Nausea is more resistant to effective treatment . Effects of cannabinoids on nausea in rats. MAGL is expressed in the area postrema in the rat (Suárez et al., ), but has Anti-emetic effects of cannabinoids and endocannabinoids. Thus, as demonstrated in humans, THC (through CB1 receptor agonism) has an antinausea effect in the rat conditioned gaping model (acute.
in nausea on Effects rats of cannabinoids
In addition, it may be difficult to apply to a species when intake is small, and it can be produced by factors other than nausea, such as stress or pain Burchfield et al. Lying on belly in rats e. In rats, this behavior has only been evaluated as a measure of LiCl-induced nausea e.
No other emetic agents have been evaluated using this measure. Both area postrema lesions Bernstein et al. As well, pretreatment with the 5-HT 3 receptor antagonist, ondansetron, reduces LiCl-induced lying on belly in rats Tuerke et al. There have been no reports of the effect of cannabinoid manipulations on the behavior of lying on belly in rats. A major limitation in this measure of nausea-induced behavior, however, is the difficulty in discriminating lying on belly from non-specific locomotor suppression e.
Other commonly employed rodent measures of nausea are conditioned flavor avoidance learning e. These are not direct measures of nausea, but rely upon conditioning. Somewhat paradoxically, the CB 1 agonists CP55, 0. Since conditioned flavor avoidance can be produced even by rewarding drugs in non-emetic rodents it is not a particularly selective measure of nausea see Parker review in current issue.
In contrast to conditioned flavor avoidance, conditioned gapingreactions appear to be more selective measure of conditioned nausea which is only produced by emetic drugs and consistently prevented by anti-emetic drugs see Grill and Norgren, ; Pelchat et al.
Much of the work on the effects of cannabinoids and endocannabinoids on nausea in rodents using this model is reviewed by Parker et al. Here we update this review. Clearly, low doses of CB 1 agonists 0. By acting as an agonist of the somatodendritic 5-HT 1A autoreceptors located in the dorsal raphe, CBD would be expected to reduce the release of 5-HT in forebrain regions e.
The currently employed anti-anxiety compound buspirone acts as a partial 5-HT1A agonist. In humans, buspirone resulted in a reduction of self-report nausea scores in healthy human patients participating in nutrient drink test to assess gastric functioning Chial et al. Buspirione 10 mg twice orally selectively lowered nausea ratings in this test. On the other hand, intravenously administered busprione was ineffective in preventing postoperative nausea and vomiting Kranke et al.
The non-psychoactive carboxylic acidic precursor of CBD, cannabidiolic acid CBDA , is present in the fresh cannabis plant and slowly loses its acidic function decarboxylates in the plant in response to heating e. Recent evidence indicates that CBDA 0. More recently, CBDA has been shown to reduce acute nausea at a dose as low as 0.
As well, a subthreshold dose of CBDA 0. Interestingly, both CBD Mechoulam et al. Interestingly, no psychotomimetic activity was observed when THCA was administered to: Recent results Rock et al. Endocannabinoids are also effective in reducing conditioned gaping in rats. As reviewed by Parker et al. Both of these effects were reversed by the rimonabant, indicating a CB 1 mediated effect. More recently, the endocannabinoid, 2-AG, like anandamide, has been shown to reduce nausea in rats.
Pretreatment with exogenous 2-AG dose-dependently suppresses the establishment of LiCl induced conditioned gaping Sticht et al. However, unlike the anti-nausea effects of anandamide, those of 2-AG do not seem to be entirely dependent on CB 1 receptors since they can be reversed by the cyclooxygenase inhibitor, indomethacin Sticht et al.
However, since cyclooxygenase inhibition blocks the anti-nausea effects of 2-AG, it appears that 2-AG acts through several mechanisms to modulate LiCl-induced nausea. Further research is necessary to clarify the precise role of downstream endocannabinoid metabolites in the suppression of nausea.
As described above, rimonabant and AM produce both vomiting and nausea at high doses by acting as CB 1 inverse agonists. At lower doses than those that produce the nausea-induced behavior of gaping 2. On the other hand, the CB 1 receptor neutral antagonists without inverse agonist effects , AM Sink et al.
