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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cannabinoids evoke profound hypothermia in rats by activating central CB(1) receptors. Nitric oxide (NO), a prominent second messenger in central and peripheral neurons, also plays a crucial role in thermoregulation, with previous studies suggesting pyretic and antipyretic functions. Dense nitric-oxide synthase (NOS) staining and CB(1) receptor immunoreactivity have been detected in regions of the hypothalamus that regulate body temperature, suggesting that intimate NO-cannabinoid associations may exist in the central nervous system. The present study investigated the effect of N(omega)-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1-5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45 to 90 min post-injection. L-NAME (10-100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a nonhypothermic dose of L-NAME (50 mg/kg) potentiated the hypothermia caused by WIN 55212-2 (0.5-5 mg/kg). The augmentation was strongly synergistic, indicated by a 2.5-fold increase in the relative potency of WIN 55212-2. The inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(-)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), did not produce hypothermia in the absence or presence of L-NAME (50 mg/kg), confirming that cannabinoid receptors mediated the synergy. The present data are the first evidence that drug combinations of NOS blockers and cannabinoid agonists produce synergistic hypothermia. Thus, NO and cannabinoid systems may interact to induce superadditive hypothermia.
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PMID:L-NAME (N omega-nitro-L-arginine methyl ester), a nitric-oxide synthase inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a cannabinoid agonist, interact to evoke synergistic hypothermia. 1461 Feb 31

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

Cannabinoids evoke hypothermia by stimulating central CB(1) receptors. GABA induces hypothermia via GABA(A) or GABA(B) receptor activation. CB(1) receptor activation increases GABA release in the hypothalamus, a central locus for thermoregulation, suggesting that cannabinoid and GABA systems may be functionally linked in body temperature regulation. We investigated whether GABA receptors modulate the hypothermic actions of [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one] (WIN 55212-2), a selective cannabinoid agonist, in male Sprague-Dawley rats. WIN 55212-2 (2.5 mg/kg im) produced a rapid hypothermia that peaked 45-90 min postinjection. The hypothermia was attenuated by bicuculline (2 mg/kg ip), a GABA(A) antagonist. However, SCH 50911 (1-10 mg/kg ip), a GABA(B) blocker, did not antagonize the hypothermia. Neither bicuculline (2 mg/kg) nor SCH 50911 (10 mg/kg) by itself altered body temperature. We also investigated a possible role for CB(1) receptors in GABA-generated hypothermia. Muscimol (2.5 mg/kg ip), a GABA(A) agonist, or baclofen (5 mg/kg ip), a GABA(B) agonist, evoked a significant hypothermia. Blockade of CB(1) receptors with SR141716A (2.5 mg/kg im) did not antagonize muscimol- or baclofen-induced hypothermia, indicating that GABA-evoked hypothermia does not contain a CB(1)-sensitive component. Our results implicate GABA(A) receptors in the hypothermic actions of cannabinoids and provide further evidence of a functional link between cannabinoid and GABA systems.
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PMID:GABAA receptors modulate cannabinoid-evoked hypothermia. 1515 37

AM 411 ((-)-1-adamantyl-Delta8-tetrahydrocannabinol) is a novel full agonist at cannabinoid CB1 receptors. The present studies were conducted to provide behavioral characterization of this compound in rats. It was hypothesized that AM 411 should produce behavioral effects similar to known cannabinoid agonists, and that these effects should be inhibited by co-treatment with a CB1 antagonist. In Experiments 1 and 2, AM 411 dose-dependently produced behaviors consistent with CB1 agonism, including analgesia, hypothermia, catalepsy and reductions in locomotion, which were blocked by a CB1-selective antagonist. In Experiment 3, AM 411 produced a dose-dependent suppression of lever-pressing on a fixed-ratio 5 (FR5) schedule, a task known to be sensitive to administration of CB1 agonists. Detailed analysis of the temporal patterns of operant responding showed that AM 411 altered the distribution of interresponse times. Experiment 4 showed that AM 411 decreased relative interior activity in the open field, which is suggestive of an anxiogenic effect. It is concluded that AM 411 produces CB1 agonist-like behavior with potency between that of WIN 55,212-2 and AM 356. AM 411 could be a useful tool for understanding the behavioral and neural effects of CB1 receptor stimulation.
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PMID:Behavioral effects of the novel cannabinoid full agonist AM 411. 1589 67

