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 this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.
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PMID:Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol. 859 98

SR141716A has been described as a cannabinoid receptor antagonist. This study was conducted to determine whether SR141716A was capable of antagonizing the pharmacological effects of the prototypical cannabinoid agonist delta 9-THC. The AD50 (+/- 95% confidence limits) obtained after a 10 min i.v. pretreatment with SR141716A in measures of hypoactivity, hypothermia, and antinociception were: 0.12 (0.02-0.66), 0.087 (0.037-0.201), and 0.16 (0.03-1.01) mg/kg, respectively. The effect of SR141716A lasted up to 1 hr (antinociception, 10 mg/kg), 4 hr (locomotion, 1 and 3 mg/kg), or 24 hr (hypothermia, 3 mg/kg). Further evaluation revealed an AD50 value of 2.7 mg/kg (1.7-4.4) in the PPQ-stretch procedure. Additionally, the ED50 (+/- S.E.) of morphine in the tail-flick antinociception procedure was increased by SR141716A (30 mg/kg, i.v.) from 3.2 (+/- 0.3) to 5.3 (+/- 0.6) mg/kg. Finally, SR141716A produced direct effects on locomotor activity at doses greater than 3 mg/kg. Locomotion was stimulated to more than 200% of control (20 mg/kg), with an ED50 value of 4.7 (+/- 1.5) mg/kg. The ED50 value represents stimulation to levels approximately 150% of control. It is not clear whether this pharmacological activity represents an uncharacterized action of SR141716A, or an index of tonic activity of an endogenous cannabinergic system. SR141716A will be useful in establishing the biochemical events responsible for the in vivo effects of exogenous cannabinoids, as well as in establishing the existence of a putative endogenous cannabinergic system.
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PMID:In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. 862 35

The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanation for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.
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PMID:Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice. 872 Apr 87

We have previously shown that the endogenous putative cannabinoid ligand arachidonylethanolamide (anandamide, 20:4, n - 6) induces in vivo and in vitro effects typical of a cannabinoid agonist. We now report that two other endogenous anandamides, docosatetraenylethanolamide (anandamide, 22:4, n - 6) and homo-gamma-linolenylethanolamide (anandamide, 20:3, n - 6), have similar activities. The new anandamides bind to SV40-transformed African green monkey kidney cells transfected with the rat brain cannabinoid receptor cDNA and display K1 values of 253.4 +/- 41.1 and 244.8 +/- 38.7, respectively. The value found for arachidonylethanolamide was 155.1 +/- 13.8 nM. In addition, the new anandamides inhibit prostaglandin E1-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells transfected with the cannabinoid receptor, as well as in N18TG2 mouse neuroblastoma cells that express the cannabinoid receptor naturally. The IC50 values for the inhibition of adenylate cyclase in transfected Chinese hamster ovary-K1 cells were 116.8 +/- 8.7 and 109.3 +/- 8.6 nM for docosatetraenylethanolamide and homo-gamma-linolenylethanolamide, respectively. These values were similar to that obtained with arachidonylethanolamide (100.5 +/- 7.7 nM), but were significantly higher than the IC50 value observed with the plant cannabinoid delta9-tetrahydrocannabinol (9.2 +/- 8.6 nM). The inhibitory effects of the anandamides on adenylate cyclase activity were blocked by pertussis toxin, indicating the involvement of pertussis toxin-sensitive GTP-binding protein(s). In a tetrad of behavioral assays for cannabinoid-like effects, the two new anandamides exerted similar behavioral effects to those observed with delta9-tetrahydrocannabinol and arachidonylethanolamide: inhibition of motor activity in an open field, hypothermia, catalepsy on a ring, and analgesia on a hot plate.
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PMID:Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides. 874 28