Therefore, the nausea inducing effects of rimonabant and AM appear to be mediated by their inverse agonism effects at the CB 1 receptor. As indicated above, it is generally understood that nausea is regulated by central forebrain regions.
Recent evidence indicates that at least one the forebrain region regulating nausea is the visceral insular cortex. Ablation of this region Kiefer and Orr, and selective serotonin lesions of this region Tuerke et al. As well, intracranial administration of ondansetron to this region attenuates nausea induced gaping reactions Tuerke et al. Of particular interest, the location of the CB 1 receptors mediating the anti-nausea actions appear to be in the visceral insular cortex Limebeer et al.
Delivery of the CB 1 agonist, HU, to the visceral insular cortex, but not to the gustatory insular cortex, interfered with the establishment of LiCl-induced gaping reactions in rats. Rats not only display conditioned gaping reactions when re-exposed to a flavor previously paired with a nausea-inducing drug, but they also display conditioned gaping reactions when re-exposed to a context previously paired with a nausea-inducing drug Chan et al.
As well, the house musk shrew also displays conditioned retching when re-exposed to a context previously paired with toxin-induced vomiting Parker and Kemp, ; Parker et al.
These contextually elicited conditioned gaping or retching reactions represent animal models of anticipatory nausea analogous to that experienced by human chemotherapy patients, which can be produced following 3—4 conditioning trials. In human chemotherapy patients, when anticipatory nausea develops, the classic anti-emetic agent ondansetron is ineffective in reducing this symptom Hickok et al. Since these compounds are both non-psychoactive, they are promising candidates for the treatment of anticipatory nausea, as there is no current therapeutic available once anticipatory nausea does develop.
Currently, patients are given non-specific anti-anxiety drugs. Similarly, endocannabinoid enzyme inhibitors reduce contextually-elicited conditioned gaping in rats.
The FAAH inhibitor, URB, interfered with both the establishment and expression of conditioned gaping to an illness-paired context in a dose dependent manner Rock et al. Since rimonabant reversed these effects, they were most likely mediated by elevated anandamide. Recently, Limebeer et al. JZL suppressed conditioned gaping and by elevation of anandamide, but not 2-AG, an effect that was reversed by rimonabant Limebeer et al.
On its own anandamide, but not 2-AG, also suppressed contextually elicited gaping, again reversed by rimonabant. Heavy chronic cannabis use in some people, frequently young ones, leads to a constellation of symptoms that include abdominal pain, recurrent nausea and intractable cyclic vomiting Galli et al, ; Nicolson et al.
This syndrome was first reported about 10 years ago Allen et al. These symptoms are, of course, exactly the opposite of what has been outlined above and hence represent a paradoxical effect of cannabis.
Relief from these symptoms can be obtained from hot baths and showers, but standard anti-emetic treatments are not particularly effective Galli et al, ; Nicholson et al. The mechanisms underlying these effects are entirely unknown, but are speculated to be either the buildup of a toxic chemical from the cannabis plant, or are due to a downregulation of cannabinoid receptors due to the high exposure to ligand.
There are no animal models for this syndrome, which perhaps warrants further investigations. Given the relatively recent appearance of this condition, it would seem likely that recent developments in the horticulture of the plant may be responsible. As can be appreciated from the discussion in the previous sections, we believe that the endocannabinoid system has the potential to be used for the treatment of nausea and likely as an adjunct therapy for the treatment of emesis, particularly delayed emesis, where current therapies are limited in their degree of efficacy.
There are, however, many gaps in our knowledge, most of which were highlighted above. One of the biggest limitations is the very widespread nature of the CB 1 receptor and the many critical functions in the synaptic control of neurotransmission that it subserves. Any compounds that either act directly at the receptor or increase or reduce ligand availability, have the potential to radically alter brain functions beyond that of nausea and vomiting.
So, for example, enhancing endocannabinoid biosynthesis, which would, on the face of it, seem like a good anti-emetic strategy, is unlikely to be specific and might lead to many unwanted side-effects. Reducing endocannabinoid metabolism seems to carry with it a lot of potential and to date, side-effects of FAAH and MAGL inhibitors seem to be rather minimal, at least in animal models.
