective NK₁ receptor agonist GR73632 can induce vomiting in least shrews [28,29]. NK₁ receptor and Substance P are expressed in central and peripheral locations, including the brainstem dorsal vagal complex emetic nuclei, vagal afferent neurons, enteric neurons, and enterochromaffin cells of the gastrointestinal tract [44]. Furthermore, Substance P can stimulate NK₁ receptor activation in the AP neurons, leading to vomiting. Specific deletion of intestinal or brainstem NK₁ receptor abolishes vomiting induced by the NK₁R selective agonist GR73632 [45]. Clinical studies suggest that NK₁R antagonists, such as aprepitant, netupitant, and rolapitant, are recommended for inhibiting delayed vomiting induced by highly emetogenic cancer chemotherapy drugs [46]. Along with the 5-HT₃ receptor antagonists plus dexamethasone are one major component of triple prophylactic antiemetic therapy [25,26,42,47]. NK₁R antagonists exhibit broad-spectrum antiemetic effects [48], and have also been clinically proven effective for postoperative nausea and vomiting [49,50].

3.3 Dopamine D_2/3 receptors

Dopamine is a monoamine neurotransmitter that acts as a pro-emetic agent by activating two classes of G protein-coupled receptors (dopamine D₁-like [D₁ and D₅]) and dopamine D₂-like [D₂, D₃, and D₄]) receptors. The involvement of dopamine in vomiting was first discovered through the pro-emetic effects of the non-selective dopamine receptor agonist, apomorphine [6]. To date, numerous studies have shown the involvement of dopamine D₂ and D₃ receptors in the regulation of vomiting [4]. Some studies have indicated that non-selective dopamine receptor agonists, such as apomorphine, dopamine D₂ receptor agonists, such as quinpirole, and dopamine D₃ receptor agonists, such as PNU95666E, 7-OH-DPAT, can induce vomiting [30–32], which can be attenuated by their respective competitive antagonists, whereas dopamine D₁/D₄/D₅ receptor-selective agonists do not exhibit pro-emetic properties. Dopamine and dopamine D₂/D₃ receptors are widely distributed in the vomiting reflex arc, including the dorsal vagal complex (AP, nucleus of the solitary tract, and dorsal motor nucleus of the vagus), vagal nerves, gastrointestinal tract, and the enteric nervous system [4]. Currently, various categories of dopamine D₂-like receptor antagonists, such as phenothiazines (e.g., chlorpromazine), butyrophenones (e.g., droperidol), and benzamides (e.g., metoclopramide, which also blocks 5-HT₃ receptor), are used clinically to prevent vomiting induced by different emetic stimuli, including postoperative nausea and vomiting, uremia, radiation sickness, and viral gastroenteritis [51].

3.4 Acetylcholine receptors

Acetylcholine has a significant role in physiology and has been shown to be a pro-emetic neurotransmitter [52]. Acetylcholine activates ligand-gated nicotinic acetylcholine receptor ion channels as well as G protein-coupled muscarinic acetylcholine receptors M₁ through M₅. Clinical medications that inhibit acetylcholine metabolism, such as acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine), induce vomiting in humans and other species [53]. Additionally, stimulation of muscarinic receptors also leads to vomiting. However, the exact role of the five muscarinic receptor subtypes in vomiting is not completely understood. Vomiting induced by muscarinic M₁ receptor has been demonstrated in animals. Intracerebroventricular injection of the M₁ receptor agonist, McN-A-343, induces dose-dependent vomiting in cats, which is prevented by ablation of the AP [33]. Furthermore, intraperitoneal injection of McN-A-343 also elicits vomiting in least shrews [30]. Currently available non-selective muscarinic receptor antagonists have also been shown to block M₁ receptor for the prevention of nausea and vomiting. Currently available but non-selective muscarinic receptor antagonists, such as scopolamine and atropine, that also block M₁ receptor are used for the prevention of nausea and vomiting caused by motion sickness [54]. Some studies have also demonstrated the efficacy of transdermal scopolamine for PONV [55,56]. These findings suggest that acetylcholine receptors may serve as potential therapeutic targets for nausea.

