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)

In the present article, we review the pharmacological properties of KDS-4103 (URB597), a highly potent and selective inhibitor of the enzyme fatty-acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide. In vitro, KDS-4103 inhibits FAAH activity with median inhibitory concentrations (IC(50)) of 5 nM in rat brain membranes and 3 nM in human liver microsomes. In vivo, KDS-4103 inhibits rat brain FAAH activity after intraperitoneal (i.p.) administration with a median inhibitory dose (ID(50)) of 0.15 mg/kg. The compound does not significantly interact with other cannabinoid-related targets, including cannabinoid receptors and anandamide transport, or with a broad panel of receptors, ion channels, transporters and enzymes. By i.p. administration to rats and mice KDS-4103 elicits significant, anxiolytic-like, antidepressant-like and analgesic effects, which are prevented by treatment with CB1 receptor antagonists. By contrast, at doses that significantly inhibit FAAH activity and substantially raise brain anandamide levels, KDS-4103 does not evoke classical cannabinoid-like effects (e.g., catalepsy, hypothermia, hyperphagia), does not cause place preference, and does not produce generalization to the discriminative effects of the active ingredient of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC). These findings suggest that KDS-4103 acts by enhancing the tonic actions of anandamide on a subset of CB(1) receptors, which may normally be engaged in controlling emotions and pain. KDS-4103 is orally available in rats and cynomolgus monkeys. Sub-chronic repeated dose studies (1,500 mg/kg, per os) in these two species have not demonstrated systemic toxicity. Likewise, no toxicity was noted in bacterial cytotoxicity tests in vitro and in the Ames test. Furthermore, no deficits were observed in rats on the rotarod test after acute i.p. treatment with KDS-4103 at doses up to 5 mg/kg or in a functional observation battery after oral doses up to 1,500 mg/kg. The results suggest that KDS-4103 will offer a novel approach with a favorable therapeutic window for the treatment of anxiety, depression and pain.
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PMID:Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). 1683 56

Cannabinoid receptor agonists have been demonstrated to inhibit medullary and spinal cord dorsal horn nociceptive neurons. The effect of cannabinoids on thermoreceptive specific neurons in the spinal or medullary dorsal horn remains unknown. In the present study, single-unit recordings from the rat medullary dorsal horn were performed to examine the effect of a cannabinoid receptor agonists on cold-specific lamina I spinothalamic tract neurons. The cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (WIN-2), was locally applied to the medullary dorsal horn and the neuronal activity evoked by cooling the receptive field was recorded. WIN-2 (1 microg/microl and 2 microg/microl) significantly attenuated cold-evoked activity. Co-administration of the CB1 receptor antagonist SR 141716 with WIN-2 did not affect cold-evoked activity. These results demonstrate a potential mechanism by which cannabinoids produce hypothermia, and also suggest that cannabinoids may affect non-noxious thermal discrimination.
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PMID:The cannabinoid receptor agonist, WIN 55,212-2, inhibits cool-specific lamina I medullary dorsal horn neurons. 1694 15

Cannabinoid (CB)1 receptor inverse agonists inhibit food intake in animals and humans but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain, and emesis. Neutral antagonist and binding properties were confirmed in HEK-293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin-stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80 +/- 0.44 nM) in competitive binding assays with the CB1/2 agonist [3H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg/kg) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg/kg), a highly anorectic dose of AM4113 (10 mg/kg) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans, they could be developed into a new class of antiobesity agents.
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PMID:A neutral CB1 receptor antagonist reduces weight gain in rat. 1795 1