Currently, another major limitation of advancing endocannabinoid therapies for the treatment of nausea and vomiting is actually our knowledge of the specific roles played by the two endocannabinoids anandamide and 2-AG. By inference from use of FAAH and MAGL inhibitors, both seem to be important, but more sophisticated approaches are required to identify the specific functional contributions of each.
As noted above, understanding the role of CB 2 receptors, particularly in nausea, also remains an important direction in research. There may be an opportunity to utilize these receptors for treatments, though as for CB 1 receptors, their widespread nature may limit or restrict the use of such therapies. Nausea and vomiting are frequently debilitating conditions that require substantial effort and cost to manage. Advances in recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system have revealed significant potential for therapeutic approaches to be developed.
Future efforts aimed at developing new endocannabinoid-based anti-nausea and anti-emetic therapies are clearly warranted. This is a PDF file of an unedited manuscript that has been accepted for publication.
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See other articles in PMC that cite the published article. Abstract Nausea and vomiting emesis are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances.
Cannabis, serotonin, emesis, brainstem, insular cortex, CB 1 receptor, CB 2 receptor. Introduction Reflex mechanisms that serve to protect a host from injury and disability represent important and frequently well-conserved adaptations to a hostile external environment.
The endocannabinoid system at sites in the brain and gastrointestinal tract involved in nausea and vomiting The key components of the brain-gut circuitry mediating emesis have been well described Andrews and Horn, ; Hornby, Anti-emetic effects of cannabinoids and endocannabinoids Cannabis is a well-known anti-emetic whose actions have been extensively reviewed Cotter, ; Darmani and Chebolu, ; Izzo and Sharkey, ; Parker et al.
Cannabinoids and endocannabinoids in the control of nausea in humans There is clearly a need of treatments for acute, delayed and anticipatory nausea in chemotherapy treatment e. Cannabinoid and endocannabinoid regulation of nausea in animal models Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex Hornby, ; however, the central mechanisms regulating nausea are still not well understood Andrews and Horn, Contextually-elicited conditioned gaping reactions: A model of anticipatory nausea Rats not only display conditioned gaping reactions when re-exposed to a flavor previously paired with a nausea-inducing drug, but they also display conditioned gaping reactions when re-exposed to a context previously paired with a nausea-inducing drug Chan et al.
Future directions in using the endocannabinoid system in the treatment of nausea and vomiting As can be appreciated from the discussion in the previous sections, we believe that the endocannabinoid system has the potential to be used for the treatment of nausea and likely as an adjunct therapy for the treatment of emesis, particularly delayed emesis, where current therapies are limited in their degree of efficacy. An efficient new cannabinoid antiemetic in pediatric oncology.
Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Supply and demand for endocannabinoids. The 5-hydroxytryptamine receptor antagonists as antiemetics: Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases. Cannabinoid CB2 receptor expression in the rat brainstem cochlear and vestibular nuclei.
Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties. Area postrema mediation of physiological and behavioral effects of lithium chloride in the rat. Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin. Chemical probes of endocannabinoid metabolism. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.
Fos expression in ferret dorsal vagal complex after peripheral emetic stimuli. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation.
Phylogenic and neurologic aspects of the vomiting process. Physiology and pharmacology of vomiting. Ultrastructural localization of neuronal brain CB2 cannabinoid receptors. Ann NY Acad Sci. Geophagia in response to stress and arthritis. Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. Expression of cannabinoid CB1 receptors by vagal afferent neurons: Cannabinoid receptors CB1 and CB2 form functional heteromers in brain.
Deltatetrahydrocannabinol in cancer chemotherapy: Neural mechanisms of emesis. Can J Physiol Pharmacol. Endocannabinoid signaling and synaptic function. The role of the anterior insular cortex in ictal vomiting: A stereotactic electroencephalography study. Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat. AM produces sustained reductions in food intake and body weight that are resistant to tolerance and conditioned taste aversion.
A neutral CB1 receptor antagonist reduces weight gain in rat. Lipopolysaccharide LPS blocks the acquisition of LiCl-induced gaping in a rodent model of anticipatory nausea. Delatatetrahydrocannabinol as an antiemetic in cancer patients receiving high-dose methotrexate. A prospective, randomized evaluation. Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Motion sickness, stress and the endocannabinoid system. A novel, peripherally restricted, cannabinoid 1 CB1 receptor antagonist AM reduces food intake and body weight, but does not cause malaise, in rodents.