Recent breakthroughs in cannabinoid research, including the identification of two cannabinoid receptors (CB receptors) and a family of endogenous ligands, the anandamides, may shed new light on the sequelae of pre- and perinatal exposure to cannabinoid receptor ligands and enable the experimental manipulation of the endogenous ligand in the developing organism. In the present study we examined the behavioural response to anandamide (ANA) in developing mice from day 13 into adulthood. We observed that depression of ambulation in an open field and the analgetic response to ANA are not fully developed until adulthood. In a separate set of experiments, we administered five daily injections of ANA (SC, 20 mg/kg) during the last trimester of pregnancy. No effects on birth weight, litter size, sex ratio and eye opening were detected after maternal ANA treatment. Further, no effects on open field performance of the offspring were observed until 4 weeks of age. However, from 40 days of age, a number of differences between the prenatal ANA and control offspring were detected. Thus, the offspring from ANA-treated dams showed impaired responsiveness to a challenge with ANA or delta 0-THC expressed as a lack of immobility in the ring test for catalepsy, hypothermia and analgesia. On the other hand, without challenge, they exhibited a spontaneous decrease in open field activity, catalepsy, hypothermia and a hypoalgetic tendency. These data suggest that exposure to excessive amounts of ANA during gestation alters the functioning of the ANA-CB receptor system. Further experiments investigating responsivity of the immune system suggest an increased inflammatory response to arachidonic acid, and enhanced hypothermic response to lipopolysaccharide in prenatally treated offspring. The results are discussed in relation to other manipulations of the maternal milieu, especially prenatal stress. It is concluded that alterations induced by prenatal exposure to ANA, cannabinoids and other psychotropic drugs or prenatal stress, share common features, but the data also suggest specific effects on the ANA-CB receptor system.
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PMID:Developmental aspects of anandamide: ontogeny of response and prenatal exposure. 877 60

1. Arachidonylethanolamide (AEA; anandamide) has been isolated from mammalian brain and found to bind to, and is thought to be, an endogenous ligand for the cannabinoid receptor. In order to understand better its behavioural and physiological properties, we have examined its acute effects in unanaesthetized freely behaving rats. 2. Intravenous AEA caused dose-related decreases in locomotor behaviour, a pronounced hyperreflexia, and a moderate antinociceptive state. At doses between 3 and 30 mg kg-1, a dose-dependent hypothermia and profound, time-dependent cardiovascular changes were also observed. 3. An immediate bradycardia exceeding 50% was seen within 10-15 s of administration and lasted up to 11 min following the highest dose of the drug. In contrast, the change in mean arterial pressure was biphasic: an immediate 20% decrease in mean arterial pressure followed by a significant increase in blood pressure that lasted about 13 min after the highest dose. 4. These data demonstrate that AEA in the unanaesthetized rat exerts behavioural and physiological effects generally similar to those seen following natural cannabinoids and synthetic cannabimimetic agents and suggests a role for AEA in regulation of various physiological processes.
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PMID:Physiological and behavioural effects of the endogenous cannabinoid, arachidonylethanolamide (anandamide), in the rat. 887 63

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.
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PMID:Cannabinoid modulation of rat pup ultrasonic vocalizations. 890 27

delta 8-Tetrahydrocannabinol (delta 8-THC) is a naturally occurring cannabinoid with a characteristic pharmacological profile of in vivo effects. Previous studies have shown that modification of the structure of delta 8-THC by inclusion of a nitrogen-containing functional group alters this profile and may alkylate the cannabinoid receptor, similar to the manner in which beta-funaltrexamine (beta-FNA) alkylates the micro-opioid receptor. Two novel analogs of delta 8-THC were synthesized: a nitrogen mustard analog with a dimethylheptyl side chain (NM-delta 8-THC) and a cyano analog with a dimethylpentyl side chain (CY-delta 8-THC). Both analogs showed high affinity for brain cannabinoid receptors and when administered acutely, produced characteristic delta 9-THC-like effects in mice, including locomotor suppression, hypothermia, antinociception and catalepsy. CY-delta 8-THC shared discriminative stimulus effects with CP 55,940; for NM-delta 8-THC, these effects also occurred, but were delayed. Although both compounds attenuated the effects of delta 9-THC in the mouse behavioral tests, evaluation of potential antagonist effects of these compounds was complicated by the fact that two injections of delta 9-THC produced similar results, suggesting that acute tolerance or desensitization might account for the observations. NM-delta 8-THC, but not CY-delta 8-THC, attenuated the discriminative stimulus effects of CP 55,940 in rats several days following injection. Hence, addition of a nitrogen-containing functional group to a traditional cannabinoid structure does not eliminate agonist effects and may produce delayed attenuation of cannabinoid-induced pharmacological effects.
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PMID:Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol. 907 59

