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)

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

The following NEKY have been studied: 1-kynurenine (KYN), 3-hydroxyKYN (3HKYN), kynurenic (KYNA), anthranilic (ANT), 3-hydroxyANT (3HANT), quinolinic (QUIN), picolinic (PICA), xanthurenic (XAN), nicotinic (NIC) acids, 3-indole-pyruvate (IPA), nicotinamide (NAM). NEKY antagonize the central effects of precursors of serotonin (tryptophan and 5-HTP), and tryptamine as well. Seizures induced by central administration of KYN and QUIN are prevented by centrally injected dopamine and diminished by noradrenaline and adrenaline. KYN, 3HANT, PIC and NIC potentiate oxotremorine hypothermia mediated by acetylcholine. Central administration of GABA, glycine or taurine, as well as proline and melatonin, prevented seizures induced by QUIN and KYN. Behavioral inhibitory effects of these amino acids are diminished by pretreament with KYN, 3HKYN and QUIN. Elevation of concentrations of corticosteroids is resulted in rise of level of NEKY due to hormonal induction of liver tryptophan pyrrolase and brain 2,3 dioxigenase. NEKY, in their turn, activate both enzymes. Thus, a "vicious circle" is formed and it supports an elevated level of NEKY for a long time, hours and days. Long-lasting increased concentrations of NEKY in tissues can lead to significant after-effects and numerous pathogenic consequences. One can not exclude that a rise of the level of some NEKY, e.g. KYNA, IPA, PIC and XAN, may play an "adaptogenic" role in stress antagonizing some pathologic effects of KYN and QUIN, e.g. anxiogenic, neurotoxic and proconvulsive. It has been demonstrated that the excitatory NEKY, KYN, 3HKYN, QUIN, possess an anxiogenic activity in the standard animal models of anxiety. NEKY with opposite neuroactivities, namely KYNA, IPA, PICA and XAN, have a pharmacological profile of anxiolytics and antagonize both anxiogenic NEKY and standard anxiogens, like caffeine, pentylenetetrazole and yohimbine. Major emphasis is made on KYN as a putative endogenous anxiogen. Studies on the interaction of NEKY with other endogenous metabolites involved in anxiety (beta-phenylethylamine, cholecystokynine, melatonin) are in progress.
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PMID:Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. 1520 24

GABA(B) receptors are the G-protein-coupled receptors for the neurotransmitter GABA. GABA(B) receptors are broadly expressed in the nervous system. Their complete absence in mice causes premature lethality or--when mice are viable--epilepsy, impaired memory, hyperalgesia, hypothermia, and hyperactivity. A spatially and temporally restricted loss of GABA(B) function would allow addressing how the absence of GABA(B) receptors leads to these diverse phenotypes. To permit a conditional gene inactivation, we flanked critical exons of the GABA(B(1)) gene with lox511 sites. GABA(B(1)) (lox511/lox511) mice exhibit normal levels of GABA(B(1)) protein, are fertile, and do not display any behavioral phenotype. We crossed GABA(B(1)) (lox511/lox511) with Cre-deleter mice to produce mice with an unrestricted GABA(B) receptor elimination. These GABA(B(1)) (-/-) mice no longer synthesize GABA(B(1)) protein and exhibit the expected behavioral abnormalities. The conditional GABA(B(1)) allele described here is therefore suitable for generating mice with a site- and time-specific loss of GABA(B) function.
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PMID:Floxed allele for conditional inactivation of the GABAB(1) gene. 1549 18

Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.
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PMID:Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat. 1584 Mar 98

