Search

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of patients with cancer receiving chemotherapeutic drugs. However, the pathological mechanism of CINV is biologically multifaceted and has not yet been fully elucidated. Despite this, increasing evidence indicates that gastrointestinal (GI) inflammation dramatically contributes to the incidence of CINV. It is well established that 5-hydroxytryptamine and substance P are critical meditators in both of CINV and GI inflammation by binding to their corresponding receptors. Meanwhile, antiemetic drugs used for the prophylaxis of CINV have demonstrated surprising effects on relieving GI inflammation, and anti-inflammatory drugs are also effective in preventing CINV. The commonalities between the pathogenesis and clinical treatment of GI inflammation and CINV indicate that GI inflammation is an essential mechanism in CINV. In this review, we provide novel insights into the crucial role of GI inflammation in CINV, with the aim to discover the novel antiemetic drugs against CINV from the perspective of alleviating GI inflammation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Akt (protein kinase B) signaling is frequently activated in diverse cancers. Akt inhibitors such as perifosine and MK-2206 have been evaluated as potential cancer chemotherapeutics. Although both drugs are generally well tolerated, among their most common side-effects vomiting is a major concern. Here we investigated whether these Akt inhibitors evoke emesis in the least shrew model of vomiting. Indeed, both perifosine and MK-2206 induced vomiting with maximal efficacies of 90% at 50 mg/kg (i.p.) and 100% at 10 mg/kg (i.p.), respectively. MK-2206 (10 mg/kg, i.p.) increased c-Fos immunoreactivity both centrally in the shrew brainstem dorsal vagal complex (DVC) emetic nuclei, and peripherally in the jejunum. MK-2206 also evoked phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both the DVC emetic nuclei and the enteric nervous system in the jejunum. The ERK1/2 inhibitor U0126 suppressed MK-2206-induced emesis dose-dependently. We then evaluated the suppressive efficacy of diverse antiemetics against MK-2206-evoked vomiting including antagonists/inhibitors of the: L-type Ca 2+ channel (nifedipine at 2.5 mg/kg, subcutaneously (s.c.)); glycogen synthase kinase 3 (GSK-3) (AR-A014418 at 10 mg/kg and SB216763 at 0.25 mg/kg, i.p.); 5-hydroxytryptamine 5-HT 3 receptor (palonosetron at 0.5 mg/kg, s.c.); substance P neurokinin NK 1 receptor (netupitant at 10 mg/kg, i.p.) and dopamine D 2/3 receptor (sulpride at 8 mg/kg, s.c.). All tested antagonists/blockers attenuated emetic parameters to varying degrees. In sum, this is the first study to demonstrate how pharmacological inhibition of Akt evokes vomiting via both central and peripheral mechanisms, a process which involves multiple emetic receptors., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Δ 9 -THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB 1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT 3 -and neurokinin NK 1 -receptors to induce vomiting. Δ 9 -THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT 3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ 9 -THC and related CB 1 /CB 2 receptor agonists (WIN55,212-2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK 1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ 9 -THC (i.p. or s.c.), WIN55,212-2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ 9 -THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ 9 -THC against SP-induced vomiting was prevented by low non-emetic doses of the CB 1 receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK 1 receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ 9 -THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK 1 receptor agonists via stimulation of cannabinoid CB 1 receptors., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ca 2+ plays a major role in maintaining cellular homeostasis and regulates processes including apoptotic cell death and side-effects of cancer chemotherapy including vomiting. Currently we explored the emetic mechanisms of FPL64176, an L-type Ca 2+ channel (LTCC) agonist with maximal emetogenic effect at its 10 mg/kg dose. FPL64176 evoked c-Fos immunoreactivity in shrew brainstem sections containing the vomit-associated nuclei, nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus. FPL64176 also increased phosphorylation of proteins ERK1/2, PKCα/βII and Akt in the brainstem. Moreover, their corresponding inhibitors (PD98059, GF 109203X and LY294002, respectively) reduced FPL64176-evoked vomiting. A 30 min subcutaneous (s.c.) pretreatment with the LTCC antagonist nifedipine (10 mg/kg) abolished FPL64176-elicited vomiting, c-Fos expression, and emetic effector phosphorylation. Ryanodine receptors (RyRs) and inositol trisphosphate receptors (IP 3 Rs) mediate intracellular Ca 2+ release from the sarcoplasmic/endoplasmic reticulum. The RyR antagonist dantrolene (i.p.), or a combination of low doses of nifedipine and dantrolene, but not the IP 3 R antagonist 2-APB, significantly attenuated FPL64176-induced vomiting. The serotonin type 3 receptor (5-HT 3 R) antagonist palonosetron (s.c.), the neurokinin 1 receptor (NK 1 R) antagonist netupitant (i.p.) or a combination of non-effective doses of netupitant and palonosetron showed antiemetic potential against FPL64176-evoked vomiting. Serotonin (5-HT) and substance P immunostaining revealed FPL64176-induced emesis was accompanied by an increase in 5-HT but not SP-immunoreactivity in the dorsomedial subdivision of the NTS. These findings demonstrate that Ca 2+ mobilization through LTCCs and RyRs, and subsequent emetic effector phosphorylation and 5-HT release play important roles in FPL64176-induced emesis which can be prevented by 5-HT 3 R and NK 1 R antagonists., (Copyright © 2018 Elsevier B.V. All rights reserved.)