Inactivation of the interoceptive insula disrupts drug craving and malaise induced by lithium. Efficacy of crude marijuana and synthetic deltaTetrahydrocannabinol as treatment for chemotherapy-induced nausea and vomiting: How do you feel? Nabilone and metoclopramide in the treatment of nausea and vomiting due to cisplatinum: Med Oncol Tumor Pharmacother.
A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues. Eur J Cancer Clin Oncol. Deltatetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB 1 receptors in the least shrew.
The role of endocannabinoids and arachidonic acid metabolites in emesis. Molecular, Pharmacological, Behavioral and Clinical Features. Behaviorally active doses of the CB1 receptor antagonist SR A increase brain serotonin and dopamine levels and turnover.
Cisplatin increases brain 2-arachidonoylglycerol 2-AG and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew.
Antiemetic and motor-depressive actions of CP55, Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors.
Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve. Arterioscler Thromb Vasc Biol. Why do cannabinoid receptors have more than one endogenous ligand? Brain monoglyceride lipase participating in endocannabinoid inactivation. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.
Br J Clin Pharmacol. Basic mechanisms of migraine and its acute treatment. A new perspective on N-acylethanolamines as neural signaling molecules. Amelioration of cancer chemotherapy-induced nausea and vomiting by deltatetrahydrocannabinol. Effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther.
Ictus emeticus and the insular cortex. Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction. A prospective, randomized evaluation. Amelioration of cancer chemotherapy-induced nausea and vomiting by deltatetrahydrocannabinol. Deltatetrahydrocannabinol as an antiemetic for patients receving cancer chemotherapy.
A comparison with prochlorperazine and a placebo. Delta 9-tetrahydrocannabinol THC as an antiemetic in patients treated with cancerchemotherapy; a double-blind cross-over trial against placebo. Lucas VS, Laszlo J. Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy.
WIlson HE, et al. Comparative trial of the antiemetic effects of THC and haloperidol. Antiemetic effect of tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Antiemetic effect of delta 9-tetrahydrocannabinol in chemotherapy-associated nausea and emesis as compared to placebo and compazine.
Delta 9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. Inhalation marijuana as an antiemetic for cancer chemotherapy. N Y State J Med. Elder J, Knoderer HM. Characterization of dronabinol usage in a pediatric oncology population. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage.
Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Nabilone versus prochlorperazine for control of cancer chemotherapy-induced emesis in children: Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. A double-blind, controlled trial of nabilone vs.
A multi-institutional phase III study of nabilone vs. Nabilone in the management of prochlorperazine resistant cancer chemotherapy induced emesis. Crossover comparison of the antiemetic efficacy of nabilone and alizapride in patients with nonseminomatous testicular cancer receiving cisplatin therapy. Niiranen A, Mattson K.
A cross-over comparison of nabilone and prochlorperazine for emesis induced by cancer chemotherapy. Am J Clin Oncol. Prospective randomized double-blind trial of nabilone versus domperidone in the treatment of cytotoxic-induced emesis.
Double-blind comparison of the antiemetic effects of nabilone and prochlorperazine on chemotherapy-induced emesis. Double-blind, randomized, crossover trial of nabilone vs. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.
Br J Clin Pharmacol. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation.
Effects of general anesthesia on anandamide blood levels in humans. Motion sickness, stress and the endocannabinoid system. Pretreatment nausea in cancer chemotherapy: Anticipatory nausea among ambulatory cancer patients undergoing chemotherapy: An experimental analysis of classically conditioned nausea during cancer chemotherapy.
The role of patients' expectations in the development of anticipatory nausea related to chemotherapy for cancer. Anticipatory nausea in cancer patients receiving chemotherapy: Integr Physiol Behav Sci. Anticipatory nausea and vomiting in pediatric cancer patients: J Dev Behav Pediatr.
Anticipatory nausea and emesis, and psychological morbidity: Foubert J, Vaessen G. Eur J Oncol Nurs. Progress in reducing anticipatory nausea and vomiting: Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin.