3.5 Histamine H₁ receptor

The physiologic effects of histamine are mediated through four types of histamine receptors (H₁, H₂, H₃, and H₄) [57]. Preclinical studies indicate that during motion sickness, heightened vestibular function activates the histaminergic neuronal system, ultimately stimulating histamine H₁ receptor in the brainstem and leading to vomiting [34]. Additionally, inhibiting the histamine-metabolizing enzyme, histamine N-methyltransferase (HNMT), increases endogenous histamine and exacerbates motion sickness in dogs, as well as sensitivity to conditioned taste aversion in rats [34]. Further research has suggested that microinjection of the H₁ receptor antagonist, promethazine, into the dorsal vagal complex in rats alleviates conditioned taste aversion, while injection of recombinant lentivirus carrying rat HNMT-shRNA into the DVC promotes motion sickness. Moreover, increased levels of histamine in the hypothalamus and brainstem nuclei, such as the vestibular nucleus and dorsal vagal complex, are considered the main triggers of motion sickness [34,58,59]. Although mice do not vomit, motion sickness induces an increase in the histamine level, histamine H₁ receptor mRNA, and H₁ receptor protein expression in the hypothalamus and brainstem, which can be significantly reduced by pretreatment with hesperidin, a flavonoid compound that inhibits mast cell synthesis and release of histamine [34]. Histamine H₁ receptor blockers, such as dimenhydrinate and diphenhydramine, are commonly used antiemetic agents against nausea and vomiting secondary to motion sickness [35,36]. Furthermore, many H₁ receptor antagonists have anticholinergic properties, which may also contribute to antiemetic effects [54]. Histamine also serves as a peripheral emetic agent because histamine is released from intestinal mast cells and participates in vomiting induced by staphylococcal enterotoxin poisoning. Staphylococcal enterotoxin binds to intestinal mucosal mast cells, inducing mast cell degranulation and histamine release, which triggers vomiting by stimulating vagal afferent neurons and transmitting to the brainstem vomiting center [60]. Additionally, clinical studies have shown that preoperative use of H₁ receptor antagonists significantly reduces the incidence of PONV in gynecologic laparoscopic surgery [61], indicating that H₁ receptor also have an important role in the progression of PONV.

3.6 Opiate receptors

Although the exact physiologic mechanisms by which opioid drugs induce nausea and vomiting have not been fully elucidated, some studies suggest that this process involves activation of opioid receptors in the AP, vestibular organs, and gastrointestinal tract [62]. Three types of opioid receptors (μ, κ, and δ) may have a role in opioid-induced nausea and vomiting, but some research indicates that activation of μ receptors is crucial in vomiting. Expression of μ opioid receptors has been confirmed in tissues, such as the AP, solitary tract nucleus, vagal afferent neurons, and gastrointestinal tract. Administration of morphine can induce significant conditioned taste aversions (CTA) in rats and activation of specific subtypes of opioid receptors revealed differences in morphine aversion effects in different rat strains, implicating activation of mu-opioid receptors (MOR) [37,38]. Administration of naloxone significantly reduces morphine-induced CTA. Other animal models have shown that the μ receptor antagonist, naldemedine, significantly inhibits morphine-induced dry heaves and vomiting frequency and duration in ferrets [39]. It has been confirmed that the μ opioid receptor agonist loperamide can induce vomiting in ferrets, which is not affected by abdominal vagal nerve transection but is eliminated by ablation of the AP [40], suggesting that vagal afferent signals may not be important for μ opioid receptor-mediated vomiting. Opioid receptor agonists may influence dopamine D2 receptor and the 5-HT3 signaling pathway in the AP, as well as sensory inputs from the histamine H1 and acetylcholine systems to the solitary tract nucleus. The solitary tract nucleus may have output pathways to the dorsal motor nucleus of the vagus nerve, which generates the vomiting reflex, as well as projection pathways to the midbrain and forebrain for nausea perception [63]. Although μ opioid receptors in the AP are involved in vomiting regulation, μ opioid receptors in the solitary tract nucleus have an inhibitory effect on vomiting [64]. Genetic variations in μ receptor genes also have different effects on the emetic potency of opioid drugs [65]. Therefore, further elucidation of the function of opioid receptors will provide important references for the prevention and treatment of nausea and vomiting with drugs and non-pharmacologic methods.

