Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound ...Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance.
To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew.
Shrews were injected with vehicle or one of two cannabinoids Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg) 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716.
Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716.
These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.
When intraorally infused with a flavored solution previously paired with an emetic drug, rats display a characteristic gaping reaction that reflects conditioned nausea in this species that is unable ...to vomit. The commonly used conditioned taste avoidance measure, is not a selective measure of nausea because nearly every drug tested (even rewarding drugs) is capable of producing a conditioned taste avoidance. In contrast, only emetic drugs produce conditioned gaping reactions in rats, and anti-emetic drugs interfere with the establishment and the expression of conditioned gaping reactions but do not interfere with conditioned taste avoidance. The conditioned gaping reaction can be used as a pre-clinical tool to evaluate the side effects of nausea that might result from newly developed pharmaceutical agents.
BACKGROUND AND PURPOSE
Conditioned gaping reactions reflect nausea‐induced behaviour in rats. Cannabinoid 1 receptor (CB
1
) agonists interfere with the establishment of nausea‐induced conditioned ...gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB
1
receptors.
EXPERIMENTAL APPROACH
We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB
1
agonist, CB13, on the establishment of LiCl‐induced gaping in rats. We further evaluated the ability of HU‐210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl‐induced conditioned gaping and determined if this effect was mediated by CB
1
receptors.
KEY RESULTS
Central, but not peripheral, CB13 suppressed LiCl‐induced conditioned gaping. Central administration of the potent CB
1
agonist, HU‐210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl‐induced gaping reactions, but not LiCl‐induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU‐210 delivered to the VIC prevented LiCl‐induced nausea, but not learning
per se
. The suppression of LiCl‐induced conditioned gaping by HU‐210 was mediated by CB
1
receptors because it was prevented by co‐administration of CB
1
antagonist/inverse agonist, AM‐251, into the VIC. A high dose of AM‐251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions.
CONCLUSIONS AND IMPLICATIONS
The nausea‐relieving effects of CB
1
agonists, but not the nausea‐inducing effects of CB
1
inverse agonists, are mediated, at least in part, by their action at the VIC in rats.
BACKGROUND AND PURPOSE Conditioned gaping reactions reflect nausea-induced behaviour in rats. Cannabinoid 1 receptor (CB sub(1)) agonists interfere with the establishment of nausea-induced ...conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB sub(1) receptors. EXPERIMENTAL APPROACH We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB sub(1) agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB sub(1) receptors. KEY RESULTS Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB sub(1) agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB sub(1) receptors because it was prevented by co-administration of CB sub(1) antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 mu g) administered alone into the VIC did not produce conditioned gaping reactions. CONCLUSIONS AND IMPLICATIONS The nausea-relieving effects of CB sub(1) agonists, but not the nausea-inducing effects of CB sub(1) inverse agonists, are mediated, at least in part, by their action at the VIC in rats.
A growing body of evidence suggests that cannabinoid CB1 receptor antagonists have potential therapeutic utility as appetite suppressants. However, the specific mechanisms underlying the reduction in ...food intake produced by these drugs are not well understood.
Considering the known antiemetic and motor-suppressive effects of CB1 agonists, the present studies were conducted to determine if the reductions in food intake induced by the CB1 antagonist AM 251 could result from nausea or impairments in intake-related motor control, rather than solely from appetite suppression.
Three experiments were conducted to examine the effects of AM 251 (2.0, 4.0, or 8.0 mg/kg or vehicle) on detailed parameters of food intake, on the development of conditioned taste avoidance, and on taste reactivity.
In the first experiment, acute administration of AM 251 dose-dependently decreased food intake; nevertheless, feeding rate (grams consumed per time spent eating) and food handling were unaffected, which suggests that food intake was not reduced because of severe motor impairments. In the second experiment, AM 251 dose-dependently reduced intake of a flavor with which it had previously been associated, indicating that conditioned taste avoidance had developed. Lastly, AM 251 was found to induce conditioned rejection reactions in a dose-dependent manner.
The CB1 antagonist AM 251 may reduce food intake in part by inducing nausea or malaise, but not because of incoordination or motor slowing related to feeding.
