Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Active cannabimimetic drugs are known to bind to two receptor subtypes: one, called CB1, is mainly localised in the central nervous system while the other (CB2) is expressed preferentially in the immune system. SR 141716A has been demonstrated to have a nanomolar affinity for CB1 receptor subtypes and a micromolar affinity for CB2 receptors. Moreover, it is an effective antagonist at these receptors both in vitro (antagonism of cannabinoid activity in vas deferens) and in vivo (suppression of the hypothermia elicited by WIN 55,212-2). The present experiments were thus undertaken to investigate the role of CB1 receptors in cannabinoid discrimination. Rats were trained to discriminate WIN 55,212-2 (0.3mg/kg s.c.) from saline in a standard operant (FR10) food rewarded discrimination procedure. Acquisition of the discrimination required 16 days on average and the ED(50) of WIN 55,212-2 was 0.032mg/kg s.c. CP55,940 and delta-9-tetrahydrocannabinol (Delta(9)-THC) generalised to the WIN 55,212-2 stimulus with the respective ED(50)s of 0.007mg/kg (s.c.) and 0.64mg/kg (p.o.). Pretreatment with SR 141716A antagonised the cue elicited by WIN 55,212-2 (ED(50) = 1.6mg/kg) as well as the generalisation to CP 55,940 (ED(50) = 0.08mg/kg) and to Delta(9)-THC (ED(50) = 0.15mg/kg). SR 140098 is a CB1 antagonist as potent as SR 141716A in vitro. This compound is unlikely to pass into the brain since it failed to displace [(3)H]-CP55, 940 from rat brain membranes ex vivo, and to reverse WIN 55,212-2-induced hypothermia. SR 140098, in contrast to SR 141716A, did not antagonise the WIN 55,212-2 stimulus. Taken together, the present results demonstrate that the brain CB1 receptor subtype mediates the cannabinoid cue.
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PMID:Central mediation of the cannabinoid cue: activity of a selective CB1 antagonist, SR 141716A. 1122 95

Although the majority of cannabinoid users smoke marijuana, the preponderance of laboratory animal research is based on administration of Delta9-tetrahydrocannabinol (Delta9-THC) or other cannabinoid agents via injection. The aim of the present study was to evaluate the impact of inhaling marijuana, or ethanol-extracted placebo smoke in the mouse model of cannabinoid activity by assessing inhibition of spontaneous activity, antinociception, catalepsy, and body temperature. In order to determine dosimetry, blood levels of Delta9-THC were obtained following either marijuana exposure or intravenous injection of Delta(9)-THC. Inhalation exposure to marijuana produced dose-related increases in antinociception and catalepsy, with estimated ED50 doses of Delta9-THC of 2.4 and 3.8 mg/kg, respectively. However, hypothermia and locomotor depression occurred in both the placebo- and marijuana-exposed mice. The CB1 receptor antagonist, SR 141716A antagonized the antinociceptive effects of marijuana (AD50 = 0.6 mg/kg), but only slightly decreased marijuana-induced catalepsy, and failed to alter either the hypothermic or locomotor depressive effects. In contrast, SR 141716A antagonized the antinociceptive, cataleptic, and hypothermic effects of intravenously administered Delta9-THC in mice that were exposed to air alone, though all subjects exhibited locomotor depression, possibly related to the restraint. In accordance with reports of others, these data suggest that exposure to smoke alone has pharmacological consequences. Our findings also indicate that marijuana-induced antinociception is mediated through a CB1-receptor mechanism of action and are consistent with the notion that Delta9-THC is mainly responsible for this effect.
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PMID:The pharmacological activity of inhalation exposure to marijuana smoke in mice. 1137 14