The present study investigated a potential role for cannabinoid CB(1) and CB(2) receptors in capsaicin-evoked hypothermia. Capsaicin (1 mg/kg, s.c.) caused rapid and significant hypothermia in rats. Pretreatment with SR 141716A (1, 2.5 and 5 mg/kg, i.p.), a CB(1) antagonist, or SR 144528 (1, 2.5 and 5 mg/kg, i.p.), a CB(2) antagonist, did not affect capsaicin-induced hypothermia. In separate experiments, the hypothermia caused by WIN 55212-2 (5 mg/kg, i.m.), a cannabinoid agonist, was not significantly altered by capsazepine (10 and 30 mg/kg, i.p.) or SB 366791 (2 mg/kg, i.p.), a novel TRPV1 antagonist. These data suggest that capsaicin causes hypothermia by a CB(1)- and CB(2)-independent mechanism, and that WIN 55212-2 causes hypothermia by a TRPV1-independent mechanism.
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PMID:Capsaicin evokes hypothermia independent of cannabinoid CB1 and CB2 receptors. 1630 33

Cannabinoids have neuroprotective potentials, and the expression of endocannabinoids as well as cannabinoid receptors is induced after cerebral ischemia. They also induce hypothermia by lowering the hypothalamic set point. We have estimated the significance of such hypothermia in ischemic neuroprotection following systemic administration of WIN 55,212-2, a synthetic cannabinoid receptor agonist. Results showed that WIN 55,212-2 significantly reduced infarct volumes of rats subjected to focal cerebral ischemia (middle cerebral artery occlusion) and significantly decreased ischemic CA1 damage in rats subjected to global cerebral ischemia (two-vessel occlusion). A significant (approximately 50%) part of this neuroprotection was provided by WIN 55,212-2 induced hypothermia (33.7+/-1.1 degrees C/34.9+/-1.6 degrees C), because prevention of hypothermia by maintaining body core temperatures between 37.0 and 38.0 degrees C dissolved the neuroprotective effect into a hypothermic component and an unidentified component. Finally, the ability of WIN 55,212-2 to reduce levels of the proinflammatory cytokine IFNgamma in the infarcted hemisphere of rats subjected to focal cerebral ischemia required hypothermia. For the cannabinoid WIN 55,212-2, we have isolated and directly demonstrated that hypothermia is only part of, although significant, cannabinoid mediated neuroprotection in both global and focal cerebral ischemia. We conclude that cannabinoids are reliable candidates for drug-induced hypothermia and neuroprotection. These neuroprotective effects of cannabinoids could provide the basis for potential therapeutic uses of cannabinoids and/or endocannabinoids in stroke.
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PMID:Estimation of the hypothermic component in neuroprotection provided by cannabinoids following cerebral ischemia. 1673 99

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

Agmatine blocks morphine withdrawal symptoms and enhances morphine analgesia in rats. Yet, the role of agmatine in the pharmacological effects of other abused drugs has not been investigated. The present study investigates the effect of agmatine administration on the hypothermic response to cannabinoids. Hypothermia is an effective endpoint because cannabinoid agonists produce a rapid, reproducible, and significant decrease in body temperature that is abolished by cannabinoid CB(1) receptor antagonists. WIN 55212-2, a cannabinoid agonist, was administered to rats by itself and with agmatine. WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.) caused a significant hypothermia. Agmatine (10, 25 and 50 mg/kg, i.p.) was ineffective. For combined administration, agmatine (50 mg/kg, i.p.) enhanced the hypothermic effect of WIN 55212-2 (1, 2.5, 5 and 10 mg/kg, i.m.). The enhancement was strongly synergistic, indicated by a 2.7-fold increase in the relative potency of WIN 55212-2. The central administration of agmatine (25 and 50 mug/rat, i.c.v.) significantly increased the hypothermic effect of WIN 55212-2 (2.5 mg/kg, i.m.). This indicates that agmatine acts through a central mechanism to augment cannabinoid-evoked hypothermia. Idazoxan (2 mg/kg, i.p.), an imidazoline antagonist, blocked the enhancement by agmatine, thus suggesting that imidazoline receptor activation is required for agmatine to enhance cannabinoid-evoked hypothermia. The present data reveal that agmatine and a cannabinoid agonist interact to produce a hypothermic synergy in rats. These results show that agmatine acts in the brain and via imidazoline receptors to enhance cannabinoid-evoked hypothermia.
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PMID:Agmatine and a cannabinoid agonist, WIN 55212-2, interact to produce a hypothermic synergy. 1710 46