A prospective randomized trial. Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: Intra-visceral insular cortex 2-arachidonoylglycerol, but not N-arachidonoylethanolamide, suppresses acute nausea-induced conditioned gaping in rats. A wide range of doses was not effective in reducing motion-induced emesis in the S. The anti-emetic effect of CBD does not appear to be mediated by its action at CB 1 receptors, because it is not reversed by the CB 1 antagonist, rimonabant Kwiatkowska et al.
Indeed, Russo et al. Recently, our laboratory has investigated the mechanism of action for the anti-emetic effects of CBD. This activation of the 5-HT 1A receptors results in a reduction of the rate of firing of 5-HT neurones, ultimately reducing the release of forebrain 5-HT Blier and de Montigny, In addition, a recent finding suggests that CBD may also act as an allosteric modulator of the 5-HT 3 receptor Yang et al.
These findings suggest that allosteric inhibition of 5-HT 3 receptors by CBD may also contribute to its role in the modulation of emesis. Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting e. Andrews and Horn, and therefore remains a significant problem in chemotherapy treatment and as a side effect from other pharmacological therapies, such as anti-depressants. Even when the cisplatin-induced emetic response is blocked in the ferret by administration of a 5-HT 3 receptor antagonist, c-fos activation still occurs in the AP, suggesting that an action here may be responsible for some of the other effects of cytotoxic drugs, such as nausea or reduced food intake Reynolds et al.
In rats, the gastric afferents respond in the same manner to physical and chemical intragastric copper sulphate and cisplatin stimulation that precedes vomiting in ferrets, presumably resulting in nausea that precedes vomiting Hillsley and Grundy, ; Billig et al.
Furthermore, 5-HT 3 antagonists that block vomiting in ferrets also disrupt this preceding neural afferent reaction in rats. That is, in the rat the detection mechanism of nausea is present, but the vomiting response is absent.
Nauseogenic doses of cholecystokinin and LiCl induce specific patterns of brainstem and forebrain c-fos expression in ferrets that are similar to c-fos expression patterns in rats Reynolds et al.
In a classic review paper, Borrison and Wang suggest that the rats' inability to vomit can be explained as a species-adaptive neurological deficit and that, in response to emetic stimuli, the rat displays autonomic and behavioural signs corresponding to the presence of nausea, called the prodromata salivation, papillary dilation, tachypnoea and tachycardia. The typical measure used in the literature to evaluate the nauseating potential of a drug is conditioned taste avoidance.
However, taste avoidance is not only produced by nauseating doses of drugs, it is also produced by drugs that animals choose to self-administer or that establish a preference for a distinctive location e.
Berger, ; Wise et al. In fact, when a taste is presented prior to a drug self-administration session, the strength of subsequent avoidance of the taste is a direct function of intake of the drug during the self-administration session Wise et al. This paradoxical phenomenon was initially interpreted as another instance of taste aversion learning. Because Garcia et al. However, in an animal capable of vomiting, the S.
Since rats are incapable of vomiting, it is likely that conditioned taste avoidance produced by rewarding drugs in this species is based upon a learned fear of anything that changes their hedonic state e. Gamzu, when that change is paired with food previously eaten. Another approach to understanding the role that nausea plays in the establishment of taste avoidance in rats is to evaluate the potential of anti-nausea treatments to interfere with avoidance of a flavour paired with an emetic treatment.
Early work suggested that anti-nausea agents interfered with the expression of previously established taste avoidance produced by LiCl Coil et al. Furthermore, there is considerable evidence that anti-nausea treatments either do not interfere with the establishment of conditioned taste avoidance learning Rabin and Hunt, ; Rudd et al.
Two prominent anti-nausea treatments include drugs that reduce 5-HT availability and drugs that elevate the activity of the endocannabinoid system in rats see Parker et al. Over the past number of years, our laboratory has provided considerable evidence that conditioned nausea in rats may be displayed as conditioned disgust reactions Parker, ; ; ; ; Limebeer and Parker, ; ; Limebeer et al. Rats display a distinctive pattern of disgust reactions including gaping, chin rubbing and paw treading when they are intraorally infused with a bitter tasting quinine solution.