Dysregulation of the endocannabinoid and dopamine systems has been implicated in schizophrenia. The purpose of this study was to examine the effects of sub-chronic treatment with two antipsychotics on CB1 receptor-mediated in vitro and in vivo effects. Adult and adolescent male and female rats were injected twice daily with haloperidol (0.3 mg/kg), clozapine (10 mg/kg), or saline for 10 days. Subsequently, CB1 receptor number and function were assessed by [3H]SR141716 and WIN55,212-2-stimulated [35S]GTPgammaS binding, respectively. The effects of sub-chronic antipsychotic treatment on the in vivo actions of Delta9-tetrahydrocannabinol (Delta9-THC) were also evaluated. In adult female rats, antipsychotic treatment attenuated maximal stimulation of CB1 receptor-mediated G-protein activity in the striatum (clozapine) and prefrontal cortex (both antipsychotics), but not in the ventral midbrain. Associated changes in CB1 receptor number were not observed, suggesting that this attenuation was not due to downregulation. In vivo, sub-chronic treatment with clozapine, but not haloperidol, attenuated Delta9-THC-induced suppression of activity in adult females, whereas neither drug altered hypothermia or catalepsy. In contrast, antipsychotic treatment did not change CB1 receptor-mediated G-protein activation in any brain region in adult male rats and in adolescents of either sex. In vivo, haloperidol, but not clozapine, enhanced Delta9-THC-mediated suppression of activity and hypothermia in adult male rats whereas neither antipsychotic affected Delta9-THC-induced in vivo effects in adolescent rats. These findings suggest that modulation of the endocannabinoid system might contribute in a sex- and age-selective manner to differences in motor side effects of clozapine versus haloperidol.
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PMID:Antipsychotic-induced alterations in CB1 receptor-mediated G-protein signaling and in vivo pharmacology in rats. 1870 79

2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
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PMID:Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. 1908 12

We sought to determine whether sex differences exist for the cannabinoid modulation of appetite, body temperature and neurotransmission at pro-opiomelanocortin (POMC) synapses. Gonadectomized male and female guinea pigs were outfitted to monitor core body temperature and injected with either the CB1 receptor agonist WIN 55,212-2 (1 mg/kg s.c.), antagonist AM251 (3 mg/kg s.c.) or vehicle (1 ml/kg s.c.) and evaluated for changes in six indices of feeding behavior under ad libitum conditions for 7 days. WIN 55,212-2 elicited an overt, sexually differentiated hyperphagia in which males displayed larger increases in hourly and daily intake, consumption/gram body weight, meal size and meal duration. The agonist also produced a more robust acute hypothermia in males than in females. In addition, males were more sensitive to the hypophagic effect of AM251, manifested by comparatively sizeable decreases in hourly intake, consumption/gram body weight, meal frequency and hyperthermia. To gain additional insight into the cellular mechanism underlying cannabinoid regulation of energy homeostasis, we performed whole-cell patch clamp recordings in hypothalamic slices prepared from gonadectomized male and female guinea pigs, and monitored miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in arcuate (ARC) neurons. ARC neurons from females exhibited a higher basal mEPSC frequency. WIN 55,212-2 dose-dependently reduced mEPSC and mIPSC frequency; however, cells from males were far less sensitive to the CB1 receptor-mediated decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as POMC neurons. These data reveal pronounced sex differences in how cannabinoids influence the hypothalamic control of homeostasis.
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PMID:Sex differences in the cannabinoid modulation of appetite, body temperature and neurotransmission at POMC synapses. 1913 14

The dietary polyphenols trans-resveratrol [5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol; found in red wine] and curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1E,6E-heptadiene-3,5-dione] (found in curry powders) exert anti-inflammatory and antioxidant effects via poorly defined mechanisms. It is interesting that cannabinoids, derived from the marijuana plant (Cannabis sativa), produce similar protective effects via CB1 and CB2 receptors. We examined whether trans-resveratrol, curcumin, and ASC-J9 [1,7-bis(3,4-dimethoxyphenyl)-5-hydroxy-1E,4E,6E-heptatriene-3-one] (a curcumin analog) act as ligands at cannabinoid receptors. All three bind to human (h) CB1 and mouse CB1 receptors with nanomolar affinities, displaying only micromolar affinities for hCB2 receptors. Characteristic of inverse agonists, the polyphenols inhibit basal G-protein activity in membranes prepared from Chinese hamster ovary (CHO)-hCB1 cells or mouse brain that is reversed by a neutral CB1 antagonist. Furthermore, they competitively antagonize G-protein activation produced by a CB1 agonist. In intact CHO-hCB1 cells, the polyphenols act as neutral antagonists, producing no effect when tested alone, whereas competitively antagonizing CB1 agonist mediated inhibition of adenylyl cyclase activity. Confirming their neutral antagonist profile in cells, the polyphenols similarly attenuate stimulation of adenylyl cyclase activity produced by a CB1 inverse agonist. In mice, the polyphenols dose-dependently reverse acute hypothermia produced by a CB1 agonist. Upon repeated administration, the polyphenols also reduce body weight in mice similar to that produced by a CB1 antagonist/inverse agonist. Finally, trans-resveratrol and curcumin share common structural motifs with other known cannabinoid receptor ligands. Collectively, we suggest that trans-resveratrol and curcumin act as antagonists/inverse agonists at CB1 receptors at dietary relevant concentrations. Therefore, these polyphenols and their derivatives might be developed as novel, nontoxic CB1 therapeutics for obesity and/or drug dependence.
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PMID:The dietary polyphenols trans-resveratrol and curcumin selectively bind human CB1 cannabinoid receptors with nanomolar affinities and function as antagonists/inverse agonists. 1994 Jan 10