3.7 Neuropeptide Y2 receptors

The neuropeptide Y receptor family is activated by three endogenous ligands (neuropeptide Y, peptide YY [PYY], and pancreatic polypeptide). Neuropeptide Y receptors consist of five G protein-coupled receptor subtypes (Y1, Y2, Y4, Y5, and Y6), mediating various physiologic and pathologic processes [66]. In dogs and rats, high-affinity binding sites for PYY are primarily located in the AP of the brainstem. Peripherally, Y2 receptors are predominantly distributed in neurons, including vagal afferent, extrinsic enteric, and submucosal neurons. The Y2 receptor agonist, PYY (3-36), has been shown to exhibit anorectic effects via Y2 receptors in the arcuate nucleus, while pretreatment with the selective Y2 receptor antagonist, JNJ-31020028, significantly reduces PYY (3-36)-induced vomiting [67]. Additionally, peripheral administration of PYY (3-36) produces appetite suppression effects via Y2 receptors in the solitary tract nucleus, which are abolished by abdominal vagal nerve transection [68]. This appetite suppression effect has also been used as an indicator of nausea in rodents [69]. Studies have shown that PYY (3-36) infusion also induces nausea in humans [70]. Furthermore, the common dietary mycotoxin, deoxynivalenol, triggers vomiting in ferrets and elevates plasma levels of peptide YY (3-36) and 5-HT, effects that can be inhibited by the calcium-sensing receptor antagonist, NPS-2143, or the transient receptor potential vanilloid-1 antagonist, ruthenium red [71]. These findings collectively indicate the significant role of Y2 receptors in inducing nausea and vomiting, and further research targeting Y2 receptors may provide more possibilities for the prevention and treatment of nausea and vomiting.

3.8 GFRAL receptor

Growth differentiation factor 15 (GDF15) is a cytokine expressed in various tissues, which when stimulated is secreted into the circulation and targets activation of glial-derived neurotrophic factor receptor alpha-like (GFRAL) receptors in the brainstem (AP and solitary tract nucleus) [72]. Cisplatin induces elevated levels of GDF15 in the circulation and activates GFRAL-positive neurons in the dorsal vagal complex area (AP/solitary tract nucleus) in mice [69]. Neutralizing GDF15 with monoclonal antibodies alleviates cisplatin-induced vomiting in non-human primates [73]. Elevated endogenous GDF15 has become a well-known biomarker associated with pregnancy-related nausea and vomiting [74–76]. Additionally, systemic administration of GDF15 can induce vomiting in ferrets, while central or systemic injection of glial cell-derived neurotrophic factor (GDNF) can induce emetogenic behaviors, such as food aversion and increased kaolin intake, in species that do not vomit [69]. Furthermore, exogenous administration of GDF15 induces anorexia by eliciting nausea and vomiting, suggesting that the anorectic response to GDF15 is driven by feelings of nausea and discomfort [69]. GDF15 appears to transmit a range of somatic stress signals to the brain by promoting avoidance behavior to reduce exposure to corresponding stressful conditions. Therefore, further research is warranted to explore the role of GDF15 in nausea and vomiting and identify new therapeutic targets.

3.9 Other receptors

Phospholipase A2 releases arachidonic acid metabolites from cell membrane phospholipids, including prostaglandins and leukotrienes, which are termed inflammatory mediators and are increasingly recognized for their roles in the gastrointestinal tract. Due to their unstable nature, arachidonic acid metabolites are rapidly released from cells upon formation and exert their functions locally through specific G protein-coupled receptors on target cells. Major types of prostaglandins include prostacyclin I₂ (PGI₂), prostaglandin D₂ (PGD₂), prostaglandin E₂ (PGE₂), and prostaglandin F_2α (PGF_2α) [77]. Among these prostaglandins, PGE₂ is the most abundant [78]. Ten subtypes of prostaglandin receptors have been identified in humans (DP1-2, EP1-4, FP, IP1-2, and TP) [79]. Elevated serum levels of PGE₂ are associated with an increased frequency of nausea and vomiting during pregnancy [80]. Several prostaglandins have been shown to have potential emetic effects in preclinical studies. Intraperitoneal injection of the prostaglandin TP receptor agonist, U46619, induces vomiting behavior in ferrets [81] and least shrews [82,83]. Additionally, PE₂ induces vomiting in ferrets [84]. A selective agonist of the prostaglandin EP3/1 receptor, sulprostone, also induces vomiting in ferrets [85], possibly involving central mechanisms unrelated to vagal afferents [86]. Moreover, several prostaglandins have been shown to elicit strong emetic responses in musk shrews [87]. These studies on various prostaglandin receptor agonists inducing emesis suggest that different prostaglandin receptor subtypes may have roles in mediating nausea and vomiting. Corticosteroids block prostaglandin biosynthesis by inhibiting phospholipase A2 and cyclooxygenase, helping alleviate cisplatin-induced acute/delayed vomiting in animals [88] and humans [89]. In least shrews, cysteinyl leukotrienes (LTC4, LTD4, and LTE4) induce vomiting, with varying emetic potencies [90]. Intraperitoneal injection of LTC4-induced vomiting is prevented by the cysteinyl leukotriene CysLT1 receptor antagonist, pranlukast, indicating the crucial role of CysLT1 receptor in vomiting [90]. Studies on another classic CysLT1 antagonist, montelukast, suggest the effectiveness of montelukast in reducing kaolin intake induced by sevoflurane anesthesia in rats [91]. Therefore, inhibiting the leukotriene pathway may aid in the treatment of nausea and vomiting.