The effects of the novel GABA analogue (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxations (TLOSRs) were studied in the dog. In addition, the GABA(A)/GABA(B) selectivity was determined in vitro and in vivo, and the pharmacokinetics and the metabolism of the compound were studied in the dog and rat. TLOSRs were reduced by 55 +/- 8% after intragastric administration of AFPSiA at 14 mumol kg(-1) and did not decrease further at higher doses. When evaluated 2 and 4 h after administration, the effect declined to 37 +/- 6 and 16 +/- 9%, respectively. Spontaneous swallowing was only significantly inhibited at 100 micromol kg(-1). The oral availability of AFPSiA was 52 +/- 17 and 71 +/- 4% in the dog and rat, respectively. A fraction of AFPSiA was oxidised to the corresponding sulphonate, (2R)-(3-amino-2-fluoropropyl)sulphonic acid (AFPSoA) after oral administration to the rat and dog. In rat brain membranes, AFPSiA was found to have ten times higher affinity for rat brain GABA(B) (K(i) =47 +/- 4.4 nM) compared to GABA(A) (K(i) = 430 +/- 46 nM) binding sites. The compound was a full agonist at human recombinant GABA(B(1a,2)) receptors (EC(50) = 130 +/- 10 nM). In contrast, the metabolite AFPSoA was considerably more selective for binding to rat brain GABA(A) (K(i) = 37 +/- 3.1 nM) vs GABA(B) (K(i) = 6800 +/- 280 nM) receptors. In the mouse, high doses (1-8 mmol kg(-1)) of AFPSiA induced a rapid and mild hypothermia followed by a profound and sustained hypothermia at the higher doses tested (6 and 8 mmol kg(-1)). This effect was unaffected by the selective GABA(B) receptor antagonist CGP62349. AFPSoA (1 and 2 mmol kg(-1)) produced transient and moderate hypothermia while the hypothermic response was considerably larger at 4 mmol kg(-1).It is concluded that AFPSiA inhibits but does not abolish TLOSRs in the dog. High doses of the compound induce hypothermia in the mouse, which probably is attributable to activation of the GABA(A) receptor. The latter effect may be caused both by AFPSiA and its oxidised sulphonic acid metabolite AFPSoA.
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PMID:Effects of (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA) on transient lower oesophageal sphincter relaxation in dogs and mechanism of hypothermic effects in mice. 1598 Aug 75

Mice were forced to swim for 5 min in water at a temperature of 12 degrees C (cold water swim stress) or 32 degrees C (warm water swim stress), and stress-induced analgesia (SIA) was measured using the tail-flick test. The cold water swim stress induced non-opioid SIA as well as hypothermia, whereas the warm water swim stress caused opioid SIA. The in vivo binding of [(3)H]-Ro15-4513 was measured in the stressed mice and compared with that in control mice. The specific binding of [(3)H]-Ro15-4513 in the cerebral cortex, hippocampus, and cerebellum was significantly altered by forced swimming in cold water. Apparent association and dissociation rate of [(3)H]-Ro15-4513 binding were decreased, and the change in the dissociation rate was most pronounced in the hippocampus. In contrast, no significant alterations were observed in in vitro binding. The hypothermia induced by the cold water swim stress seems to be the main reason for alterations in the specific binding of [(3)H]-Ro15-4513. The kinetics of a saturable amount of [(3)H]-Ro15-4513 in the blood and brain were also measured. The relative ratio of the radioactivity concentration in the brain to that in the blood was significantly decreased by forced swimming in cold water, indicating that the cold water swim stress induced changes in the nonspecific binding of [(3)H]-Ro15-4513 in the brain. These results together with previous reports suggested that non-opioid SIA induced by the cold water swim stress might be related to alterations in the rates of general ligand-receptor interactions including GABA(A)/benzodiazepine system. Changes in the nonspecific binding might be also involved in non-opioid SIA.
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PMID:Changes in in vivo [(3)H]-Ro15-4513 binding induced by forced swimming in mice. 1603 51

Hypothermic responses of rodents to the peripheral or intraventricular injection of many individual neurotransmitter receptor agonists have been well documented. Because many hypothermia-inducing agonists are also known to activate G-protein-gated potassium (GIRK) channels, we investigated the hypothermic response to several of these agents on Girk2 null mutant mice. Core body temperatures were measured through radiotelemetry, and animals were maintained in special temperature-regulated chambers to ensure the accuracy of the measurements. The resulting data indicate that the activation of GIRK2-containing potassium channels plays a significant role in hypothermia induced by the activation of serotonergic (5-HT(1A)), GABAergic (GABA(B)), muscarinic (m2), adenosine (A1), and mu, delta, and kappa opioid receptors. These channels also are involved in the alcohol-induced hypothermic response. These results have implications for the understanding of pharmacologically induced hypothermia and thermoregulatory mechanisms.
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PMID:G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. 1612 Jul 81

Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.
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PMID:Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats. 1613 4

Hypoxia-induced cognitive deficits are mainly due to disturbances of the balance between the GABAergic and glutamatergic systems. Acquisition, consolidation and retention impairment in passive avoidance test, hypolocomotion in the open field test, an anxiogenic-like effect in the elevated plus-maze test and hypothermia were observed in rats subjected to hypoxia. Drugs which reduce glutamate release may possess neuroprotective activity. Both, agonists of GABA(B) (baclofen) and group III mGlu receptors (L-AP4) influence the release of glutamate. We studied the behavioral effects of baclofen on hypoxia-induced amnesia and the role of L-AP4 in these processes. Baclofen impaired acquisition, produced an anxiogenic-like effect and lowered body temperature but reduced the hypoxia-induced deficit of acquisition and consolidation of conditioned avoidance, diminished the anxiogenic-like effect, and reduced the motor inhibition produced by hypoxia. L-AP4 improved the acquisition, consolidation and retrieval processes as well as the hypoxia-induced consolidation deficit in the passive avoidance test. Co-administration of baclofen with L-AP4 improved consolidation and enhanced the baclofen activity vs. the respective group without hypoxia. In a group of rats that had undergone hypoxia, joint administration of baclofen and L-AP4 improved retrieval as well as enhanced the effect of baclofen and L-AP4 vs. their respective group without hypoxia. The agonist of group III mGluRs did not change locomotor activity but diminished baclofen-induced motility in rats without hypoxia. L-AP4 given alone or with baclofen produced an anxiogenic-like effect in rats without hypoxia but produced an anxiolytic-like effect in those that had undergone hypoxia. L-AP4 did not influence the activity of baclofen in the elevated plus-maze test. L-AP4 given alone or with baclofen did not change body temperature. It is concluded that baclofen and L-AP4 may cooperate in the consolidation process in rats without hypoxia and in retrieval of passive avoidance in animals that had undergone hypoxia. The observed interaction is probably the result of activation of the presynaptic receptors which influence glutamate and GABA release.
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PMID:Effects of baclofen and L-AP4 in passive avoidance test in rats after hypoxia-induced amnesia. 1653 35

Some synthetic taurine analogues, namely ethanolamine-O-sulphate (EOS), N,N-dimethyltaurine (DMT), N,N,N-trimethyltaurine (TMT) and 2-aminoethylphosphonic acid (AEP) were shown to interact with rabbit brain GABA(A)- or GABA(B)-receptors, while (+/-)piperidine-3-sulfonic acid (PSA) inhibited the activity of rabbit brain 4-aminobutyrate transaminase. This suggests that they behave like direct/indirect GABA agonists or GABA antagonists and affect thermoregulation and gross motor behaviour (GMB) which are under GABA control. In the present study micromole (1.2-48) amounts of these compounds were i.c.v. injected in conscious, restrained rabbits while monitoring rectal temperature (RT), ear skin temperature (EST) and GMB. AEP, EOS, DMT and TMT induced a dose-related hyperthermia, ear vasoconstriction and excitation of GMB, while PSA induced a dose-related hypothermia, ear vasodilation and inhibition of GMB. EOS antagonized in a dose-related fashion hypothermia induced by 60 nmol THIP, a GABA(A) agonist, while AEP, DMT and TMT counteracted that induced by 8 nmol R(-)Baclofen, a GABA(B) agonist. In conclusion, EOS and AEP, DMT, TMT seem to act as GABA(A) and GABA(B) antagonists, respectively, while PSA behaves like an indirect GABA agonist, all affecting the central mechanisms which drive rabbit thermoregulation.
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PMID:GABA-mediated effects of some taurine derivatives injected i.c.v. on rabbit rectal temperature and gross motor behavior. 1658 17


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