5-HT receptors are implicated in many gastrointestinal disorders. However, the precise role of 5-HT in mediating GI responses in Suncus murnius is still unclear. Therefore in this study, the effects of 5-HT and its agonists were investigated in Suncus. The involvement of 5-HT 2C receptors in mediating emesis was also investigated. The ability of 5-HT and its agonists/antagonists at 5-HT 1A and 5-HT 2 to modify GI motility was investigated in vitro and in vivo. WAY100635 (a 5-HT 1A antagonist) inhibited the contraction response to 5-HT in the proximal segments without affecting the maximum response; whilst enhancing the contraction to 5-HT (>30.0nM) in the distal intestine. The selective 5-HT 2A and 5-HT 2B receptor antagonists MDL-100907 and RS-127445 attenuated 5-HT-induced contractions (<10.0µM) in the distal segments. RS-127445 also attenuated 5-HT-induced contractions in the central segments. The selective 5-HT 2C receptor antagonist SB-242084, attenuated the responses to 5-HT (> 3.0nM) in the proximal and central but not the distal regions. 8-OH-DPAT-induced relaxation was resistant to the antagonism by 5-HT 1A/7 antagonists. DOI in the presence of 5-HT 1A/2A/2B/2C antagonists induced greater contraction responses (>1.0µM) in most tissues, whilst RS-127445, or SB-242084, reduced the responses to DOI (< 1.0µM) in some tissues. SB-242084 also suppressed emesis-induced by motion and intragastric CuSO 4 . In conclusion, within different regions of intestine, 5-HT 2 receptors are differently involved in contraction and emetic responses and that 8-OH-DPAT induces relaxation via non-5-HT 1A/7 receptors. Suncus could provide a model to investigate these diverse actions of 5-HT., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The introduction of second generation serotonin 5-HT 3 receptor (5-HT 3 ) antagonist palonosetron combined with long-acting substance P neurokinin NK 1 receptor (NK 1 ) antagonists (e.g. netupitant) has substantially improved antiemetic therapy against early- and delayed-phases of emesis caused by highly emetogenic chemotherapeutics such as cisplatin. However, the improved efficacy comes at a cost that many patients cannot afford. We introduce a new class of antiemetic, the antiasthmatic leukotriene CysLT1 receptor antagonist pranlukast for the suppression of cisplatin-evoked vomiting. Pranlukast (10mg/kg) by itself significantly reduced the mean frequency of vomits (70%) and fully protected least shrews from vomiting (46%) during the delayed-phase of cisplatin (10mg/kg)-evoked vomiting. Although, pranlukast tended to substantially reduce both the mean frequency of vomits and the number of shrews vomiting during the early-phase, these reductions failed to attain significance. When combined with a first (tropisetron)- or a second (palonosetron)-generation 5-HT 3 receptor antagonist, pranlukast potentiated their antiemetic efficacy during both phases of vomiting. In addition, pranlukast by itself prevented several intracellular signal markers of cisplatin-evoked delayed-vomiting such as phosphorylation of ERK1/2 and PKA. When pranlukast was combined with either palonosetron or tropisetron, these combinations suppressed the evoked phosphorylation of: i) ERK1/2 during both acute- and delayed-phase, ii) PKCα/β at the peak acute-phase, and iii) PKA at the peak delayed-phase. The current and our published findings suggest that overall behavioral and intracellular signaling effects of pranlukast via blockade of CysLT1 receptors generally appear to be similar to the NK 1 receptor antagonist netupitant with some differences., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5mg/kg, i.p.) suppressed, but did not completely block, LiCl-induced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Activation of serotonergic 5-HT3 receptors by its selective agonist 2-methyl serotonin (2-Me-5-HT) induces vomiting, which is sensitive to selective antagonists of both 5-HT3 receptors (palonosetron) and L-type calcium channels (LTCC) (amlodipine or nifedipine). Previously we demonstrated that 5-HT3 receptor activation also causes increases in a palonosetron-sensitive manner in: i) intracellular Ca(2+) concentration, ii) attachment of calmodulin (CaM) to 5-HT3 receptor, and iii) phosphorylation of Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) and extracellular-signal-regulated kinase 1/2 (ERK1/2). Here, we investigate the role of the short-acting LTCC blocker nifedipine on 2-Me-5-HT-evoked intracellular Ca(2+) increase and on downstream intracellular emetic signaling, which have been shown to be coupled with 2-Me-5-HT׳s emetic effects in the least shrew. Using the cell-permeant Ca(2+) indicator fluo-4 AM, here we present evidence for the contribution of Ca(2+) influx through LTCCs (sensitive to nifedipine) in 2-Me-5-HT (1µM) -evoked rise in cytosolic Ca(2+) levels in least shrew brainstem slices. Nifedipine pretreatment (10mg/kg, s.c.) also suppressed 2-Me-5-HT-evoked interaction of 5-HT3 receptors with CaM as well as phosphorylation of CaMKIIα and ERK1/2 in the least shrew brainstem, and 5-HT3 receptors -CaM colocalization in jejunum of the small intestine. In vitro exposure of isolated enterochromaffin cells of the small intestine to 2-Me-5-HT (1µM) caused CaMKIIα phosphorylation, which was also abrogated by nifedipine pretreatment (0.1µM). In addition, pretreatment with the CaMKII inhibitor KN62 (10mg/kg, i.p.) suppressed emesis and also the activation of CaMKIIα, and ERK in brainstem caused by 2-Me-5-HT (5mg/kg, i.p.). This study provides further mechanistic explanation for our published findings that nifedipine can dose-dependently protect shrews from 2-Me-5-HT-induced vomiting., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: to review the topic of prognostic factors for chemotherapy-induced nausea and vomiting. Multiple patient factors such as age, gender and alcohol intake have been found that affect the likelihood of emesis with a given chemotherapy. Pharmacogenomics has also been explored as a cause for variation in emetic response. In theory these risk factors could be used to optimize antiemetic therapy for individual patients but guidelines for prophylactic antiemetics are based solely upon the type of chemotherapy administered. Attempts to identify subgroups of patients for whom guidelines recommendations are suboptimal have thus far been unsuccessful except for those with a poor experience in a previous cycle of the same chemotherapy. At present, there is no basis for deviating from evidence-based guidelines when prescribing antiemetics prior to the first cycle of chemotherapy., (© 2013 Published by Elsevier B.V.)

Complete control of emesis caused by cyclophosphamide (CPA) is of immense interest to both patients and physicians. Serotonin 5-HT3- and tachykinin NK1-receptor antagonists are widely used antiemetics in clinic, but they fail to completely control CPA-induced emesis. New antiemetic targets for the full control of CPA-induced vomiting are lacking. We therefore examined the effects of CPA on emetic targets downstream of 5-HT3- and NK1- receptors in an attempt to better understand the molecular bases of CPA-induced emesis. Acute CPA (200 mg/kg, i.p.) administration in the least shrew caused a biphasic pattern of emesis over a 40 h observation period, with maximal peak vomit frequency during the 1st hour of treatment (acute phase), followed by a delayed-phase which peaks at 27th hour. The NK1 receptor mRNA levels increased significantly at 8 h post-CPA treatment in the brainstem, and at 28 h in the whole intestine. Substance P mRNA levels tended to increase both in the brainstem and intestine at most time-points post-CPA injection, however due to large variability, they failed to attain significance. Likewise, protein expression profiles of both NK1- and 5-HT3 -receptors in the brainstem were unchanged at any time-point. However, phosphorylation levels of protein kinase A (PKA), but not of extracellular signal-regulated protein kinase 1/2 (ERK1/2), were increased at 2, 8, 22, 28, and 33 h time-points after the treatment with CPA. Moreover, brainstem but not frontal cortex cAMP tissue levels tended to be elevated at most time-points, but significant increases occurred only at 1 and 2 h post-CPA treatment. The phosphodiesterase inhibitor, rolipram, caused significant increases in shrew brainstem cAMP levels which were associated with its capacity to produce vomiting, while pretreatment with SQ22536, an inhibitor of adenylyl cyclase, prevented rolipram-induced emesis. The results demonstrate that accumulation of cAMP and subsequent activation of PKA in the brainstem may help to initiate and sustain emesis induced by CPA in the least shrew. Our findings suggest that suppression of the cAMP/PKA cascade may have antiemetic potential in the management of CPA-induced emesis.