Furthermore, the role of the TRPV1 receptor in nausea and vomiting has also been reported [92]. Chronic excessive use of cannabis can lead to cannabinoid hyperemesis syndrome, while hot water therapy and local capsaicin treatment significantly inhibit the occurrence of cannabinoid hyperemesis syndrome, suggesting that heat-induced TRPV1 activation may exert antiemetic effects, similar to the role of cannabis in central descending pain pathways. Long-term use of cannabis preparations containing high concentrations of tetrahydrocannabinol may induce vomiting by activating CB1 receptor and downregulating TRPV1 [93]. The role of TRPV1 in nausea and vomiting has been further demonstrated by its agonist, resiniferatoxin (RTX), which at lower doses significantly inhibits vomiting induced by various emetogens in least shrews [30]. Additionally, several other TRPV1 agonists, such as arvanil, arachidonamide, and N-arachidonoyl-dopamine, also exhibit antiemetic effects [94]. These results collectively suggest that TRPV1 activation may also serve as a potential target for nausea and vomiting treatment.

The glucagon-like peptide 1 receptor (GLP-1R) is a receptor that binds to glucagon-like peptide 1 (GLP-1), a hormone involved in glucose metabolism, appetite regulation, and gastrointestinal motility [95]. Activation of the GLP-1R helps regulate insulin secretion, glucose homeostasis, and satiety, and GLP-1R has also been linked to effects on nausea and vomiting. Medications that target the GLP-1R, such as GLP-1R agonists (GLP-1RAs) that are used for diabetes management, can affect nausea and vomiting as side effects or therapeutic outcomes [96]. In clinical practice, the most common side effects of GLP-1RAs are gastrointestinal (GI), typically including upper-GI effects (e.g., nausea or vomiting) and/or lower-GI effects (diarrhea or constipation) [97]. One preclinical study in three different species (i.e., mice, rats, and musk shrews) showed that GLP-1R activation by GLP-140 causes emesis and illness-like behaviors (i.e., pica and CTA), and glucose-dependent insulinotropic polypeptide receptor (GIPR) activation attenuates the emetic side effect profile of GLP-1R activation [98].

The ghrelin receptor, also known as the growth hormone secretagogue receptor (GHS-R), is involved in regulating appetite and energy balance, as well as nausea and vomiting [99]. Studies have indicated that ghrelin receptor agonists, such as ghrelin, alleviate anorexia and vomiting in animal models of dyspepsia and vomiting and reduce cachexia and nausea in cancer patients [100]. In addition, subcutaneous injection of relamorelin (a ghrelin receptor agonist) has been shown to reduce nausea, vomiting, and the sense of fullness in patients with gastroparesis [101]. Together, these studies revealed the important role of ghrelin receptor in nausea and vomiting but the underlying mechanisms by which ghrelin modifies nausea need to be further explored in future studies.

4. CURRENT CLINICAL RESEARCH, PREVENTION, AND TREATMENT MEASURES OF PONV

PONV refers to the occurrence of nausea, retching, or vomiting within 24–48 h after surgery, which is one of the most common side effects post-surgery. Between 30% and 50% of patients undergoing general anesthesia with inhalational agents experience PONV, with a higher incidence following major surgeries and in high-risk patients [10,102]. Mild PONV can cause various discomforts, affecting patients’ quality of life. Severe cases can lead to increased arterial pressure, intracranial pressure, intraocular pressure, wound dehiscence, incisional hernia formation, electrolyte imbalance, acid-base imbalance, wound rupture infection, and even life-threatening situations [103]. In addition to impacting patient recovery, PONV also prolongs the time spent by patients in post-anesthesia care units and increases hospitalization costs, thus reducing patient satisfaction [104]. PONV is associated with various factors, including female gender, motion sickness, history of PONV, cigarette smoking, or age. Current pharmacologic treatments are not always effective for everyone or may have unpleasant side effects [105].Clinical research indicates that the main causes of PONV are the use of inhalational anesthetics, such as nitrous oxide, sevoflurane, isoflurane, and halothane [63,106,107], and opioid analgesics, such as morphine and fentanyl [3,106,108], for perioperative pain management.