The first endocannabinoid, anandamide, was discovered in 1992. Since then, two other endocannabinoid agonists have been identified, 2-arachidonyl glycerol and, more recently, noladin ether. Here, we report the identification and pharmacological characterization of a novel endocannabinoid, virodhamine, with antagonist properties at the CB1 cannabinoid receptor. Virodhamine is arachidonic acid and ethanolamine joined by an ester linkage. Concentrations of virodhamine measured by liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometry in rat brain and human hippocampus were similar to anandamide. In peripheral tissues that express the CB2 cannabinoid receptor, virodhamine concentrations were 2- to 9-fold higher than anandamide. In contrast to previously described endocannabinoids, virodhamine was a partial agonist with in vivo antagonist activity at the CB1 receptor. However, at the CB2 receptor, virodhamine acted as a full agonist. Transport of [(14)C]anandamide by RBL-2H3 cells was inhibited by virodhamine. Virodhamine produced hypothermia in the mouse and acted as an antagonist in the presence of anandamide both in vivo and in vitro. As a potential endogenous antagonist at the CB1 receptor, virodhamine adds a new form of regulation to the endocannabinoid system.
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PMID:Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. 1202 33

Fatty acid amides (FAAs) represent a class of neuromodulatory lipids that includes the endocannabinoid anandamide and the sleep-inducing substance oleamide. Both anandamide and oleamide produce behavioral effects indicative of cannabinoid activity, but only anandamide binds the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been proposed to induce its behavioral effects by serving as a competitive substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and inhibiting the degradation of endogenous anandamide. To test the role that FAAH plays as a mediator of oleamide activity in vivo, we have compared the behavioral effects of this FAA in FAAH(+/+) and (-/-) mice. In both genotypes, oleamide produced hypomotility, hypothermia, and ptosis, all of which were enhanced in FAAH(-/-) mice, were unaffected by the CB1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(-/-) mice. Additionally, oleamide displayed negligible binding to the CB1 receptor in brain extracts from either FAAH(+/+) or (-/-) mice. In contrast, anandamide exhibited a 15-fold increase in apparent affinity for the CB1 receptor in brains from FAAH(-/-) mice, consistent with its pronounced CB1-dependent behavioral effects in these animals. Contrary to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (-/-) mice. Collectively, these results indicate that FAAH is a key regulator, but not mediator of FAA activity in vivo. More generally, these findings suggest that FAAs represent a family of signaling lipids that, despite sharing similar chemical structures and a common pathway for catabolism, produce their behavioral effects through distinct receptor systems in vivo.
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PMID:Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. 1206 2

(-)-(R)-3-(2-Hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) is a new high-affinity cannabinoid receptor subtype 1 (CB1 receptor) ligand (K(i) = 0.46-1.85 nM; rat brain, human cortex, or recombinant human CB1 receptor), structurally unrelated to any cannabinoid receptor ligand known so far. BAY 38-7271 was characterized as a CB1 receptor agonist in 5-[gamma(35)S]-thiophosphate triethylammonium salt binding assays using rat or human CB1 receptors. In the rat hypothermia assay, BAY 38-7271 induced a dose-dependent reduction in body temperature (minimal effective dose = 6 microg/kg, i.v.); whereas in rats trained to discriminate the CB1/CB2 receptor agonist (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940; 0.03 mg/kg, i.p.) from vehicle, BAY 38-7271 induced complete generalization (3 microg/kg, i.v.). In both in vivo models, a specific CB1 receptor-mediated mechanism was confirmed by demonstrating that the effects of CP 55,940 and BAY 38-7271 were blocked by pretreatment with the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride. In the rat traumatic brain injury model, BAY 38-7271 demonstrated highly potent and efficient neuroprotective properties when administered as a 4-h infusion immediately after induction of subdural hematoma (70% infarct volume reduction at 100 ng/kg/h). Even when applied with a 3-h delay, a significant neuroprotective efficacy could be observed (59% infarct volume reduction at 300 ng/kg/h). The neuroprotective potential of BAY 38-7271 was confirmed in a rat model of focal cerebral ischemia induced by permanent occlusion of the middle cerebral artery. It is concluded that the CB1/CB2 receptor agonist BAY 38-7271 shows pronounced neuroprotective properties that do not result from drug-induced hypothermia and that occur in a dose range devoid of typical cannabinoid-like side effects.
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PMID:Characterization of the diarylether sulfonylester (-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate (BAY 38-7271) as a potent cannabinoid receptor agonist with neuroprotective properties. 1206 38