Glucocorticoids, used primarily as anti-allergic and anti-inflammatory drugs, are also effective, alone or combined with other antiemetics, for preventing nausea and vomiting. Dexamethasone, one of the glucocorticoids, has been suggested as a first-line drug for preventing low-level emetogenic chemotherapy- and radiotherapy-induced nausea and vomiting, and in patients with only one or two risks for postoperative nausea and vomiting (PONV). Dexamethasone combined with 5-HT3 or tachykinin NK1 antagonists is also suggested for higher-level emetogenic chemotherapy and radiotherapy and for patients at high risk for PONV. Glucocorticoids may act via the following mechanisms: (1) anti-inflammatory effect; (2) direct central action at the solitary tract nucleus, (3) interaction with the neurotransmitter serotonin, and receptor proteins tachykinin NK1 and NK2, alpha-adrenaline, etc.; (4) maintaining the normal physiological functions of organs and systems; (5) regulation of the hypothalamic-pituitary-adrenal axis; and (6) reducing pain and the concomitant use of opioids, which in turn reduces opioid-related nausea and vomiting., (© 2013 Published by Elsevier B.V.)

Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ(9)-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ(9)-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ(9)-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3-1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ(9)-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5-50 times lower than Δ(9)-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 min but not at 2 h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually., (© 2013 Published by Elsevier B.V.)

Over the past decades major improvements in the management of chemotherapy induced nausea and vomiting (CINV) were obtained. With the correct use of antiemetic drugs, CINV can be prevented in almost 70%, and even up to, 80% of patients. Treatment guidelines enable physicians to integrate the latest clinical research into their daily practice. The large volume of rapidly evolving clinical data has been summarised and incorporated into treatment recommendations by well-known and reliable institutions. These organisations include the Multinational Association of Supportive Care in Cancer (MASCC), the European Society of Medical Oncology (ESMO), the American Society for Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN). However, despite the availability of these guidelines, there is an emerging evidence that adherence to, and implementation of, treatment recommendations is less than optimal. This review will especially focus on the content of the current antiemetic guidelines and will address the important question of how these guidelines are implemented in routine practice., (© 2013 Published by Elsevier B.V.)

Olanzapine is an atypical antipsychotic agent of the thiobenzodiazepine class. It blocks multiple neurotransmitter receptors including dopaminergic at D1, D2, D3, D4 brain receptors, serotonergic at 5-HT2a, 5-HT2c, 5-HT3, 5-HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors. Olanzapine has five times the affinity for 5-HT2 receptors than D2 receptors and has been used to treat schizophrenia and delirium. Olanzapine's activity at multiple receptors, particularly at the D2, 5-HT2c, and 5-HT3 receptors which appear to be involved in nausea and emesis, has prompted its use in the treatment of nausea and vomiting refractory to standard antiemetics. Case reports and formal clinical trials have demonstrated its efficacy in the treatment of chronic nausea, the prevention of chemotherapy-induced nausea and emesis, and the treatment of breakthrough chemotherapy-induced nausea and emesis. Phase II and phase III clinical trials have demonstrated that there is a significant improvement in nausea when olanzapine is added to guideline directed prophylactic antiemetic agents 5-HT3 receptor antagonists and tachykinin NK1 receptor antagonists in patients receiving moderately or highly emetogenic chemotherapy Common side effects of olanzapine when used over a period of months include weight gain as well as an association with the onset of diabetes mellitus, but these effects have not been seen with short term use of daily doses of less than one week., (© 2013 Published by Elsevier B.V.)

Cisplatin-like chemotherapeutics cause vomiting via release of multiple neurotransmitters (dopamine, serotonin (5-HT), or substance P (SP)) from the gastrointestinal enterochromaffin cells and/or the brainstem via a calcium dependent process. Diverse channels in the plasma membrane allow extracellular Ca(2+) entry into cells for the transmitter release process. Agonists of 5-HT3 receptors increase calcium influx through both 5-HT3 receptors and L-type Ca(2+) channels. We envisaged that L-type calcium agonists such as FPL 64176 should cause vomiting and corresponding antagonists such as nifedipine would behave as broad-spectrum antiemetics. Administration of FPL 64176 did cause vomiting in the least shrew in a dose-dependent fashion. Nifedipine and the 5-HT3 receptor antagonist palonosetron, potently suppressed FPL 64176-induced vomiting, while a combination of ineffective doses of these antagonists was more efficacious. Subsequently, we investigated the broad-spectrum antiemetic potential of nifedipine against diverse emetogens including agonists of serotonergic 5-HT3- (e.g. 5-HT or 2-Me-5-HT), SP tachykinin NK1- (GR73632), dopamine D2- (apomorphine or quinpirole), and cholinergic M1- (McN-A-343) receptors, as well as the non-specific emetogen, cisplatin. Nifedipine by itself suppressed vomiting in a potent and dose-dependent manner caused by the above emetogens except cisplatin. Moreover, low doses of nifedipine potentiated the antiemetic efficacy of non-effective or semi-effective doses of palonosetron against vomiting caused by either 2-Me-5-HT or cisplatin. Thus, our findings demonstrate that activation of L-type calcium channels causes vomiting, whereas blockade of these ion channels by nifedipine-like antagonists not only provides broad-spectrum antiemetic activity but can also potentiate the antiemetic efficacy of well-established antiemetics such as palonosetron. L-type calcium channel antagonists should also provide antiemetic activity against drug-induced vomiting as well as other emetogens including bacterial and viral proteins.

Pathogenic bacteria use various strategies to interact with the host organisms. Among them, toxin production constitutes an efficient way to alter specific functions of target cells. Various enterotoxins interact with the enteric nervous system, by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, diarrhea, or in the intestinal inflammation process. Staphylococcus aureus produces a wide variety of toxins including staphylococcal enterotoxins (SEs) with demonstrated emetic activity; and staphylococcal enterotoxin-like (SEl) proteins, which are not emetic in a primate model or have yet to be tested. SEs and SEls have been traditionally subdivided into classical (SEA to SEE) and new (SEG to SElX) types. These toxins possess superantigenic activity and are highly resistant to denaturation which allows them to remain intact in contaminated foods and trigger food poisoning outbreaks. Symptoms are of rapid onset, and include nausea and violent vomiting. SEA is the most recognizable toxin causing food poisoning in humans throughout the world. However, it remains unclear how SEs induce emesis and via which signal pathway. This review is divided into four parts, and will focus on the following: (1) how bacterial toxins interact with the nervous system, (2) biological characteristics of SEs and SEls, (3) mechanisms of SE-induced emesis, and (4) use of a vaccine for the prevention of SE-induced emesis., (© 2013 Elsevier B.V. All rights reserved.)

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future, using combination agents (opioids combined with agents which may nullify emetic effects), currently nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/vomiting (OINV)., (© 2013 Published by Elsevier B.V.)

Nausea and vomiting are very common symptoms in cancer both treatment and non-treatment related. Many complications of advanced cancer such as gastroparesis, bowel and outlet obstructions, and brain tumors may have nausea and vomiting or either symptom alone. In a non-obstructed situation, nausea may be more difficult to manage and is more objectionable to patients. There is little research on management of these symptoms except the literature on chemotherapy induced nausea where guidelines exist. This article will review the etiologies of nausea and vomiting in advanced cancer and the medications which have been used to treat them. An etiology based protocol to approach the symptom is outlined., (© 2013 Published by Elsevier B.V.)

Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency., (© 2013 Elsevier B.V. All rights reserved.)