Nitrous oxide can act on opioid receptors and dopamine receptors, stimulating the sympathetic nervous system and leading to intestinal distension and flatulence. Nitrous oxide can also diffuse into the middle ear cavity, causing an increase in pressure, which can result in nausea and vomiting. Studies have shown that isoflurane can increase the expression of c-Fos in the rat AP [109], suggesting that the emetic effect of volatile anesthetics may be related to the activation of brainstem nucleus neurons. Increased vagal afferent activity can affect the vestibular system, which may also contribute to nausea and vomiting induced by inhalational anesthetics [63]. Inhalational anesthetics can enhance the function of the 5-HT₃ receptor, which may also contribute to nausea and vomiting [6]. In patients undergoing general anesthesia and experiencing postoperative nausea and vomiting, a significant increase in substance P plasma concentration has been observed, suggesting that substance P levels can serve as an objective indicator of PONV [110].

Due to the simplicity of administration, inhalational anesthetics remain the main anesthesia method in clinical practice [111]. Opioid drugs are commonly used for perioperative pain control, which helps to balance anesthesia. Opioids inhibit gastrointestinal motility and delay gastric emptying, which can independently induce nausea and vomiting [106]. The possible underlying mechanism involves the action on opioid receptors in the body, leading to decreased muscle tone and weakened gastrointestinal motility. Additionally, opioids can directly act on the emetic center, leading to vomiting. Moreover, the dose of opioid drugs is positively correlated with the incidence of PONV. Although intraoperative use of opioid drugs is not a continuous stimulus factor for PONV, postoperative monitoring and the use of opioid analgesics for pain management in the late stages of anesthesia and after discharge can also lead to PONV [112,113].

Surgical tissue trauma and inflammation appear to be another independent risk factor for PONV. The longer the duration of surgery, the greater the risk of PONV. Additionally, several types of surgeries have been shown to increase the risk of PONV in patients. Some potential PONV-inducing surgical types include cholecystectomy, gynecologic laparoscopic surgery, and otolaryngologic surgery [106]. Gastrointestinal surgical trauma triggers an inflammatory response, leading to the local release of Substance P, 5-HT, or other mediators [114,115], which may affect the signaling involved in nausea and vomiting. Some antiemetic drugs used to treat PONV have also been shown to have anti-inflammatory effects, such as dexamethasone and 5-HT₃ and NK₁ receptor antagonists. This suggests that treatments targeting postoperative inflammatory responses may also be effective in preventing PONV.

Currently, the prevention of PONV in clinical practice generally involves assessing potential high-risk factors, eliminating causative factors, reducing high-risk factors, and selecting appropriate anesthesia methods. Treatment of PONV mainly involves antiemetic drug intervention. Based on the mechanism of action, the drugs used for treating PONV can broadly fit into the following classes: (1) serotonin-receptor antagonists, such as ondansetron and dolasetron (5-HT₃ receptor antagonists have become one of the first-line treatments for high-risk patients with PONV [116]); (2) glucocorticoids, such as dexamethasone and methylprednisolone (dexamethasone has been widely studied in prevention of postoperative nausea and vomiting); (3) NK receptor antagonists, such as aprepitant and rolapitant, which have been shown to be extremely useful in the management of CINV and are also effective in PONV [117] (compared to ondansetron, aprepitant has shown better efficacy in both acute and delayed PONV [118,119]); (4) the clinical effect of benzamides, such as metoclopramide, is due to a combination of antiemetic and promotility actions via antagonism to dopamine D2 receptor and 5-HT₃ receptor [117]; (5) antihistamines, diphenhydramine, meclizine, and promethazine are common medications in this class but less commonly used for the prevention and treatment of PONV; and (6) anticholinergics, such as scopolamine, routinely used in the prophylaxis and treatment of motion sickness and PONV [120].