Rats also display this disgust pattern when infused with a sweet tasting solution that normally elicits hedonic reactions of tongue protrusions that has previously been paired with a drug that produces vomiting such as LiCl or cyclophosphamide in species capable of vomiting. Only drugs with emetic properties produce this conditioned disgust reaction when paired with a taste. The most reliable conditioned disgust reaction in the rat is that of gaping Breslin et al.
If conditioned gaping reflects nausea in rats, then anti-nausea drugs should interfere with this reaction. Limebeer and Parker demonstrated that when administered prior to a saccharin-LiCl pairing, the 5-HT 3 antagonist, ondansetron, prevented the establishment of conditioned gaping in rats, presumably by interfering with LiCl-induced nausea.
Since ondansetron did not modify unconditioned gaping elicited by bitter quinine solution, the effect was specific to nausea-induced gaping. Subsequently, Limebeer and Parker demonstrated a very similar pattern following pretreatment with the 5-HT 1A autoreceptor antagonist, 8-OH-DPAT, that also reduces 5-HT availability and serves as an anti-emetic agent in animal models.
Most recently, Limebeer et al. The orofacial characteristics of the rat gape are very similar to those of the shrew retch just before it vomits Parker, Indeed, Travers and Norgren suggest that the muscular movements involved in the gaping response mimic those seen in species capable of vomiting.
Using the conditioned gaping response as a measure of nausea in rats, we have demonstrated that a low dose 0. The potent agonist, HU 0. When administered 30 min prior to the conditioning trial, rimonabant did not produce conditioned gaping on its own, but it did potentiate the ability of LiCl to produce conditioned gaping.
This same pattern has been reported in the emesis literature Van Sickle et al. Van Sickle et al. More compelling evidence that the endocannabinoid system may serve as a regulator of nausea is the recent finding that prolonging the duration of action of anandamide by pretreatment with URB, a drug that inhibits the enzyme FAAH, also disrupts the establishment of LiCl-induced conditioned gaping reactions in rats Cross-Mellor et al.
Rats pretreated with URB 0. Rats given the combination of URB 0. Although inhibition of FAAH produces an elevation of a variety of fatty acids that act at different receptors, the effect of URB on conditioned nausea was reversed by AM, indicating that it was mediated by CB 1 receptors. On the other hand, the silent CB 1 antagonists, AM and AM, which do not have inverse agonist properties, do not produce conditioned gaping Sink et al.
In addition, the peripherally restricted silent CB 1 antagonist, AM, which also suppresses feeding at equivalent doses of AM Cluny et al. Finally, neither the silent antagonist, AM which crosses the blood—brain barrier nor AM with limited CNS penetration , potentiate LiCl-induced nausea, an effect evident with low doses 2.
AMinduced conditioned nausea is thus mediated by inverse agonism of the CB 1 receptor. Recent research Rock et al. Research aimed at determining the forebrain regions e.
AN often develops over the course of repeated chemotherapy sessions Nesse et al. For instance, Nesse et al. He experienced the same nausea when returning for routine follow-up visits, even though he knew he would not receive treatment. The nausea gradually disappeared over repeated follow-up visits. AN is best understood as a classically conditioned response CR Pavlov, Control over AN could be exerted at the time of conditioning or at the time of re-exposure to the conditioned stimulus CS.
If an anti-emetic drug is presented at the time of conditioning, then a reduction in AN would be the result of an attenuated unconditioned response UCR ; that is, reduced nausea produced by the toxin at the time of conditioning thereby attenuating the establishment of the CR. Indeed, when administered during the chemotherapy session, the 5-HT 3 antagonist, granisetron, has been reported to reduce the incidence of AN in repeat cycle chemotherapy treatment Aapro et al.
On the other hand, if a drug is delivered prior to re-exposure to cues previously paired with the toxin-induced nausea, then suppressed AN would be the result of attenuation of the expression of the CR conditioned nausea ; the 5-HT 3 antagonists are ineffective at this stage Nesse et al. Although there has been considerable experimental investigation of unconditioned retching and vomiting in response to toxins, there have been relatively few reports of conditioned retching; that is, emetic reactions elicited by re-exposure to a toxin paired cue.