Rats display conditioned rejection reactions during an oral infusion of a flavor previously paired with an emetic drug; considerable evidence indicates that these rejection reactions reflect nausea. ...Here we report that cannabidiol, a major non-psychoactive cannabinoid found in marijuana and its synthetic dimethylheptyl homolog interfere with nausea elicited by lithium chloride and with conditioned nausea elicited by a flavor paired with lithium chloride. These results suggest that cannabinoids without psychoactive side-effects may have therapeutic value in the treatment of chemotherapy-induced nausea.
When rats are intraorally exposed to saccharin solution that has previously been paired with lithium chloride (LiCl), they display Pavlovian conditioned disgust reactions. When exposed to LiCl-paired ...saccharin solution by bottle, they display suppressed instrumental approach to the bottle resulting in suppressed consumption. The present experiments demonstrated that while neither neurotoxin-induced lesions of the basolateral amygdala (BLA) nor the central nucleus of the amygdala (CeA) attenuated the display of Pavlovian conditioned disgust reactions, lesions of the BLA (but not the CeA) attenuated instrumental conditioned avoidance of the taste. The results are discussed in light of current models of the role of the amygdala in aversive learning.
Oral Tolerance: Overview and Historical Perspectives MOWAT, ALLAN McI; PARKER, LUCY A.; BEACOCK-SHARP, HELEN ...
Annals of the New York Academy of Sciences,
December 2004, Letnik:
1029, Številka:
1
Journal Article
Recenzirano
: Oral tolerance was first detailed almost 100 years ago, and since then, it has been shown repeatedly that feeding a wide variety of nonpathogenic antigens can inhibit subsequent systemic immune ...responses. All systemic immune responses are susceptible, but the degree and scope of the suppression depends on the nature and dose of the fed antigen. Oral tolerance has been described in most mammals, including humans, and it may be the homeostatic mechanism that prevents hypersensitivity to food antigens, as is found in celiac disease. A similar process may prevent the aberrant immune responses to commensal bacteria that occur in inflammatory bowel disease. The ability of oral tolerance to modulate experimental models of autoimmune and inflammatory disease has led to clinical trials in such diseases as rheumatoid arthritis, multiple sclerosis, and type I diabetes, with only variable success. Despite intense research, the exact mechanisms responsible for the systemic tolerance and the reasons why tolerance is the default response to many fed antigens remain controversial. Early studies suggested that CD8+“suppressor” T cells were important, but it is now accepted that it may involve either anergy/deletion of CD4+ T cells, or the induction of regulatory CD4+ T cells that produce IL‐10 and/or TGFβ. There may also be a role for CD4+ CD25+ Treg, but how and when all these different mechanisms operate is still unclear. The ability of fed antigens to induce tolerance probably reflects their uptake by “quiescent” antigen‐presenting cells in the intestine, with presentation to specific CD4+ T cells in the absence of costimulation, or with the involvement of inhibitory costimulatory molecules. Dendritic cells in the Peyer's patches or mucosal lamina propria are the most likely APCs involved, but it remains to be determined exactly where these interactions occur and what the precise nature of the relevant dendritic cells is.
Paradoxically, drugs that animals will self-administer also produce conditioned taste avoidance at similar dosage levels. The present review presents evidence that the taste avoidance produced by ...these rewarding drugs differs qualitatively from the taste avoidance produced by the nonrewarding, emetic drug, lithium chloride. An analysis of data pooled across 6 experiments compares the nature of flavor-drug associations produced by various rewarding drugs (amphetamine, cocaine, methamphetamine, methylphenidate, morphine, nicotine and phencyclidine) with that produced by lithium. The data from the groups conditioned with the rewarding drugs and with lithium were combined into the two categories of low/moderate and high doses. When assessed by the CTA test, the rewarding drugs did not differ from lithium in the strength of the CTA at low/moderate or at high doses. However, when assessed by the TR test, lithium produced more prominent aversive taste reactions than did the rewarding drugs. These findings suggest that the flavor-drug association produced by lithium and rewarding drugs differs qualitatively. With the large pooled data set we also assessed the relationship among the various TR categories, resulting in two factors of “Ingestion” and “Aversion” accounting for 55% of the total variability within the data.
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