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)

Three different syndromes produced by congeners of morphine have been identified in the nondependent chronic spinal dog. These syndromes have been attributed to interaction of agonists with three distinguishable receptors (mu, kappa and sigma). Morphine is the prototype agonist for the mu receptor, ketocyclazocine for the kappa receptor and SKF-10,047 for the sigma receptor. The morphine syndrome (mu) in the dog is characterized by miosis, bradycardia, hypothermia, a general depression of the nociceptive responses and indifference to environmental stimuli. Ketocyclazocine (kappa) constricts pupils, depresses the flexor reflex and produces sedation but does not markedly alter pulse rate or the skin twitch reflex. SKF-10,047 (sigma), in contrast to morphine and ketocyclazocine, causes mydriasis, tachypnea, tachycardia and mania. The effects of these three drugs can be antagonized by the pure antagonist naltrexone, indicating that they are agonists. Further, chronic administration of morphine, ketocyclazocine and SKF-10,047 induces tolerance to their agonistic effects. Morphine suppresses abstinence in morphine-dependent dogs while ketocyclazocine does not. Ketocyclazocine at best precipitated only a liminal abstinence syndrome in the morphine-dependent dog, indicating that it had little affinity for the morphine receptor. Ketocyclazocine thus appears to be a selective agonist at the kappa receptor. Further, it has been shown that buprenorphine is a partial agonist of the mu type which both suppressed and precipitated abstinence in the morphine-dependent dog while morphine and propoxyphene are stronger agonists. Apomorphine and SKF-10,047 produce similar pharmacologic effects suggesting that sigma activity may involve a dopaminergic mechanism.
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PMID:The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. 94 47

Injection of ibotenic acid (IA), a glutamate agonist, into the ventral medullary raphe (VMR; especially the nucleus raphe magnus) of the rat produced respiratory failure and death following a predictable course of events. The response to the IA injection was characterized initially by increased respiratory frequency and was followed by pulmonary arterial hypertension, systemic arterial hypoxemia, acidosis, and hypothermia. Within 90 min apnea occurred as a terminal event in all animals. Gravimetric, bronchoalveolar lavage protein, and histological analyses revealed no evidence of pulmonary edema. Intracerebral (VMR) pretreatment with PPP, a sigma receptor agonist, or scopolamine, a muscarinic cholinergic antagonist, prevented pulmonary failure and death even though postmortem histological analysis showed VMR cell loss and gliosis consequent to the cytotoxic IA injection. Based on the results of the study, it is suggested that the VMR has a role in regulation of pulmonary blood flow. Preliminary pharmacological studies suggested that a disruption of glutamatergic and cholinergic mechanisms mediates the lethal pulmonary phenomenon.
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PMID:Respiratory failure without pulmonary edema following injection of a glutamate agonist into the ventral medullary raphe of the rat. 137 23

The current study investigated the effects of the acute s.c. and i.c.v. administration of 1,3-di-o-tolylguanidine (DTG) on body temperature in rats. The effects of putative sigma receptor antagonists BMY 14802 and rimcazole on DTG-induced changes in body temperature also were evaluated. The acute s.c. administration of DTG (10.0 and 20.0 mg/kg) produced hypothermia but no observable behavioral effects. Similarly, the acute i.c.v. administration of DTG (12.0-100.0 micrograms/rat) produced hypothermia, but ataxia occurred after this route of administration. The s.c. administration of BMY 14802 alone (25.0 mg/kg) decreased body temperature and enhanced the DTG-induced hypothermia, whereas the administration of rimcazole (25.0 mg/kg) neither altered body temperature nor affected the hypothermia produced by DTG. Neither BMY 14802 nor rimcazole produced any behavioral effects when administered alone. The inability of the putative sigma receptor antagonists BMY 14802 and rimcazole to antagonize DTG-induced hypothermia suggests that either these compounds at the dose used have little sigma receptor antagonist activity, or that the DTG-induced hypothermia is not due to specific interactions with sigma receptors.
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PMID:Effects of subcutaneous and intracerebroventricular administration of the sigma receptor ligand 1,3-Di-o-tolylguanidine on body temperature in the rat: interactions with BMY 14802 and rimcazole. 167 44

