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

A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.
 ...
PMID:[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)]. 738 58

The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of delta 9-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED50 = 0.13 mg/kg). delta 9-THC and WIN-55,212-2 disrupted maze-choice accuracy at equipotent doses (ED50 values = 2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of delta 9-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED50 = 8 micrograms/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.
 ...
PMID:Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. 767 62

A series of 3-alkyl-2'-yne (side chain) acetylenic analogs of delta 9-THC were synthesized and evaluated for in vitro and in vivo activity. Analogs were evaluated for receptor affinity in a [3H]CP-55,940 displacement assay and for in vivo pharmacological activity in a mouse procedure utilizing a tetrad of measures. These compounds represent a preliminary exploration of the consequences of restricting the flexibility of the side chain regarding cannabimimetic activity. All analogs proved to have receptor affinities (4-11 nM) that were five to ten times greater than that observed for delta 9-THC. However, the in vivo activities of these compounds varied greatly. All analogs proved to possess the greatest potency for production of antinociception, with activity similar to or less than that observed for the production of hypomotility, hypothermia, and catalepsy. The most potent analog 11b exhibited an ED50 of 0.031 mg/kg in the tail-flick procedure, with values in other measures being between 0.5 and 1.0 mg/kg. The least active compound (11c), though still possessing a KI of 11 nM, exhibited ED50 values of 3.1 and 9.3 mg/kg for tail-flick and temperature procedures, as well as 41 and 48 mg/kg for ring-immobility and spontaneous locomotor activity, respectively. This profile (high receptor affinity but low in vivo potency) would normally be suggestive of a compound with antagonist properties (at least for immobility and activity measures). It is unclear why these acetylenic analogs were so potent in vitro, while only one (11b) exhibited the degree of in vivo potency anticipated based upon comparison to values for delta 9-THC. It is possible these side chain modifications do not interfere with receptor recognition, but limit receptor activation or second messenger signal transduction. Regardless, it is clear these novel analogs provide a basis for the further exploration of the cannabinoid receptor pharmacophore.
 ...
PMID:A novel class of potent tetrahydrocannabinols (THCS): 2'-yne-delta 8- and delta 9-THCS. 777 26

Anandamide (arachidonylethanolamide), a putative endogenous ligand for the cannabinoid receptor, produces a tetrad of behavioral effects in mice characteristic of psychoactive cannabinoids including catalepsy, antinociception, hypothermia, and hypomobility. The present study examined the discriminative stimulus effects of anandamide in rats trained to discriminate delta 9-tetrahydrocannabinol or the potent cannabinoid receptor ligand CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol)] from vehicle. Intraperitoneal injections of anandamide substituted for delta 9-tetrahydrocannabinol and for CP 55,940; however, unlike substitution dose-effect curves with the training drugs, anandamide substitution occurred at a single dose (30 or 45 mg/kg) and was accompanied by severe decreases in response rates. The results of the present study suggest that, although systemic anandamide administration may have cannabimimetic effects similar to those of delta 9-tetrahydrocannabinol and CP 55,940, some differences in the behavioral effects of anandamide and other psychoactive cannabinoids also are apparent.
 ...
PMID:Discriminative stimulus effects of anandamide in rats. 778 95

In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.
 ...
PMID:Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212. 799 50