Anandamide is the newly discovered endogenous cannabinoid ligand that binds to brain cannabinoid receptors and shares most, but not all, of the pharmacological properties of delta 9-THC. Therefore, this study was undertaken to determine whether its interaction with the CB1 receptor in brain was identical to that of delta 9-THC. Anandamide depressed spontaneous activity and produced hypothermia, antinociception and immobility in mice after i.v. administration. However, none of these effects was blocked by pretreatment with the selective CB1 antagonist, SR 141716A. However, the metabolically stable analog 2-methyl-2'-fluoroethylanandamide produced reductions in motor activity and antinociception in mice, effects that were blocked by the antagonist. To determine whether anandamide's receptor binding mimicked that of other cannabinoids, an autoradiographic comparison of anandamide, SR 141716A and CP 55,940 competition for [3H]CP55,940 binding was conducted throughout rat brain. The receptor affinities for all three compounds did not change according to brain area. As expected, Bmax values differed dramatically among differ brain areas. However, the Bmax values for each brain area were similar regardless of the compound used for displacement. These data suggest that anandamide, SR 141716A and CP 55,940 compete for the same cannabinoid receptor throughout brain despite SR 141716A's failure to block anandamide's pharmacological effects. Although there is no question that anandamide binds to the cannabinoid receptor, failure of SR 141716A to block its pharmacological effects in mice poses a dilemma. The results presented herein raise the possibility that anandamide may not be producing all of its effects by a direct interaction with the CB1 receptor.
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PMID:Assessment of anandamide interaction with the cannabinoid brain receptor: SR 141716A antagonism studies in mice and autoradiographic analysis of receptor binding in rat brain. 949 85

The role of nitric oxide (NO) in the development of cannabinoid tolerance was examined by using N(omega)-nitro-L-arginine methyl ester (L-NAME) as an inhibitor of NO synthase. R(+)-[2,3-Dihydro-5-methyl-3 [(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-napht halenyl)methanone mesylate (WIN 55,212-2), a cannabinoid receptor agonist, or L-NAME plus WIN 55,212-2 was acutely or chronically injected i.p. to mice and analgesia, body temperature and immobility were measured. A single injection of WIN 55,212-2 induced time- and dose-dependent analgesia, hypothermia and catalepsy. L-NAME (50 mg/kg), which per se was ineffective, administered 20 min before WIN 55,212-2 did not modify the analgesic, hypothermic and cataleptic responses to the cannabinoid. When WIN 55,212-2 was administered once a day, the animals became completely tolerant to the analgesic, hypothermic and cataleptic effects within five, seven and nine days respectively. L-NAME injected once daily 20 min before WIN 55,212-2 inhibited the development of tolerance to the hypothermic and cataleptic actions but not to the analgesic action of WIN 55,212-2. Since L-NAME given chronically by itself did not modify the analgesia, hypothermia and catalepsy induced by acute administration of WIN 55,212-2, our findings suggest L-NAME acts with some selectivity on the mechanisms involved in cannabinoid tolerance.
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PMID:A role of nitric oxide in WIN 55,212-2 tolerance in mice. 957 Apr 63


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