John A. Rudd

The Role of Tachykinins and the Tachykinin NK1 Receptor in Nausea and Emesis

Nausea and vomiting are both components of the body’s defensive system to protect against the effects of accidentally ingested toxins. Whilst these responses have survival value in the wild, they can also be induced by diseases and disease treatments with one of the most unpleasant examples being the treatment of cancer using cytotoxic drugs and radiation. Understanding the mechanisms by which this occurs has been a major impetus to the identification of novel anti-emetic agents. The recent licensing of an NK1 receptor antagonist for the treatment of chemotherapy-induced emesis provides the first example of a drug acting to block the effects of substance P. Whilst the blockade of emesis by selective NK1 receptor antagonists provides the most powerful evidence implicating substance P in emesis there is a considerable body of supporting evidence including: presence of substance P (usually by immunohistochemistry) in relevant sites (e.g. vagal afferents, nucleus tractus solitarius, gastrointestinal mucosa); presence of NK1, receptors in relevant sites (e.g. nucleus tractus solitarius); induction of emesis by administration of NK1 receptor agonists. Pre-clinical studies in a variety of species revealed the broad-spectrum anti-emetic effects of NK1 receptor antagonists against stimuli including the anti-cancer agent cisplatin (acute and delayed phases), radiation, opioids, copper sulphate, apomorphine, motion and electrical stimulation of abdominal vagal afferents. Species differences in response to NK1 receptor antagonists and species-specific iso-forms of the receptor are discussed and the potential implications for transfer of data from these animal models to humans reviewed. The spectrum of antiemetic effects against stimuli acting via both peripheral and centrally acting emetic stimuli, a requirement for brain penetration and blockade of emesis by microinjection of antagonists into the brain stem all support a central site of action with the nucleus tractus solitarius and the vicinity of the Botzinger complex being the favoured locations although definitive studies are awaited. Evidence for a contribution from a peripheral site in the delayed phase of cytotoxic druginduced emesis is reviewed. The unique pre-clinical profile and especially the observation that NK1, receptor antagonists could block both the acute and delayed phase of cisplatin-induced emesis prompted clinical trials of a number of agents [CJ11974 (ezlopitant), GR205171 (vofopitant), MK869/L754030 (aprepi-tant)] in patients undergoing chemotherapy. These studies and others in motion and post-operative nausea and vomiting are reviewed in detail. In general the trials in chemotherapy show NK1 receptor antagonists have demonstrable efficacy against acute (first 24 h after therapy) emesis when given alone and enhance the efficacy of 5-hydroxytryptamine3 receptor antagonists and dexamethasone when given in combination. Of particular clinical significance is the efficacy of NK1 receptor antagonists given in combination with dexamethasone to reduce emesis in the delayed phase (days 2–5) as this phase of emesis is poorly con trolled using current treatments. Efficacy against nausea has been reported but to date the effects appear less clear than against emesis and further studies are required. The availability of NK1 receptor antagonists in the clinic will provide a useful tool to further investigate the involvement of NK1 receptors in emesis and to explore the roles of central and peripheral substance P in health and disease.

Telemetry in a motion-sickness model implicates the abdominal vagus in motion-induced gastric dysrhythmia.

In humans, motion sickness is associated with disruption of normal gastric myoelectric activity, and it has been proposed that this results from an imbalance of autonomic nervous system activity. We used the established Suncus murinus (house musk shrew) model of motion‐induced emesis to investigate the effect of horizontal motion on gastric myoelectric activity (recorded using telemetry) and the involvement of the abdominal vagi. Surgical vagotomy increased baseline dysrhythmia and reduced the dominant power of the gastric myoelectric signals. In response to motion, normal gastric myoelectric activity was reduced in sham‐operated animals but not in vagotomized animals. Vagotomy, however, failed to affect motion‐induced emesis. In conclusion, motion had a differential effect in sham‐operated and vagotomized animals, which is consistent with the hypothesis that motion‐induced dysrhythmia arises from an autonomic nervous system imbalance.