Although most of the antiemetic can have adverse effects, such as headache, dizziness, drowsiness, dry mouth, blurred vision, and QT prolongation [3], antiemetic medications are generally well tolerated. However, the effectiveness can be inconsistent and varies widely among patients. Emerging evidence suggests that gender differences may influence treatment outcomes. Gender has been proved to affect the incidence, susceptibility, presentation, diagnosis, and severity of many psychiatric disorders, such as schizophrenia and eating disorders. Female gender generally has much higher incidence of these diseases than males and the clinical symptoms are often different [121,122]. Female gender is one of five factors in the simplified risk-scoring system for PONV in adults that was developed by Apfel et al. [123]. The other four factors are history of PONV, motion sickness, non-smoking status, and postoperative opioids. Female gender was the strongest overall predictor of PONV in an evidence-based analysis study [106]. In the post-anesthesia care unit, a register-based cohort study found low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. The gender-specific differences in the incidence of PONV (female > males) was observed and confirmed [124]. Studies have shown a link between hormonal fluctuations and PONV in females of reproductive age. However, reports on PONV frequency during the pre- and post-ovulatory phases of the menstrual cycle are still debated [125]. Even so, giving full consideration of the sex hormone levels and psychosocial status during menstrual cycle in female surgical populations is very likely helpful to reduce the risk of PONV.

Nausea and vomiting can be triggered by multiple pathways, including central, peripheral, and gastrointestinal factors. Multi-target therapies can address several of these pathways simultaneously, potentially providing more effective symptom relief than single-target treatments. For the prevention of PONV in patients at moderate-to-high risk, a combination of prophylactic antiemetic drugs with different mechanisms of action is often used [3]. Within 48 h postoperatively, the combined use of the dopamine D_2/3 receptor antagonist (droperidol), glucocorticoids (dexamethasone), the 5-HT₃ receptor antagonist (ondansetron), and the NK₁ receptor antagonist (aprepitant) significantly reduces the cumulative incidence of vomiting compared to monotherapy [126]. To use a combination of antiemetic drugs with different mechanisms of action, the multifactorial etiology of PONV should be addressed through a multimodal approach to pain management. Additionally, some non-pharmacologic therapies are also used to treat PONV, such as transcutaneous electrical nerve stimulation, acupuncture, and acupressure in traditional Chinese medicine alone or in combination. Non-pharmacologic treatments in traditional Chinese medicine are widely used as adjunctive therapies for PONV.

One challenge in evaluating treatment efficacy is the subjective nature of nausea and vomiting, which can be influenced by numerous factors, including psychological and environmental variables. This variability makes it difficult to establish a one-size-fits-all treatment approach.

5. CONCLUSION AND PERSPECTIVES

Nausea and vomiting are important defensive mechanisms of the human body that help to clear substances that may cause harm or disease, promote recovery, and avoid further damage. Nausea and vomiting are crucial for survival. In contrast, nausea and vomiting are major side effects of surgeries and chemotherapy with complex mechanisms influenced by various factors. These symptoms significantly increase the physiological, psychological, and economic burden on patients and severely impact the quality of life and treatment outcomes. Although pharmacologic and non-pharmacologic interventions can significantly reduce the incidence of PONV, the available antiemetic medications are still limited and there is no unified treatment method or medication guidelines. In-depth analysis of the mechanisms of nausea and vomiting and the development of safer and more effective antiemetic drugs and treatment strategies remain urgent needs in both basic and clinical research.

The vomiting reflex is common among several mammalian species, including carnivores, primates, and insectivores. This reflects the evolutionary significance of vomiting as a protective mechanism against ingesting toxins. However, rodents, such as rats and mice, lack the vomiting reflex, which has been attributed to anatomic and neural differences in the upper alimentary tract and brainstem circuitry [127]. This is a well-documented phenomenon and underscores the limitations of using these animals for certain types of research. Although those research present challenges and may not fully capture the physiologic processes of nausea and vomiting, it is undeniable that the physiologic processes provide us much deep insights into the mechanism underlying nausea and vomiting. Alternative models that more accurately represent emetic responses are still needed to draw the complete picture.

Currently, multiple neurotransmitters, receptors, and neural pathways have been confirmed to be involved in the occurrence and development of nausea and vomiting. This further expands our understanding of the mechanisms underlying nausea and vomiting, providing important clues for new preventive and therapeutic strategies, as well as related drug development. In the future, with deeper research into the molecular and neural mechanisms of nausea and vomiting, the introduction of new medications, and advances in more intelligent postoperative management strategies, prevention, and treatment of postoperative nausea and vomiting will continue to evolve towards more personalized and precise approaches. This development is crucial for reducing the diagnostic and therapeutic pressures on patients, enhancing their postoperative comfort, facilitating rapid recovery, and improving overall quality of life.

CONFLICTS OF INTEREST

The authors declare that they have no competing conflict interests in this study.

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