We found that 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503), a potent and selective sigma 1 receptor agonist, significantly enhanced the cerebral acetylcholine (ACh) release in the rat using in vivo brain microdialysis technique. Interestingly, the significant enhancement of ACh release elicited by SA4503 was observed in the rat frontal cortex and hippocampus, although the striatal ACh release was unchanged. This cortical ACh release was fully reversed by haloperidol, a prototype sigma receptor antagonist, or by N, N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride, a putative sigma 1 receptor antagonist. In addition, this enhanced ACh release by SA4503 was inhibited by tetrodotoxin, a Na+ channel blocker. However, tetrahydroaminoacridine, an acetylcholinesterase inhibitor, significantly increased the extracellular ACh level in the rat frontal cortex and weakly increased the hippocampal level. This compound also showed the significant increase of extracellular ACh level in the rat striatum. Moreover, tetrahydroaminoacridine markedly produced cholinomimetic side-effects, such as hypothermia, tremor, miosis and lacrimation. However, SA4503 did not produce these cholinomimetic side-effects. These findings suggest that SA4503 enhances the ACh release that is mediated through a novel mechanism, namely sigma 1 receptor subtype. Furthermore, SA4503 has regional differences in the enhancement of cerebral ACh release, and did not produce cholinomimetic side-effects. These profiles are different from tetrahydroaminoacridine.
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PMID:Enhancement of acetylcholine release by SA4503, a novel sigma 1 receptor agonist, in the rat brain. 885 82

The behavioral and biochemical effects of EMD 57445, a selective sigma receptor ligand with potential antipsychotic activity, on the 5-hydroxytryptamine (5-HT) system were studied in rats and mice. The drug influence was investigated in three behavioral tests: 8-OH-DPAT (5-HT1A agonist)-induced behavioral syndrome in rats, m-chlorophenylpiperazine (m-CPP, 5-HT1B agonist)-induced hypothermia in mice and L-5-hydroxytryptophan (L-5-HTP)-induced head twitches (5-HT2A stimulation) in rats. EMD 57445 did not show any activity in all three behavioral models. In biochemical studies, no changes in the 5-HT and 5-HIAA levels in rat brain cortex, nucleus accumbens, striatum, hypothalamus and hippocampus were found. The results indicate that EMD 57445 does not interact with 5-HT (5-HT1A, 5-HT1B, 5-HT2A) receptor subpopulations and does not affect 5-HT metabolism.
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PMID:EMD 57445, the selective sigma receptor ligand, has no effect on the 5-hydroxytryptamine system. 956 54

Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds. In the mouse micronucleus assay, the compounds were administered orally at three levels up to the maximum tolerated dose (MTD). Negative results were obtained for all three drug candidates in the Ames test and in the mouse-lymphoma assay, both in the absence or presence of metabolic activation. In the mouse micronucleus test, there was no effect on the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow after oral administration of any of the three test compounds, at any dose level or sampling time (24 and 48h). Administration of all three compounds at the MTD induced a clear decrease in mouse body-temperature of 3.1-4.8 degrees C below normal; the temperature returned to normal within 8h of dose administration. The produced mild hypothermia and absence of micronucleus induction was in contrast to the induction of MNPCE secondary to marked hypothermia reported for a structurally similar PTHPB-derived sigma-receptor ligand, the antipsychotic compound E-5842. The results obtained in the current series of studies suggest that exposure to the three tested PTHPB-derived drug candidates would not pose a genotoxic risk under clinical conditions.
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PMID:Evaluation of the genotoxic potential of three phenyltetrahydropyridinyl butylazole-derived sigma-receptor ligand drug candidates. 1850 68

The antipsychotic sigma-1 (sigma(1)) receptor ligand E-5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound-induced hypothermia. Interaction with sigma(1) receptor has been considered a plausible contributing factor for E-5842-induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E-5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in sigma(1) receptor knockout (sigma(1)R-KO) and wild type (WT) mice. After administration, animal's rectal temperature was recorded and peripheral blood and bone marrow samples were obtained (48 hr) and assessed for induction of micronucleated reticulocytes (MNRET) and MNPCE, respectively. E-5842 administration produced marked hypothermia both in sigma(1)R-KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5 degrees C in sigma(1)R-KO and WT mice, respectively. Temperature returned to normal approximately 32 hr after administration. Bone marrow examination revealed a statistical significant increase (P < 0.05) in MNPCE frequency both in sigma(1)R-KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in sigma(1)R-KO mice. No similar effect was observed among WT animals. The results obtained after E-5842 administration to sigma(1)R-KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with sigma(1) receptor, ruling out concern for a possible class effect of similar high affinity sigma(1) receptor ligands in the mouse MN test.
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PMID:Induction of hypothermic conditions associated with increased micronuclei formation in sigma-1 receptor knockout mice after administration of the antipsychotic compound E-5842. 1880 Mar 45