Paradoxically, erythromycin is associated with nausea when used as an antibiotic but at lower doses erythromycin activates motilin receptors and is used to treat delayed gastric emptying and nausea. The aim of this study was to characterise pro- and anti-emetic activity of erythromycin and investigate mechanisms of action. Japanese House musk shrews (Suncus murinus) were used. Erythromycin was administered alone or prior to induction of emesis with abnormal motion or subcutaneous nicotine (10mg/kg). The effects of erythromycin and motilin on vagal nerve activity and on cholinergically mediated contractions of the stomach (evoked by electrical field stimulation) were studied in vitro. The results showed that erythromycin (1 and 5mg/kg) reduced vomiting caused by abnormal motion (e.g., from 10.3 ± 1.8 to 4.0 ± 1.1 emetic episodes at 5mg/kg) or by nicotine (from 9.5 ± 2.0 to 3.1 ± 2.0 at 5mg/kg), increasing latency of onset to emesis; lower or higher doses had no effects. When administered alone, erythromycin 100mg/kg induced vomiting in two of four animals, whereas lower doses did not. In vitro, motilin (1, 100 nM) increased gastric vagal afferent activity without affecting jejunal afferent mesenteric nerve activity. Cholinergically mediated contractions of the stomach (prevented by tetrodotoxin 1 μM or atropine 1 μM, facilitated by l-NAME 300 μM) were facilitated by motilin (1-100 nM) and erythromycin (10-30 μM). In conclusion, low doses of erythromycin have anti-emetic activity. Potential mechanisms of action include increased gastric motility (overcoming gastric stasis) and/ or modulation of vagal nerve pathways involved in emesis, demonstrated by first-time direct recording of vagal activation by motilin., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Scant information is available regarding the effects of cisplatin on the expression profile of tachykinin NK(1) receptors and downstream signaling during cisplatin-induced emesis. Cisplatin causes peak early- and delayed-phase emesis in the least shrew at 1-2 and 33 h post-injection. To investigate the expression profile of NK(1) receptor during both emetic phases, we cloned the cDNA corresponding to a ~700 base pairs of mRNA flanked by two stretches of nucleotides conserved among different species and demonstrated that the shrew NK(1) receptor nucleotide sequence shares ~90% sequence identity with the human NK(1) receptor. Of the 12 time-points tested, significant increases in expression levels of NK(1) receptor mRNA in the shrew brainstem occurred at 2 and 28 h post-cisplatin injection, whereas intestinal NK(1) receptor mRNA was increased at 28 h. Shrew brainstem and intestinal substance P mRNA levels also tended to increase during the two phases. Furthermore, expression levels of NK(1) receptor protein were significantly increased in the brainstem at 2, 8, and 33 h post-cisplatin. No change in brainstem 5-HT(3) receptor protein expression was observed. The temporal enhancements in NK(1) receptor protein expression were mirrored by significant increases in the phosphorylation status of the brainstem ERK1/2 at 2, 8, and 33 h post-cisplatin. Phosphorylation of PKA significantly increased at 33rd and 40th hour. Our results indicate associations between cisplatin's peak immediate- and delayed-phase vomiting frequency with increased: (1) expression levels of NK(1) receptor mRNA and its protein level, and (2) downstream NK(1) receptor-mediated phosphorylation of ERK1/2 and PKA signaling., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nausea and vomiting are among the most common and distressing consequences of cytotoxic chemotherapies. Nausea and vomiting can be acute (0-24h) or delayed (24-72 h) after chemotherapy administration. The introduction of 5-HT(3) receptor antagonists in the 90s was a major advance in the prevention of acute emesis. These receptor antagonists exhibited similar control on acute emesis but had no effect on delayed emesis. These findings led to the hypothesis that serotonin plays a central role in the mechanism of acute emesis but a lesser role in the pathogenesis of delayed emesis. In contrast, delayed emesis has been largely associated with the activation of neurokinin 1 (NK(1)) receptors by substance P. However, in 2003, a new 5-HT(3) receptor antagonist was introduced into the market; unlike first generation 5-HT(3) receptor antagonists, palonosetron was found to be effective in preventing both acute and delayed chemotherapy induced nausea and vomiting. Recent mechanistic studies have shown that palonosetron, in contrast to first generation receptor antagonists, exhibits allosteric binding to the 5-HT(3) receptor, positive cooperativity, persistent inhibition of receptor function after the drug is removed and triggers 5-HT(3) receptor internalization. Further, in vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT(3) receptor. It appears that the crossroads of acute and delayed emeses include interactions among the 5-HT(3) and NK(1) receptor neurotransmitter pathways and that inhibitions of these interactions lend the possibility of improved treatment that encompasses both acute and delayed emeses., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Many chemotherapeutic agents activate multiple signaling systems, including potentially emetogenic arachidonic acid metabolites. Of these messengers, the emetic role of the leukotriene family has been neglected. The aims of this study were to test the emetic potential of key leukotrienes (LTA(4), LTB(4), LTF(4), and the cysteinyl leukotrienes LTC(4), LTD(4) and LTE(4)), and to investigate whether the leukotriene CysLT(1) receptor antagonist pranlukast or mixed leukotriene CysLT(1/2) receptor antagonist Bay u9773 can prevent the LTC(4)-induced emesis. Least shrews were injected with varying doses of one of the six tested leukotrienes and vomiting parameters were measured for 30min. LTC(4) and LTD(4) were most efficacious, and significantly increased both the frequency and percentage of animals vomiting at doses from 0.1 and 0.05mg/kg, respectively. The other tested leukotrienes were either weakly emetic or ineffective at doses up to 4mg/kg. The relative emetogenic activities of the cysteinyl leukotrienes (LTC(4)=LTD(4)>LTE(4)) suggest that leukotriene CysLT(2) receptors have a key role in emesis. However, pranlukast dose-dependently, and at 10mg/kg completely, blocked LTC(4)-induced vomiting, implicating a leukotriene CysLT(1) receptor-mediated emetic effect. Bay u9773 dose-dependently reduced the percentage of animals vomiting, but did not significantly reduce vomiting frequency. Fos immunoreactivity, measured subsequent to LTC(4)-induced vomiting to define its putative anatomical substrates, was significantly increased in the enteric nervous system and medullary dorsal vagal complex following LTC(4) (P<0.05) versus vehicle injections. This study is the first to show that some leukotrienes induce emesis, possibly involving both central and peripheral leukotriene CysLT(1) and/or leukotriene CysLT(2) receptors.