Conditioned retching has been observed to occur in coyotes, wolves and hawks upon re-exposure to cues previously paired with lithium-induced toxicosis Garcia et al. This effect was replicated more recently and extended to demonstrate that CBD also interferes with the expression of conditioned retching in the shrew, but the 5-HT 3 antagonist ondansetron was completely ineffective Parker et al. The doses employed were selected on the basis of their potential to interfere with toxin-induced vomiting in the S.
Rats also display conditioned gaping reactions when re-exposed to a context previously paired with LiCl-induced nausea Limebeer et al. Following four pairings of a distinctive, vanilla odour-laced chamber with LiCl-induced illness, rats were returned to the context for 30 min and received a 1 min intraoral infusion of novel saccharin solution every 5 min.
During the infusions, the rats displayed gaping reactions. Surprisingly, the rats also gaped during intervals when they were not being infused with saccharin while in the LiCl-paired context. The finding that rats express conditioned gaping responses when re-exposed to an odour-laced context previously paired with LiCl during inter-infusion intervals Limebeer et al.
Meachum and Bernstein had previously shown the re-exposure to a lithium-paired odour cue elicited gaping reactions in rats. Recently, Limebeer et al. Most recently, Rock et al. Indeed, inhibition of FAAH by URB also prevented the establishment of LiCl-induced conditioned gaping elicited by the contextual cues when administered 2 h prior to each conditioning trial. These results suggest that cannabinoid compounds may be effective agents in the treatment of AN in chemotherapy patients.
Since the discovery of the mechanism of action of cannabinoids, our understanding of the role of the endocannabinoid system in the control of nausea and vomiting has greatly increased. In the ferret and shrew models, the site of action has been identified in the emetic area of the brainstem, the DVC.
The shrew model, in particular, is cost effective for the evaluation of the anti-emetic properties of agents. The conditioned gaping response in the rat has provided a glimpse into the anti-nausea mechanisms of action of cannabinoids, in the absence of a vomiting response.
Since nausea is a more difficult symptom to control than vomiting, the gaping model may serve as a useful tool for the development of new anti-nausea treatments, as well as for the evaluation of the potential side effects of nausea in newly developed pharmacological treatments.
Recent work has also supported anecdotal reports that cannabis may attenuate AN. Although chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea acute, delayed and anticipatory continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation e. Both preclinical and human clinical e.
Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex e. Hornby, ; however, the neural mechanisms of nausea are still not well understood Andrews and Horn, One limitation in the preclinical screening of the nauseating side effect of compounds and the potential of compounds to treat nausea has been the lack of a reliable preclinical rodent model of nausea.
For years researchers have been using conditioned taste avoidance in rats as a model of nausea, but it has been well documented that non-nauseating treatments also produce taste avoidance — it is not a selective measure of nausea e.
However, the considerable amount of evidence reviewed above indicates that conditioned disgust in rats elicited by an illness-paired flavour e.
This model may be a useful tool for elucidating the neurobiology of nausea and the role that the endocannabinoid system plays in the regulation of this distressing condition. This research was supported by a research grant to L. National Center for Biotechnology Information , U. Journal List Br J Pharmacol v. Author information Article notes Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Abstract Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. Introduction A major advance in the control of acute emesis in chemotherapy treatment was the finding that blockade of one subtype of the 5-hydroxytryptamine 5-HT receptor, the 5-HT 3 receptor, could suppress the acute emetic response retching and vomiting induced by cisplatin in the ferret and the shrew Costall et al.
Anti-emetic effects of cannabinoids in human clinical trials The cannabis plant has been used for several centuries for a number of therapeutic applications Mechoulam, , including the attenuation of nausea and vomiting. Effects of cannabinoids on vomiting in animal models To evaluate the anti-emetic potential of drug therapies, animal models have been developed.
Anti-emetic effect of cannabinoids: Effects of cannabinoids on nausea in animal models Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting e.
Cannabinoid Regulation of Acute and Anticipatory Nausea
THC is effective in interfering with nausea and vomiting in human cancer patients (see Effect of THCA on LiCl-induced conditioned gaping to a flavour in rats. The anti-emetic effect of cannabinoids has been shown across a wide variety of (nausea) in rats as they suppress vomiting in emetic species. Cannabinoids: Effects on vomiting and nausea in animal models . Since rats and mice do not vomit in response to a toxin challenge, it is necessary to use.