The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret

The anti-cancer chemotherapeutic agent cisplatin induces an acute (approximately 24 h) and delayed (approximately 24-72 h+) emetic response in humans; whereas the mechanism mediating the acute phase has been characterised, the delayed phase is relatively poorly understood. We have used nerve lesions (abdominal vagus, VX; greater splanchnic nerve, GSNX) and area postrema ablation (APX) in the ferret model of cisplatin (5 mg/kg, i.p.) delayed emesis and demonstrated that VX and VX+GSNX did not significantly modify the delayed emetic response (24-72 h), which consisted of 276.0+/-62.8 retches+vomits (R+V) in sham-operated ferrets and 167.2+/-34.0R+V and 214.8+/-40.2R+V, in the VX and VX+GSNX groups, respectively. APX virtually abolished the delayed phase of emesis and sham-operated ferrets had 93.0+/-22.9R+V whilst only 6.0+/-3.6R+V (p=0.009) were observed in APX animals. These data suggest that, in contrast to the acute emetic response triggered by cisplatin, the delayed phase does not rely on abdominal visceral afferents but is mediated via the area postrema.

Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis

Doxorubicin induced functional deteriorations and elevations of USP7‐related apoptotic/catabolic signalling in the senescent heart Resveratrol protects against doxorubicin‐induced alterations through the restoration of SIRT1 deacetylase activity

Olvanil: a non-pungent TRPV1 activator has anti-emetic properties in the ferret.

Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05-5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants. In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-emetic activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-emetic properties via central and/or peripheral mechanisms after peripheral administration.

Motion sickness, nausea and thermoregulation: The “toxic” hypothesis

Principal symptoms of motion sickness in humans include facial pallor, nausea and vomiting, and sweating. It is less known that motion sickness also affects thermoregulation, and the purpose of this review is to present and discuss existing data related to this subject. Hypothermia during seasickness was firstly noted nearly 150 years ago, but detailed studies of this phenomenon were conducted only during the last 2 decades. Motion sickness-induced hypothermia is philogenetically quite broadly expressed as besides humans, it has been reported in rats, musk shrews and mice. Evidence from human and animal experiments indicates that the physiological mechanisms responsible for the motion sickness-induced hypothermia include cutaneous vasodilation and sweating (leading to an increase of heat loss) and reduced thermogenesis. Together, these results suggest that motion sickness triggers highly coordinated physiological response aiming to reduce body temperature. Finally, we describe potential adaptive role of this response, and describe the benefits of using it as an objective measure of motion sickness-induced nausea.

Olvanil, a non-pungent vanilloid enhances the gastrointestinal toxicity of cisplatin in the ferret

Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only at doses that have adverse effects on the cardiovascular system and on temperature homeostasis. In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator, olvanil (0.05-5 mg/kg, s.c., 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5 mg/kg, i.p.) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature. Cisplatin induced an acute (day 1: 48.0+/-18.3 retches+vomits) and delayed (day 2: 111.7+/-35.5; day 3: 147.5+/-20.2 retches+vomits) emetic response that was associated with reduced food (-98.7% at day 3, P<0.001) and water consumption (-70.2% at day 3, P<0.001) and progressive weight loss (-12.0% at day 3, P<0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (P>0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0.05 mg/kg (P<0.05) and 19.9% at 0.5 mg/kg (P<0.05). Cisplatin did not alter body temperature (basal: 37.7+/-0.1 degrees C) or heart rate (basal: 233.7+/-5.5 beats per min (BPM); P>0.05), but hypothermia (-1.6 degrees C) and increases in locomotor activity (50-90%) were recorded in animals concomitantly treated with olvanil (P<0.05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin.