The arachidonic acid derivative anandamide (arachidonylethanolamide) has been isolated from porcine brain and has been shown to bind competitively to the cannabinoid receptor. Although the pharmacological activity of this compound has not yet been fully determined, preliminary data suggest that it produces several effects similar ot the cannabinoids. In the present experiments anandamide produced effects similar to those of delta 9-tetrahydrocannabinol, including antinociception (as determined in a latency to tail-flick evaluation), hypothermia, hypomotility and catalepsy in mice after i.v., i.t. and i.p. administration. In general, the effects of anandamide occurred with a rapid onset, but with a rather short duration of action. Prominent antinociceptive effects (> 80% maximal possible effect) were measured immediately after i.v. and i.t. administration. Anandamide produced significant decreases in rectal temperature (2-4 degrees C) after either i.v. or i.t. injection. Maximal effects on motor activity (approximately 85% inhibition) were observed immediately after i.v. and i.p. administration and 10 min after i.t. administration. Maximum immobility observed after i.v. administration was over 80%, yet that produced after i.p. and i.t. administration was too small (< or = 20%) to be considered pharmacologically relevant. Anandamide was less potent (1.3 to 18 times) than delta 9-tetrahydrocannabinol in all behavioral assays. Pretreatment with nor-binaltorphimine, a kappa opioid antagonist which blocks i.t. delta 9-tetrahydrocannabinol-induced antinociception, failed to alter antinociception after i.t. anandamide administration. Binding studies demonstrating that anandamide displaces [3H]CP-55,940 from rat whole brain P2 membrane preparations with a KD of 101 +/- 15 nM. These findings demonstrate that anandamide produces effects in a tetrad of tests used to predict cannabimimetic activity and supports the contention of its role as an endogenous cannabinoid ligand. However, there appear to be distinct differences between anandamide and the cannabinoids with regard to their antinociceptive properties, and other properties vary as a function of route of administration.
 ...
PMID:The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. 803 18

It has recently been hypothesized that tail-skin temperature may exert a profound influence on the latency of the tail-flick response to radiant heat. Several recent reports in the literature urge investigators to assess tail temperatures concurrently when using the tail-flick test and to adjust the tail-flick latency by a coefficient when a change in tail temperature is detected. Because much of the supporting evidence of this hypothesis was strictly correlational, the purpose of the present study was to determine whether tail-skin temperature is an important factor contributing to the latency of the tail-flick response to radiant heat. The effects of a series of pharmacological and non-pharmacological manipulations on tail-skin temperature and response latencies were assessed using either a low-intensity or high-intensity tail-flick stimulus. In addition, colonic temperature was evaluated. None of the drug treatments yielded a significant correlation between tail temperature and tail-flick latency. Of the seven drugs tested, only mecamylamine produced a consistent change in tail-skin temperature. Although mecamylamine significantly elevated tail temperature by more than 2 degrees C, it failed to alter response latencies. Similarly tail submergence into 5 degrees C water for 10 sec led to profound decreases in tail temperature ranging from -6.5 to -7.6 degrees C while producing only minimal increases in tail-flick latency. Conversely, submerging the tail in 38 degrees C water or placing the animals over a heating pad maintained at 38 degrees C increased tail temperatures at least 2 degrees C without affecting response latencies. Inverse correlations were found between tail-flick latency and colonic temperature after morphine, delta 9-tetrahydrocannabinal (delta 9-THC), and nicotine administration; however, these relationships do not appear to be causal. Sodium barbital produced far more hypothermia than any other agent, but did not produce any antinociception. Moreover, placing subjects in heated cages increased tail-skin temperature between 2 and 4 degrees C and blocked the hypothermic effects of morphine and delta 9-THC without reducing the antinociceptive potencies of these agents. These findings indicate that tail-skin and core temperatures have a negligible influence on the tail-flick response. We conclude that monitoring tail-skin or core temperatures when employing the tail-flick test is unnecessary and altering tail-flick latencies to account for changes in tail temperature is unwarranted.
 ...
PMID:Evidence that the antinociceptive tail-flick response is produced independently from changes in either tail-skin temperature or core temperature. 809 May 23

The selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) has been shown to modulate cannabinoid-induced antinociception by delta 9-tetrahydrocannabinol (delta 9-THC). However, it is not known whether nor-BNI blocks other pharmacological effects of delta 9-THC or if this is a specific action of nor-BNI. Studies were conducted in which pretreatment with nor-BNI (2, 10 and 20 micrograms i.t.) selectively blocked delta 9-THC-induced antinociception while not significantly affecting other commonly observed cannabinoid actions, which included hypothermia, hypoactivity and catalepsy. Chronic administration studies were performed to determine if cross tolerance could be established between delta 9-THC and the highly specific kappa opioid receptor agonists, U-50,488H and CI-977. The chronic delta 9-THC-treated groups were significantly tolerant, not only to i.t. delta 9-THC-induced antinociception in the tail-flick test, but also to i.t. U-50,488 and CI-977 compared with those treated chronically with vehicle. They were not cross tolerant to either DAMGO or DPDPE. Dose-response curves were generated for both delta 9-THC (i.t.) and CI-977 (i.t.) in mice tolerant to delta 9-THC and CI-977. Parallel shifts to the right of the delta 9-THC dose-response curves were observed in animals tolerant to delta 9-THC and also in animals tolerant to CI-977. Animals tolerant to CI-977 also demonstrated parallel shifts of the dose-response curves of both delta 9-THC and CI-977. This study demonstrated that cannabinoid actions can be distinguished from each other. The pharmacological separation of antinociception from the other cannabinoid-induced actions implies that it may have a mechanism distinct from other effects. In addition, this study indicates that delta 9-THC and the kappa opioid agonists may share a common mechanism of action in the production of antinociception and that a possible interaction exists between i.t. administered cannabinoid compounds and the kappa opioid receptor.
 ...
PMID:Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice. 813 52

The oxidative metabolism of cannabidiol (CBD) at the 8,9-double bond was examined. 8R,9-Epoxy-CBD was identified by GC-MS as a new metabolite of CBD produced by hepatic microsomal fractions of guinea pigs, rats and mice. The reaction required NADPH as a cofactor and molecular oxygen. The optimal pH for the reaction was 7.4-8.0. The 8R,9-epoxy-CBD forming activity was highest in guinea pigs, followed by mice and rats in the presence of 3,3,3-trichloropropene-1,2-oxide (TCPO), an inhibitor of epoxide hydrolase. The activity was significantly suppressed by SKF 525-A, alpha-naphthoflavone, metyrapone and carbon monoxide. 8R,9-Epoxy-CBD was further converted to 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol (6 beta-CH2OH-delta 9-TCH) and 8,9-dihydro-8,9-dihydroxy-CBD by hepatic microsomes of guinea pigs, rats and mice. Microsomal formation of 6 beta-CH2OH-delta 9-THC was markedly increased in the presence of TCPO with a concomitant decrease in the formation of 8,9-dihydro-8,9-dihydroxy-CBD in all animal species examined. Furthermore, 6 beta-CH2OH-delta 9-THC was also identified as a new metabolite of CBD produced by hepatic microsomes of guinea pigs. 6 beta-CH2OH-delta 9-THC exhibited THC-like pharmacological effects, catalepsy, analgesia, pentobarbital-induced sleep prolongation and hypothermia in mice, although these effects were less marked than those of delta 9-THC. This study presents the first example of the biotransformation of CBD to a delta 9-THC derivative which exhibits some pharmacological effects.
 ...
PMID:In vitro metabolic formation of a new metabolite, 6 beta-hydroxymethyl-delta 9-tetrahydrocannabinol from cannabidiol through an epoxide intermediate and its pharmacological effects on mice. 828 29

1. Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydrocannabinol (delta-9-THC) at a dose of 20 mg kg-1 day-1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212-2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide. 2. Vasa deferentia removed from mice pretreated intraperitoneally with delta-9-THC twice at a dose of 20 mg kg-1 day-1 were less sensitive to its inhibitory effect on electrically-evoked contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the lower part of the concentration-response curve of delta-9-THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212-2 (9.6 fold) and anandamide (12.3 fold). 3. The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta-9-THC can produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance. 4. Further experiments are required to establish why tolerance to anandamide-induced hypothermia was not produced by a pretreatment with delta-9-THC that did induce tolerance to the hypothermic effects of delta-9-THC, CP 55,940 and WIN 55,212-2 and to the inhibitory effects of delta-9-THC,CP 55,940, WIN 55,212-2 and anandamide on the twitch response of the vas deferens.
 ...
PMID:Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212-2 and anandamide. 830 90


<< Previous 1 2 3 4 5 6 Next >>