The present study used the endpoint of hypothermia to investigate cannabinoid and nociceptin/orphanin FQ (N/OFQ) interactions in conscious animals. Prior work has established that cannabinoids produce hypothermia by activating central cannabinoid CB(1) receptors. The administration of N/OFQ into the brain also causes significant hypothermia. Those data suggest a link between cannabinoid CB(1) receptors and N/OFQ peptide (NOP) receptors in the production of hypothermia. Therefore, we determined if NOP receptor activation is required for cannabinoid-evoked hypothermia and if cannabinoid CB(1) receptor activation is necessary for N/OFQ-induced hypothermia. In actual experiments, a cannabinoid agonist, WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.), caused significant hypothermia in male Sprague-Dawley rats (200-225 g). A NOP receptor antagonist, JTC-801 (1 mg/kg, i.p.), did not affect body temperature. For combined administration, JTC-801 (1 mg/kg, i.p.) blocked a significant proportion of the hypothermia caused by each dose of WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.). JTC-801 (1 mg/kg, i.p.) also blocked the hypothermia caused by another cannabinoid agonist, CP-55, 940 (1 mg/kg, i.p.). In separate experiments, the direct administration of N/OFQ (9 microg/rat, i.c.v.) into the brain produced significant hypothermia. The hypothermic effect of N/OFQ was blocked by JTC-801 (1 mg/kg, i.p.) but not by a selective cannabinoid CB(1) antagonist, SR 141716A (5 mg/kg, i.m.). The finding that a NOP receptor antagonist abolishes a significant percentage of cannabinoid-induced hypothermia suggests that NOP receptor activation is required for cannabinoids to produce hypothermia. This interaction, quantitated in the present study, is the first evidence that NOP receptors mediate a cannabinoid-induced effect in conscious animals.
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PMID:NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats. 1751 52

Although the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A) blocks many of the in vivo effects of cannabinoids, the antagonist activity of SR 141716A is limited under some conditions. The general aims of this study were to: 1) examine whether the limited antagonist activity of SR 141716A generalizes to the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251); and 2) examine mechanisms by which cannabinoids produce hypothermia, catalepsy, and hypoactivity in C57BL/6J mice. SR 141716A and AM 251 were administered alone and in combination with the cannabinoid agonists triangle up(9)-tetrahydrocannabinol (triangle up(9)-THC) and R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2). triangle up(9)-THC and WIN 55212-2 produced catalepsy, hypothermia, and hypoactivity with similar potency; WIN 55212-2 produced greater hypothermia than triangle up(9)-THC, otherwise differences in maximal effect were not detected in the other assays. When administered alone, the antagonists did not produce catalepsy or alter body temperature and they decreased locomotor activity. SR 1417167A and AM 251 blocked catalepsy and hypothermia, and partially attenuated hypoactivity, produced by triangle up(9)-THC and WIN 55212-2. While the antagonists were equipotent in blocking agonist-induced hypothermia, SR 141716A was 6-fold more potent than AM 251 in blocking agonist-induced catalepsy. The results demonstrate that SR 141716A and AM 251 have strikingly similar behavioral activity, i.e., they block some and not other in vivo effects of cannabinoid agonists, and further demonstrate differences in the maximum effect of cannabinoid agonists that might be related to differences in agonist efficacy. While the results strongly suggest that cannabinoid CB(1) receptors mediate the hypothermic and cataleptic effects of cannabinoids, differences in the relative potency of antagonists suggest that mechanisms responsible for these effects are not identical.
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PMID:Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. 1755 86


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