Small rodents (mice, rats) are the species of choice for evaluating the pharmacology of centrally acting compounds, such as antipsychotics, whereas toxicology data are routinely obtained from other species (rabbits, dogs, monkeys). Whilst there is a substantial number of "therapeutically relevant" pharmacological models for "antipsychotic-like" activity in small rodents, based on hyperdopaminergic or hypoglutamatergic/NMDA approaches, there is a remarkable paucity of such models in other species. Here, we compared the efficacy and potency of reference and new generation dopamine D2/5-HT(1A) putative antipsychotics, administered orally, against apomorphine-induced emesis in dogs, a model of central D2 receptor activation that can be implemented with relative ease. Risperidone potently and fully (10 microg/kg) prevented emesis/retching induced by 0.1 mg/kg s.c. apomorphine. SLV313 and F15063 (D2 receptor antagonists/5-HT(1A) receptor agonists) also abolished emesis/retching, albeit less potently than risperidone (minimal effective dose, MEDs: 10 and 40 microg/kg, respectively). The D2 receptor partial agonists/5-HT(1A) receptor agonists aripiprazole and bifeprunox, (up to 80 microg/kg) only partially attenuated emesis, as did the peripheral D2 receptor antagonist domperidone. Under the present experimental conditions, haloperidol was only efficacious at the highest dose tested (320 microg/kg). To summarize, dogs are very sensitive to the dopaminergic blocking effects of antipsychotics in this model of D2 receptor activation. This model can thus be advantageously used to investigate the pharmacological activity of novel D2 receptor antagonists/partial agonists in dogs.

We employed an ex vivo [(3)H]rolipram binding experiment to elucidate the mechanism of emetic activity of phosphodiesterase 4 inhibitors. In Suncus murinus (an insectivore used for evaluation of emesis), emetic potential as well as ability to occupy the high-affinity rolipram binding site in brain membrane fraction in vivo were determined for phosphodiesterase 4 inhibitors. In vitro, [(3)H]rolipram bound to the membrane fraction of S. murinus brain with high affinity and its value was comparable to that for rat brain (K(d)=3.6 nM and 3.5 nM, respectively). The test compounds included denbufylline, rolipram, piclamilast, CDP840 and KF19514, each of which possessed similar affinities for the rolipram binding sites in both S. murinus and rat brain. In S. murinus, these compounds induced emesis via intraperitoneal administration. Their ED(50) values were as follows: denbufylline (1.4 mg/kg), rolipram (0.16 mg/kg), piclamilast (1.8 mg/kg), CDP840 (20 mg/kg), and KF19514 (0.030 mg/kg). In addition, these compounds occupied the high-affinity rolipram binding site in vivo as detected by dose-dependent reduction in capacity of ex vivo [(3)H]rolipram binding in brain membrane fractions. A clear correlation was observed between dose required to induce emesis and that to occupy the high-affinity rolipram binding site for individual phosphodiesterase 4 inhibitors. We conclude that the emetic effect of phosphodiesterase 4 inhibitors is caused at least in part via binding to the high-affinity rolipram binding site in brain in vivo.

In the management of pain, nausea and vomiting are some of the most distressing adverse effects induced by opioids. In the present study, we investigated the effect of the dopamine system-stabilizer aripiprazole on morphine-induced emesis. Morphine induced retching and vomiting in a dose-dependent manner in ferrets. The emetic effect of morphine was significantly suppressed by pretreatment with either the dopamine receptor antagonist haloperidol or aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced emesis.

The cough and emetic reflexes involve a synchronized firing of motor neurones involved in respiratory control. Tachykinin NK1 receptor antagonists and 5-HT1A receptor agonists are examples of centrally acting drugs that reduce cough and emesis. In the present studies, therefore, we examined the possibility that other classes of drugs known to reducing cough have anti-emetic properties to prevent emesis induced by diverse challenges. We examined the potential of codeine (1-10 mg/kg), baclofen (1-10 mg/kg), scopolamine (0.3-10 mg/kg), diphenhydramine (1-10 mg/kg), imperialine (1-30 mg/kg) and verticine (0.3-3 mg/kg) to inhibit emesis induced by nicotine (5 mg/kg, s.c.), copper sulphate (120 mg/kg, intragastric), and provocative motion (4 cm horizontal displacement, delivered at 1 Hz) in Suncus murinus (house musk shrew). Only codeine had broad inhibitory properties (P<0.05) to antagonize emesis induced by all challenges with ID50 values ranging from 1.2 to 2.3 mg/kg. Baclofen antagonized emesis induced by nicotine (maximum reduction was 44.9%, P<0.05) and motion (maximum reduction was 97.3%, P<0.01), but potentiated copper sulphate-induced emesis (maximum potentiation was 73.0%, P<0.05). Scopolamine antagonized copper sulphate-induced emesis (maximum reduction was 61.2%, P<0.05) and imperialine antagonized nicotine-induced emesis (maximum reduction was 30.2%, P<0.01), but verticine potentiated motion-induced emesis (maximum potentiation was 60.0%, P<0.05). Diphenhydramine did not significantly reduce emesis induced by any of the challenges (P>0.05). In conclusion, codeine has broad inhibitory anti-emetic actions but a known ability to reduce coughing does not necessarily predict broad inhibitory anti-emetic properties.

Cancer chemotherapy is frequently accompanied by severe emesis. The anti-cancer drugs are classified according to their clinical emetogenic potential. We have already found that kaolin ingestion behavior "pica" is analogous to emesis in rats. The aim of this study was to examine the effects of the clinical emetogenic potential of anti-cancer drugs on the induction of the pica in rats. Rats were housed in individual cages with free access to food and kaolin pellets and the daily food and kaolin intakes were measured for 3 days after the intraperitoneal administration of anti-cancer drugs (cisplatin, cyclophosphamide, actinomycin D, 5-fluorouracil and vincristine). The drugs with high potential for inducing emesis, such as cisplatin and cyclophosphamide, induced pica in all animals on the day of administration and the behavior lasted during the observation period. The drugs with moderate emetogenic potential, i.e. actinomycin D and 5-fluorouracil, also induced pica on the first and second day after the drug administration but the kaolin intake was less than that of the drugs with high potential. Vincristine, a drug with low emetogenic potential, slightly increased the kaolin intake in rats on the only first day of the administration. Cyclophosphamide, actinomycin D and vincristine induced anorexia and decreased their body weight during the observation period. These results suggested that the both amounts of kaolin intake and duration of behavior in the anti-cancer drug-induced pica are related to the clinical emetogenic potential of the drugs and the incidence of the anorexia is not related to their emetogenic potential.

The action of domperidone (1 mg/kg, i.p.) on spontaneous behaviour and the emesis and behavioural change induced by apomorphine (0.25 mg/kg, s.c.) were studied in the ferret. Domperidone was inactive to modify spontaneous behaviour but apomorphine-induced emesis and increased locomotor activity (distance travelled and velocity of movement; P<0.05); the emesis, but not the modification of locomotor activity was antagonized significantly (P<0.01) by domperidone. However, apomorphine did not modify significantly other behavioural measures (i.e. lip licking, rearing, burrowing, backward walking, curling-up activity, or defecatory frequency; P>0.05). The action of apomorphine to modify behaviour and its interaction with domperidone in this species is discussed in relation to animal models of nausea.

Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.

The action of ondansetron (1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 10 mg/kg, i.p.) on spontaneous behavior and the emesis induced by cisplatin (10 mg/kg, i.p.) was studied in the ferret. Ondansetron was inactive to modify behavior, but CP-99,994 reduced spontaneous locomotor activity and lip licking by 48% (P<0.01) and 79% (P<0.01), respectively; CP-99,994 also abolished spontaneous burrowing activity (P<0.05). Treatment of animals with cisplatin induced an emetic response that was abolished by both ondansetron and CP-99,994 (P<0.01). However, cisplatin did not significantly modify other behavioral measures although animals that received CP-99,994, cisplatin, or CP-99,994 in combination with cisplatin exhibited more episodes of defecation than animals that received ondansetron (P<0.05). The action of CP-99,994 to modify behavior in this species is discussed in relation to animal models of nausea.