This review highlights the progress made thus far in characterizing the behavioral and cellular mechanisms through which cannabinoids regulate energy homeostasis. We performed microstructural analysis of feeding behavior in gonadectomized guinea pigs and gonadally intact, transgenic CB1 receptor knockout mice to determine how cannabinoids affect circadian rhythms in food intake and meal pattern. We also implanted data loggers into the abdominal cavity to correlate the appetite-modulating properties of cannabinoids with changes in core body temperature. We then coupled the effects on feeding behavior and temperature regulation with synaptic changes in the hypothalamic feeding circuitry via whole-cell patch clamp electrophysiological recording from neurons in the arcuate nucleus (ARC), in order to gain a more global perspective on the cannabinoid modulation of energy homeostasis. We observed marked sex differences in cannabinoid effects on food intake and core body temperature--with male guinea pigs exhibiting a comparatively greater sensitivity to the hyperphagia and hypophagia, as well as the hypothermia and hyperthermia, produced by CB1 receptor agonists and antagonists, respectively. In addition, male but not female CB1 receptor knockout mice show a diminished nocturnal food intake and average daily body weight relative to their wildtype littermate controls. The disparity in the CB1 receptor-mediated hyperphagia is paralleled by sex differences in the cellular effects of cannabinoids at anorexigenic, guinea pig proopiomelanocortin (POMC) synapses. Postsynaptically, cannabinoids potentiate an A-type K+ current (I(A)) in POMC neurons from female guinea pigs, whereas in males the activation of an inwardly rectifying K+ current is observed. Presynaptically, while cannabinoids inhibit glutamatergic input onto POMC neurons in males and females to similar degrees, males are more refractory to the cannabinoid-induced inhibition of convergent GABAergic input than females. These data reveal pervasive sex differences in the cannabinoid regulation of energy homeostasis that are consistent with changes in the excitability of POMC neurons.
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PMID:Sex differences in the cannabinoid regulation of energy homeostasis. 1942 30

Acetaminophen (APAP) produces antinociception and hypothermia. Because the antinociceptive effect in rats is partially dependent on opioid and cannabinoid CB1 receptor activation, we determined if activation of these receptors also contributes to the hypothermic effect of APAP. Rats injected with APAP (100, 250, 375 or 500 mg/kg, i.p.) displayed dose-related hypothermia. For combined administration, the hypothermic effect of APAP (400 mg/kg, i.p.) was not altered by pretreatment with: naltrexone (10 mg/kg, s.c.), a non-selective opioid antagonist; naltrindole (1 mg/kg, s.c.), a delta opioid antagonist; nor-binaltorphimine (10 mg/kg, i.p.), a kappa opioid antagonist; SR 141716A (3 mg/kg, i.m.), a cannabinoid CB1 receptor antagonist; or JTC-801(1 mg/kg, i.p.), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist. The demonstration that APAP produces hypothermia independent of opioid, cannabinoid CB1 or NOP receptor activation is contrary to its antinociceptive effect, which requires opioid and cannabinoid CB1 receptor activation.
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PMID:Opioid, cannabinoid CB1 and NOP receptors do not mediate APAP-induced hypothermia in rats. 1946 66

Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.
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PMID:A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. 1978 14


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