Psychopathological disorders, and depression in particular, are strongly linked to eating attitude in obese patients. The identification of cannabinoid CB1 receptors (CB1Rs) in areas of the central nervous system (CNS) that have been implicated in regulation of mood and food intake suggests that these receptors may mediate such a behavioral link. The goal of this study was to evaluate CB1R modulation of antidepressant-like effects and food intake. For this purpose, 129/SVE and C57BL/6 male mice were acutely dosed intraperitoneally (i.p.) with the CB1R inverse agonist AM251 (3-30 mg/kg) and tested, respectively, in the tail-suspension test (TST) and in the forced-swim test (FST), which have been used widely as tests sensitive to antidepressant compounds. Like the antidepressant desipramine (DMI, 16 mg/kg), AM251 significantly reduced immobility at 10 mg/kg in the TST and at 1 and 10 mg/kg in the FST. Such a decrease of immobility was not accompanied by an increase in motor activity in the open field, suggesting that occupancy of CB1R by AM251 induced antidepressant-like effects. This was supported by two additional experiments. First, the co-administration of the CB1R agonist CP55940, at a dose that did not induce motor impairment or profound hypothermia (0.01 mg/kg), reversed effects of AM251 in the TST. Secondly, effects of AM251 in the FST were absent in CB1R knockout (KO) mice. In addition to an antidepressant-like effect, AM251 reduced fasting-induced hyperphagia over a comparable dose range. Taken together, these data suggest that regulation of mood and food intake might be obtained through inverse agonism of CB1R.
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PMID:Antidepressant-like and anorectic effects of the cannabinoid CB1 receptor inverse agonist AM251 in mice. 1466 74

This study compared the potency and efficacy of the cannabinoids delta-tetrahydrocannabinol (delta-THC), HU-210, WIN 55,212-2 and CP 55,940 in suppressing food-reinforced operant behavior, increasing reaction latency in a hot-plate test and inducing hypothermia, and tested whether these behavioral effects induced by CP 55,940 showed differential sensitivity to the cannabinoid CB1 receptor antagonist SR141716A, and to tolerance development. After acute i.p. administration to rats, operant behavior was more potently affected than reaction latency and body temperature, but the order of potency of the different drugs was similar across the tests: HU-210<CP 55,940<WIN 55,212-2=delta-THC. SR141716A blocked the hypothermic and analgesic effects more potently/efficiently than the response-rate suppressive effect of CP 55,940. After repeated administration of CP 55,940, the extent and speed of tolerance development was most pronounced in the hypothermia test, and least pronounced in the operant test. It is concluded that the more the behavioral effect induced by a cannabinoid receptor agonist is situated at the left-hand side of the dose-spectrum, the more the effect is resistant to blockade by a cannabinoid receptor antagonist and to the development of tolerance. The possible consequence of this observation for the therapeutic use of cannabinoids is discussed.
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PMID:Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development. 1507 21

Cannabinoid-MDMA interactions were examined in male Wistar rats. MDMA (4 x 5 mg/kg or 2 x 10 mg/kg over 4 h on each of 2 days) was administered with or without Delta 9-tetrahydrocannabinol (THC) (4 x 2.5 mg/kg), the synthetic cannabinoid receptor agonist CP 55,940 (2 x 0.1 or 0.2 mg/kg) or the cannabinoid receptor antagonist SR 141716 (2 x 5 mg/kg). Co-administered Delta 9-THC and CP 55,940 but not SR 141716 prevented MDMA-induced hyperthermia, causing a powerful hypothermia. Co-administered Delta 9-THC, CP 55,940 and SR 141716 all tended to decrease MDMA-induced hyperactivity. Co-administered Delta 9-THC provided protection against the long-term increases in anxiety seen in the emergence test, but not the social interaction test, 6 weeks after MDMA treatment. Co-administered Delta 9-THC and CP 55,940, but not SR 141716, partly prevented the long-term 5-HT and 5-HIAA depletion caused by MDMA in various brain regions. SR 141716 administered with CP 55,940 and MDMA prevented the hypothermic response to the CP 55,940/MDMA combination but did not alter the CP 55,940 attenuation of MDMA-induced 5-HT depletion. These results suggest a partial protective effect of co-administered cannabinoid receptor agonists on MDMA-induced 5-HT depletion and long-term anxiety. This action appears to operate independently of cannabinoid CB1 receptors.
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PMID:Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA ("Ecstasy") in rats. 1508 92