The present study evaluated the effects of 8-carboxamidocyclazocine (8-CAC), a novel mixed-action kappa/mu agonist with a long duration of action, on food- and cocaine-maintained responding in rhesus monkeys to assess the potential utility of 8-CAC as a medication for the treatment of cocaine dependence. The effects of acute and chronic (10 days) 8-CAC were examined in rhesus monkeys responding under a multiple schedule for both cocaine and food reinforcement. Acute 8-CAC (0.032-0.56 mg/kg, i.m.) dose-dependently eliminated cocaine-maintained responding in all three monkeys. However, doses of 8-CAC that decreased cocaine self-administration typically also decreased food-maintained responding, and 8-CAC-induced decreases in cocaine self-administration diminished during chronic 8-CAC treatment. These results confirm that 8-CAC acutely decreases cocaine self-administration. However, non-selective effects of 8-CAC on food-maintained responding and tolerance to 8-CAC effects on cocaine self-administration may limit its potential for the treatment of cocaine dependence.

We investigated the ability of dexamethasone to attenuate cisplatin (4 mg/kg, i.v.)-induced early and delayed emesis. These appear within the first 8-h period (early phase) and between 8 and 48 h (delayed phase), respectively, after cisplatin administration in the pigeon. Dexamethasone (0.1 and 1 mg/kg, i.m.) reduced significantly the number of emetic responses to cisplatin by 56% and 82% (P<0.05), respectively, in the early phase, and by 41% and 66% (P<0.05), respectively, in the delayed phase. Dexamethasone (1 and 10 microg/kg, i.c.v.) reduced the number of emetic responses by 66% and 91% (P<0.05), respectively, in the early phase, and by 56% and 87% (P<0.05), respectively, in the delayed phase. Indomethacin (10 mg/kg, i.m.) did not suppress cisplatin-induced early and delayed emesis. Dexamethasone (1 mg/kg, i.m.) did not affect the content of platinum in the medulla oblongata after cisplatin administration. The above results suggest that dexamethasone has antiemetic effects on both the early and delayed emetic responses to cisplatin in pigeons, partially via its central site of action, and that the antiemetic mechanism of dexamethasone is related to factors other than its inhibition of prostanoid synthesis or its membrane stabilizing effect which reduces influx of cisplatin into the medulla oblongata.

The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/kg, i.p.), was investigated in Suncus murinus. The emetic response was reduced by 76% following bilateral abdominal vagotomy (P<0.001) and by reserpine (5 mg/kg, i.p., 24 h pretreatment; P<0.05) but U46619 administered i.c.v. (30-300 ng) was not emetic, suggesting a peripheral mechanism involving monoamines. However, fenfluramine (5 mg/kg, repeated treatment) and para-chlorophenylalanine (100-400 mg/kg) and ondansetron (0.3-3 mg/kg) were inactive (P>0.05) to reduce U46619-induced emesis precluding a role of 5-HT and 5-HT(3) receptors in the mechanism. Similarly, phentolamine (0.3-3 mg/kg), propranolol (3 mg/kg), and their combination, and metoclopramide (0.3-3 mg/kg), domperidone (0.3-3 mg/kg), droperidol (0.3-3 mg/kg), scopolamine (0.3-3 mg/kg) and promethazine (0.3-3 mg/kg) were inactive (P>0.05) to reduce the retching and vomiting response. However, the tachykinin NK(1) receptor antagonist, (+)-2S,3S(-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine) (CP-122,721; 1-10 mg/kg) antagonized emesis (P<0.01). In conclusion, U46619-induced emesis appears to be mediated via a predominant peripheral mechanism sensitive to reserpine and is not likely to involve adrenoceptors, dopamine, 5-HT(3), muscarinic or histamine (H(1)) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK(1) receptor antagonists to mechanisms involving TP receptors.

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.

Ondansetron (1-3 mg/kg), granisetron (0.3-1 mg/kg) and dexamethasone (0.3-1 mg/kg), administered at 12-h intervals, were investigated for their potential to prevent cisplatin (30 mg/kg, i.p.)-induced emesis during a 72-h observation period. Ondansetron appeared more active than granisetron to antagonise the emetic response occurring in the first 4-h (P<0.05) period, but none of the regimens significantly antagonised emesis during the 0-24- and 24-72-h periods (P>0.05). However, ondansetron was more active to antagonise emesis on day 1 using a more frequent drug administration, whereas bilateral vagotomy only reduced emesis for 2 h, and 5-HT, 2-methyl-5-HT and 1-m-chloro-phenylbiguanide (up to 20-30 mg/kg, i.p.) were not emetic. The combination of ondansetron 1 mg/kg and dexamethasone 1 mg/kg, both administered every 12 h, significantly delayed the onset of emesis (P<0.05) but failed to reduce the total numbers of retches+vomits over the 3-day period (P>0.05). Results are discussed in relation to the clinical situation.

Cisplatin 5 mg/kg, i.p., induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of metyrapone and tetracosactrin and their potential interaction. The 11beta-hydroxylase enzymes inhibitor metyrapone 10-30 mg/kg, i.p., dose dependently potentiated the acute cisplatin-induce retching+vomiting response by up to 219% at the highest dose (P<0.001) but failed to affect significantly delayed emesis (P>0.05). The adrenocorticotropic hormone (ACTH) mimetic tetracosactrin 0.1 mg/kg, i.m., antagonised significantly the acute and delayed emetic response by 98% (P<0.01) and 75% (P<0.001), respectively. The anti-emetic action of tetracosactrin on acute but not delayed emesis was prevented by combination with metyrapone 10 mg/kg, i.p. Tetracosactrin 0.1 mg/kg, i.m., failed to modify apomorphine (0.25 mg/kg, s.c.)-induced emesis. The potential anti-emetic mechanism of action of metyrapone and tetracosactrin to modulate emesis is discussed.

Cisplatin (4 mg/kg, i.v.) induced both early emesis, which appears within the first 8-h period, and delayed emesis, which appears between 8 and 48 h after its administration to pigeons. GR205171 ([(2S-cis)-N-((2-methoxy-5(5-(trifluoromethyl)-1H-tetrazol-1-yl)-phenyl) methyl)-2-phenyl-3-piperidinamine dihydrochloride]) administered intramuscularly (1-10 mg/kg) reduced significantly the number of emetic response to cisplatin: this reduction was 60-81% (P < 0.05) for early emesis and 48-64% (P < 0.05) for the delayed response. Intracerebroventricularly administered GR205171 (30 microg/kg) also reduced the number of emetic responses: 53% (P < 0.05) in early emesis and 88% (P < 0.05) in the delayed response. However, the latency time to the first emesis was not affected by GR205171. Direct injection of cisplatin (10 microg/kg) into the fourth ventricle produced emesis, which was reduced by GR205171 administered via the peripheral or central route. Substance P-immunoreactive fibres were distributed throughout the dorsal vagal complex. These results suggest that the antiemetic effect of GR205171 on both emetic responses to cisplatin acts on a central site, and that the onset of the emetic response may be mediated partly via GR205171-insensitive mechanisms., (Copyright 2003 Elsevier Science B.V.)

Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).

Several prostanoids were investigated for their ability to induce emesis and/or defecation and tenesmus in the ferret. The rank order of emetic potency (dose producing four episodes, D4) was: sulprostone (5 microg/kg)>11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 8 microg/kg)>misoprostol (27 microg/kg)>17-phenyl-omega-trinor prostaglandin E2 (53 microg/kg)>prostaglandin E2 (94 microg/kg)>5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C; 148 microg/kg)>>prostaglandin F(2alpha) (13,500 microg/kg). Emesis was also induced by iloprost (D4 not determined) and prostaglandin E2 methyl ester (D4=350 microg/kg). Cicaprost and fluprostenol were virtually inactive; they also failed to modify copper sulphate (100 mg/kg, intragastric)-induced emesis (P>0.05), although cicaprost potentiated apomorphine (0.25 mg/kg, s.c.)-induced emesis (P<0.05). U46619-induced emesis was antagonised by vapiprost (P<0.05). The rank order of potency to produce defecation and tenesmus (dose producing three episodes) was: sulprostone (12 microg/kg)>misoprostol (15 microg/kg)>17-phenyl-omega-trinor prostaglandin E2 (94 microg/kg)>prostaglandin E2 (113 microg/kg)>fluprostenol (158 microg/kg)z.Gt;prostaglandin F(2alpha) (1759 microg/kg); prostaglandin E2 methyl ester also induced defecation (196 microg/kg). Data are discussed in relation to mechanisms involved in emesis and defecation.

We evaluated the antiemetic activity of resiniferatoxin, an ultrapotent capsaicin analogue, on cisplatin- and apomorphine-induced emesis in dogs, and on cisplatin-induced acute and delayed emesis in ferrets. In the dog, resiniferatoxin (10 microg/kg, s.c.) 30 min before the injection of cisplatin markedly prevented acute emesis induced by cisplatin. When animals were given resiniferatoxin (10 microg/kg, s.c.) 24 h prior to cisplatin, the emesis was still inhibited, but not significantly. Resiniferatoxin (10 microg/kg, s.c.) 30 min before the administration of apomorphine also significantly reduced the emetic responses induced by apomorphine in dogs. In the ferret, resiniferatoxin (10 microg/kg, s.c.) 30 min prior to cisplatin completely inhibited acute emesis caused by cisplatin (10 mg/kg, i.p.). When ferrets were given resiniferatoxin (10 microg/kg, s.c.) 16 h prior to cisplatin, the emesis was still significantly inhibited. Cisplatin (5 mg/kg, i.p.) induced both acute (0-24 h) and delayed (24-72 h) phase emesis, and a single injection of resiniferatoxin (10 microg/kg, s.c.) at 36 h after cisplatin significantly reduced subsequent emetic responses during the 36-72 h period. These results suggest that resiniferatoxin-related vanilloids may be useful drugs against both acute and delayed emesis induced by cancer chemotherapy.

The involvement of a central mechanism in the antiemetic effect of AS-8112 ((R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide x 2 fumarate), a novel and potent dopamine D2, D3, and 5-HT(3) receptor antagonist, was investigated in ferrets. Intracerebroventricularly administered AS-8112 dose dependently inhibited R(+)-7-OH-DPAT (R(+)-7-hydroxy-2-(N,N-di-n-propylamino) tetraline)-induced emesis (ID(50); 0.11 microg/kg, i.c.v.). In addition, AS-8112 (10 microg/kg, i.c.v.) significantly inhibited emesis induced by cisplatin. Ondansetron (10 microg/kg, i.c.v.) also inhibited cisplatin-induced emesis, but did not inhibit R(+)-7-OH-DPAT-induced emesis. S(-)-eticlopride (10 microg/kg, i.c.v.) did not inhibit emesis induced by cisplatin. However, racemic CP-99,994 ((+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine) (10 microg/kg, i.c.v.) inhibited both cisplatin- and R(+)-7-OH-DPAT-induced emesis. These results suggest that the antiemetic effects of AS-8112 are centrally mediated via dopamine D3 and 5-HT(3) receptors in ferrets.

The dibenzopyran cannabinoids (delta-9 (Delta9)-tetrahydrocannabinol and nabilone) are clinically used to suppress nausea and vomiting produced by chemotherapeutic agents such as cisplatin. The purpose of this investigation was to investigate the antiemetic potential of the aminoalkylindole cannabinoid receptor agonist WIN 55, 212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl) methyl] pyrolol [1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate] against cisplatin-induced vomiting. Different doses of WIN 55, 212-2 (0, 1, 2.5 and 5 mg/kg, i.p.) reduced both the frequency of cisplatin (20 mg/kg, i.p.)-induced emesis (ID(50)=0.5 mg/kg) as well as the percentage of shrews vomiting (ID50=1.2 mg/kg) in a dose-dependent manner. Significant reductions in emesis frequency occurred from 2.5 mg/kg dose of WIN 55, 212-2, whereas significant total protection from vomiting was afforded at its 5 mg/kg dose. The antiemetic actions of a 5-mg/kg dose of WIN 55, 212-2 against cisplatin (20 mg/kg, i.p.)-induced vomiting were reversed by nonemetic subcutaneous doses (0, 0.25, 0.5 and 1 mg/kg) of the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] (ID50=0.27 and 0.47 mg/kg, respectively) but not by a 5-mg/kg dose of the cannabinoid CB2 receptor antagonist SR 144528 [N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1] heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methybenzyl) pyrazole-3-carboxamide]. The effects of the cited doses of WIN 55, 212-2 were also investigated on several motor parameters (spontaneous locomotor activity, duration of movement and rearing frequency). Significant reductions in motor parameters were only observed at its highest tested dose (ID50=1.97, 2.75 and 2.8 mg/kg; respectively). SR 141716A (0, 0.5, 1, 5 and 10 mg/kg) also reversed the motor suppressant effects of a 5-mg/kg dose of WIN 55, 212-2 (ID50=0.39, 0.1 and 0.3 mg/kg, respectively) and significant reversals were seen from its 0.5 and 1 mg/kg doses. These results suggest that WIN 55, 212-2 reduces both emesis and indeces of locomotion via the stimulation of cannabinoid CB1 receptors. However, cannabinoid CB1 receptors in different loci are most likely responsible for the antiemetic and motor suppressive effects of WIN 55, 212-2 since reduction in the frequency of vomiting occurred at lower doses relative to its sedative actions.