The involvement of TRPV1 in emesis and anti-emesis

Diverse transmitter systems (e.g. acetylcholine, dopamine, endocannabinoids, endorphins, glutamate, histamine, 5-hydroxytryptamine, substance P) have been implicated in the pathways by which nausea and vomiting are induced and are targets for anti-emetic drugs (e.g. 5-hydroxytryptamine3 and tachykinin NK1 antagonists). The involvement of TRPV1 in emesis was discovered in the early 1990s and may have been overlooked previously as TRPV1 pharmacology was studied in rodents (mice, rats) lacking an emetic reflex. Acute subcutaneous administration of resiniferatoxin in the ferret, dog and Suncus murinus revealed that it had “broad–spectrum” anti-emetic effects against stimuli acting via both central (vestibular system, area postrema) and peripheral (abdominal vagal afferents) inputs. One of several hypotheses discussed here is that the anti-emetic effect is due to acute depletion of substance P (or another peptide) at a critical site (e.g. nucleus tractus solitarius) in the central emetic pathway. Studies in Suncus murinus revealed a potential for a long lasting (one month) effect against the chemotherapeutic agent cisplatin. Subsequent studies using telemetry in the conscious ferret compared the anti-emetic, hypothermic and hypertensive effects of resiniferatoxin (pungent) and olvanil (non-pungent) and showed that the anti-emetic effect was present (but reduced) with olvanil which although inducing hypothermia it did not have the marked hypertensive effects of resiniferatoxin. The review concludes by discussing general insights into emetic pathways and their pharmacology revealed by these relatively overlooked studies with TRPV1 activators (pungent an non-pungent; high and low lipophilicity) and antagonists and the potential clinical utility of agents targeted at the TRPV1 system.

A physiological role of glucagon-like peptide-1 receptors in the central nervous system of Suncus murinus (house musk shrew)

Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut as an incretin hormone to stimulate glucose-stimulated insulin secretion. GLP-1 is also produced in the central nervous system (CNS) as a neurotransmitter that regulates feeding behaviour. By using polyclonal antiserum against GLP-1 and GLP-1 receptors, we identified the distribution of GLP-1 immunoreactive fibres and GLP-1 receptor immunoreactivity in the ventromedial hypothalamus of Suncus murinus (house musk shrew). In functional studies, subcutaneous administration of exendin-4 (1 - 30 nmol/kg) reduced blood glucose levels dose-dependently by up to 49% during an intraperitoneal glucose tolerance test (P<0.001). The glucose-lowering effects were also observed after an intracerebroventricular (i.c.v.; 0.3 - 3 nmol) or intracerebral ventromedial hypothalamic microinfusion (iVMH; 0.3 - 3 pmol) of exendin-4. The area under the curve values for glucose after i.c.v. and iVMH administrations of exendin-4 were reduced by up to 53% (P<0.01) and 46% (P<0.01), respectively. Exendin-4 (i.c.v.; 3 nmol) also increased glucose-stimulated insulin secretion by 20% compared to controls (P<0.05). The GLP-1 receptor antagonist, exendin (9-39) (10 nmol, i.c.v.) did not modify blood glucose levels but it antagonized the glucose-lowering effect of exendin-4 (1 nmol, i.c.v.; P<0.05). The data suggests that the central GLP-1 system may regulate glucose homeostasis by increasing insulin secretion. Further, GLP-1 receptors in the ventromedial hypothalamus appear to play an important role in the regulation of glucose homeostasis in S. murinus.

Alpha-9 nicotinic acetylcholine receptors mediate hypothermic responses elicited by provocative motion in mice

Hypothermic responses accompany motion sickness in humans and can be elicited by provocative motion in rats. We aimed to determine the potential role in these responses of the efferent cholinergic vestibular innervation. To this end, we used knockout (KO) mice lacking α9 cholinoreceptor subunit predominantly expressed in the vestibular hair cells and CBA strain as a wild-type (WT) control. In WT mice, circular horizontal motion (1Hz, 4cm radius, 20min) caused rapid and dramatic falls in core body temperature and surface head temperature associated with a transient rise in the tail temperature; these responses were substantially attenuated in KO mice; changes were (WT vs. KO): for the core body temperature-5.2±0.3 vs. -2.9±0.3°C; for the head skin temperature-3.3±0.2 vs. -1.7±0.2°C; for the tail skin temperature+3.9±1.1 vs+1.1±1.2°C. There was a close correlation in the time course of cooling the body and the surface of the head. KO mice also required 25% more time to complete a balance test. We conclude: i) that the integrity of cholinergic efferent vestibular system is essential for the full expression of motion-induced hypothermia in mice, and that the role of this system is likely facilitatory; ii) that the system is involvement in control of balance, but the involvement is not major; iii) that in mice, motion-induced body cooling is mediated via increased heat flow through vasodilated tail vasculature and (likely) via reduced thermogenesis. Our results support the idea that hypothermia is a biological correlate of a nausea-like state in animals.