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (Ki = 0.56 and 3.5 nM) for both the rat brain and human CB1 recombinant receptors, respectively. It has low affinity (Ki = 400 nM) for both the rat spleen and human CB2 receptors. Furthermore, it shows no affinity for any of the over 100 targets investigated (IC50 > 1 microM). In vitro, SR147778 antagonizes the inhibitory effects of CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] on both the mouse vas deferens contractions (pA2 value = 8.1) and on forskolin-stimulated adenylyl cyclase activity in the U373 MG cell lines (pA2 value = 8.2) but not in Chinese hamster ovary (CHO) cells permanently expressing the human peripheral cannabinoid receptor (hCB2). SR147778 is able to block the mitogen-activated protein kinase activity induced by CP 55,940 in the CHO cell line expressing human brain cannabinoid receptor (IC50 = 9.6 nM) but was inactive in cells expressing hCB2. After oral administration, SR147778 displaced the ex vivo [3H]-CP 55,940 binding to mouse brain membranes (ED50 = 3.8 mg/kg) with a long duration of action, whereas it did not interact with the CB2 receptor expressed in the mouse spleen. Using different routes of administration, SR147778 (0.3-3 mg/kg) is shown to antagonize pharmacological effects (hypothermia, analgesia, and gastrointestinal transit) induced by R-(+)-(2,3-dihydro-5-methyl-3-[[4-morpholinyl]methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone in mice. Finally, per se, SR147778 (0.3-10 mg/kg) is able to reduce ethanol or sucrose consumption in mice and rats and food intake in fasted and nondeprived rats.
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PMID:SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. 1513 Dec 45

Arachidonyl ethanolamine, which is commonly known as anandamide, was the first endogenous compound to be identified that binds to the cannabinoid receptors. Anandamide mimics many of the physiological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), including hypothermia, antinociception, immobility, catalepsy, and immune modulation. In the present studies, we show that anandamide caused a concentration-dependent inhibition of interleukin-2 in primary splenocytes. The CB1 and CB2 antagonists, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorphenyl)-4-methyl-H-pyrazole-3 carboxyamidehydrochloride] and SR144528 [N-[(1S)-endo-1,3,3,-trimethylbicyclo[2,2,1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide], when used in combination, did not antagonize the inhibition of interleukin-2 by anandamide. Additionally, neither UCM707 [N-(3-furanylmethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide], the inhibitor of the putative anandamide membrane transporter (AMT), nor methyl arachidonoyl fluorophosphonate (MAFP), the inhibitor of fatty acid amidohydrolase (FAAH), were able to affect the inhibitory activity of anandamide upon interleukin-2. Interestingly, arachidonic acid caused a concentration-dependent inhibition of interleukin-2 secretion (IC(50) = 10.3 microM), which was similar to that of structurally related anandamide (IC(50) = 11.4 microM). The inhibition of interleukin-2 by anandamide and arachidonic acid was partially reversed by pretreatment with the nonspecific cyclooxygenase inhibitors, flurbiprofen and piroxicam. Moreover, NS398 [N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide], a cyclooxygenase-2-specific inhibitor, also attenuated the inhibitory effects of anandamide and arachidonic acid upon interleukin-2 secretion. Finally, pretreatment with a peroxisome proliferator-activated receptor gamma (PPARgamma)-specific antagonist, T0070907 [2-chloro-5-nitro-N-4-pyridinyl-benzamide], partially antagonized anandamide-mediated suppression of IL-2 secretion. Collectively, the aforementioned studies suggest that inhibition of interleukin-2 secretion by anandamide is independent of CB1/CB2 and the AMT/FAAH system. Additionally, these studies also suggest that inhibition of interleukin-2 is mediated by a PPARgamma, which is activated by a cyclooxygenase-2 metabolite of anandamide.
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PMID:A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. 1528 81


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