We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a newly synthesized 5-HT(3) receptor agonist, on defecation in normal and constipated ferrets, and evaluated it as an agent against constipation. YM-31636 facilitated defecation without inducing diarrhea or emetic episodes. This effect occurred within 1 h after oral administration, mostly within 30 min, whereas sodium picosulfate, a widely used laxative, tended to increase the frequency of defecation for several hours with much lower peak incidence than that of YM-31636, and induced diarrhea. UK14304 (brimonidine), an alpha2 receptor agonist, and morphine reduced the frequency of defecation and YM-31636 restored it. These effects of YM-31636 were antagonized by ramosetron, a 5-HT(3) receptor antagonist. These results suggest that YM-31636 could be promising in the treatment of constipation. Because of an early and reliable onset of action compared with sodium picosulfate, YM-31636 could make it easier to control the time of defecation.

The potential of resiniferatoxin and capsaicin to modulate emesis and genital grooming was investigated in Suncus murinus. Resinifertoxin (3-30 nmol, i.c.v.), E-capsaicin (10-100 nmol, i.c.v.) and Z-capsaicin (100 nmol, i.c.v.) induced emesis (P<0.05) and subsequently antagonised the emetic response induced by intragastric copper sulphate (480.6 micromol/kg; P<0.05). However, resiniferatoxin failed to affect nicotine-induced (30.7 mol/kg, s.c.) emesis (P>0.05). Only resiniferatoxin induced genital grooming that was antagonised (P<0.05) by capsazepine (300-600 nmol, i.c.v.) and ruthenium red (3 nmol, i.c.v.). E-capsaicin-induced emesis was antagonised by capsazepine (300-600 nmol, i.c.v.; P<0.05) and ruthenium red (3 nmol, i.c.v.; P<0.05) but resiniferatoxin-induced emesis was resistant to capsazepine (30-600 nmol, i.c.v.; P>0.05). The emetic action of resiniferatoxin but not E-capsaicin was subject to tachyphylaxis. In cross-tachyphylaxis experiments, E-capsaicin reduced the genital grooming induced by resiniferatoxin (P<0.05). The data are discussed in relation to the classification of vanilloid receptors and mechanisms involved in emesis and genital grooming.

Cisplatin 5 mg/kg, i.p. induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of several glucocorticoids. Betamethasone (0.3-3 mg/kg, i.p.) reduced the emesis occurring during the initial 0-24-h period by 71.1-99.5% (P<0.05). The action of methylprednisolone (1.0-10.0 mg/kg, i.p.) and hydrocortisone (1.0-30.0 mg/kg, i.p.) could not be assessed because the controls exhibited weak emetic responses and dexamethasone produced a non-significant 64.0% reduction at 0.3 mg/kg (P>0.05). However, all glucocorticoids dose-dependently reduced retching+vomiting during the subsequent 24-56-h period. The rank order of anti-emetic potency was betamethasone (ID(80)<0.3 mg/kg)>/=dexamethasone (ID(80)=0.32 mg/kg)>methylprednisolone (ID(80)=0.66 mg/kg)&z.Gt;hydrocortisone (ID(80)>30 mg/kg). Dexamethasone was ineffective to antagonise the retching+vomiting response during the 24-56-h period when the administration was delayed until 24 h post-cisplatin injection. None of the glucocorticoids reduced the retching+vomiting response occurring during the 56-72-h period. In conclusion, the rank order of anti-emetic potency suggests that inflammation, or mediators of inflammation, contribute to the retching+vomiting response induced by cisplatin.

The emetic action of cisplatin was investigated in the cat using a closed circuit video recording system. In initial investigations, cisplatin 3 and 5 mg/kg, i.v. induced emesis over a 2-day period following a latency of 17.6+/-9.6 and 15.6+/-7.8 h, respectively. The anti-emetic efficacy of granisetron and dexamethasone was investigated in the cisplatin 5 mg/kg, i.v.-induced emesis model. In these experiments, cisplatin induced 47.0+/-14.0 and 20.0+/-9.0 retches+vomits on days 1 and 2, respectively, following a latency of 2.4+/-0.4 h. Granisetron (1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response induced by cisplatin on days 1 and 2 by 100.0% (P<0.05) and 75.0% (P<0.05), respectively; dexamethasone (0.01-1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response by 68.8-100.0% (P<0.05) and 33.3-100.0% (P<0.05) on days 1 and 2, respectively. The emetic action of cisplatin 7.5 mg/kg, i.v. was also investigated. This dose of cisplatin-induced emesis following a latency of 1.2+/-0.2 h and comprised 119.0+/-20.8 retches+vomits over a 24-h period. Granisetron and dexamethasone antagonized the emesis occurring in the first 3-h period (P<0.05) but were less effective to antagonize the subsequent emetic response (P0.05). The pharmacological sensitivity of low dose cisplatin-induced emesis in the cat is variable but unique and not representative of the clinical situation.

After its discovery in 1931, substance P (SP) remained the only mammalian member of the family of tachykinin peptides for several decades. Tachykinins thus refer to peptides sharing the common C-terminal amino acid sequence Phe-X-Gly-Leu-Met x NH2. In recent years the family of mammalian tachykinins has grown with the isolation of two novel peptides from bovine and porcine central nervous system (CNS), neurokinin A and neurokinin B. In parallel with the identification of multiple endogenous tachykinins several classes of tachykinin receptors were discovered. The receptors described so far are named tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK1 receptor, respectively. The present review focuses on the pharmacology and putative function of tachykinin NK1 receptors in brain. The natural ligand with the highest affinity for the tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the tachykinin NK1 receptor is the C-terminal hexapeptide. A rapid advance of knowledge was caused by development of non-peptidic tachykinin NK1 receptor antagonists. This area is under rapid development and a variety of different chemical classes of compounds are involved. Species-dependent affinities of tachykinin NK1 receptor antagonists reveal two clusters of compounds, targeting the tachykinin NK1 receptor subtype found in guinea pig, human or ferret or the one in rat or mouse, respectively. The most recently developed compounds are highly selective, enter the brain and are orally bioavailable. Distinct behavioural effects in experimental animals suggest the involvement of tachykinin NK1 receptors in nociceptive transmission, basal ganglia function or anxiety and depression. Recent clinical trials in man showed that tachykinin NK1 receptor antagonists are effective in treating depression and chemotherapy-induced emesis. Therefore, it is well possible that tachykinin NK1 receptor antagonists will be clinically used for treatment of specific CNS disorders within a short period of time.

We investigated the emetic effects of cisplatin and methotrexate in dogs, the effects of ondansetron on cisplatin-induced vomiting, and the effects of ondansetron, dexamethasone and a combination of the two on the vomiting induced by methotrexate. Ondansetron was administered 30 min before cisplatin administration. Ondansetron, dexamethasone or a combination of the two was administered 8, 24 and 48 h after methotrexate administration. Cisplatin (3 mg/kg, i.v.) induced acute vomiting but failed to induce delayed vomiting. The acute vomiting was markedly inhibited by ondansetron (3 mg/kg, p.o.; 1 mg/kg, i.v.). Methotrexate (2.5 mg/kg, i.v.) caused delayed vomiting, which was partly inhibited by ondansetron (1 mg/kg, i.v.) or dexamethasone (2.5 mg/kg, i.v.). The combination of the two agents was more effective. These results suggest that methotrexate-induced emesis in dogs would be useful for studying delayed emesis.

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.