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)

When an opioid acting selectively at the kappa opioid receptor is administered subcutaneously to rats along with a neuroleptic at an ambient temperature of 20 degrees C a marked hypothermia ensues. The combination of U-50,488H (a kappa agonist) and chlorpromazine (a neuroleptic) caused a drop in body temperature amounting to as much as 11 degrees C, with all animals recovering after 24-48 h. Naloxone partially reversed the hypothermia. Similar, but less dramatic, decreases in body temperature occurred with other neuroleptics and weaker kappa agonists. The induction of poikilothermia was indicated when the body temperature approached the environment temperature and lethality resulted in 100% of the animals at ambient temperatures of 5 degrees C or 35 degrees C. The potential utility of this or similar combinations of drugs lies in such diverse applications as cardiac surgery, treatment of the near-drowning syndrome and space travel.
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PMID:Hypothermia and poikilothermia induced by a kappa-agonist opioid and a neuroleptic. 288 6

Experiments were conducted in order to examine the mechanism of changes in body temperature induced by phencyclidine (PCP) in mice. It is well known that morphine changes body temperature in a biphasic manner. PCP also produced hyperthermia at low doses (5 and 10 mg/kg) and hypothermia at high dose (40 mg/kg). The changes in body temperature induced by PCP were blocked by naloxone, a mu antagonist. Pretreatment with morphine (2.5 mg/kg), a mu agonist, or ethylketocyclazocine (EKC: 2.5 mg/kg), a kappa agonist, potentiated hypothermia induced by high dose of PCP. Effects of morphine and EKC on PCP-induced hypothermia were antagonized by naloxone. N-Allylnormetazocine (SKF 10 047: 20 mg/kg), a kappa and mu antagonist, antagonized PCP- and EKC + PCP-induced hypothermia but not morphine + PCP-induced hypothermia. Furthermore, Mr 2266, a kappa antagonist, antagonized PCP (10mg/kg)-induced hyperthermia and EKC + PCP-induced hypothermia. It is suggested that PCP may affect thermoregulation through mu and/or kappa opioid receptor mechanisms.
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PMID:Involvement of opioid receptors in hypo- and hyperthermic effects induced by phencyclidine in mice. 302 Feb 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.
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PMID:Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice. 813 52

Previous studies showed that parenterally administered morphine at 4-16 mg/kg markedly increased body temperature in the rat, but higher doses of morphine (> or = 30 mg/kg, subcutaneously, sc) caused a profound decrease in body temperature. Based on the use of selective opioid agonists and antagonists, we postulated that these effects were due to morphine's actions on mu and kappa receptors, respectively. In the present study, we sought to determine whether an antisense (AS) oligodeoxynucleotide (oligo) against cloned mu or kappa opioid receptors could affect morphine-induced body temperature changes. AS oligos were directed against nucleotides 1-18 of the coding region of the mu receptor and 4-21 of the coding region of the kappa receptor. Male SD rats were surgically implanted with intracerebroventricular (icv) cannulae. Rats received icv injections of vehicle or oligo in the animal colony room on days 1, 3 and 5. Either AS oligo or missense (MS) oligo was infused in a volume of 5 microliters over 30 s to freely moving animals. On day 6, the rats were tested. The results showed that icv treatment with an AS oligo against mu opioid receptors, but not an MS oligo against the mu opioid receptor or an AS oligo against the kappa opioid receptor, significantly attenuated the hyperthermia normally produced by a relatively low dose of morphine administered sc. In addition, treatment with an AS oligo against kappa receptors, but not an MS oligo against kappa opioid receptor or an AS oligo against the mu opioid receptor, significantly blocked the hypothermia induced by a high dose of morphine. This study confirms our earlier postulate that morphine at 4 mg/kg, sc, induces an increase in body temperature primarily via mu opioid receptors in the brain and a high dose (30 mg/kg) of morphine administered sc produces a decrease primarily through kappa opioid receptors in the brain.
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PMID:Antisense confirmation of mu- and kappa-opioid receptor mediation of morphine's effects on body temperature in rats. 902 67

Opioids administered by i.c.v. injection produce body temperature (Tb) changes and analgesic responses in rats. The present study was undertaken to investigate the effects on Tb and analgesia of highly selective mu and kappa opioid receptor agonists and antagonists delivered directly into the preoptic anterior hypothalamus (POAH) and periaqueductal gray (PAG) by the intracerebral microdialysis method. Microdialyzed into the POAH, the mu receptor agonist Tyr-Pro-N-MePhe-D-Pro-NH2 induced dose-related hyperthermia that could be prevented or antagonized by the mu receptor antagonist cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 or by naloxone, but not by the kappa receptor antagonist nor-binaltorphimine. The kappa receptor agonist dynorphin A(1-17), microdialyzed into the POAH, induced dose-related hypothermia that was prevented or antagonized by nor-binaltorphimine but not cyclic D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2. Neither Tyr-Pro-N-MePhe-D-Pro-NH2 nor dynorphin A(1-17) microdialyzed into the PAG produced significant changes in Tb. However, these agonists microdialyzed into the PAG produced analgesic responses that did not occur after administration into the POAH. These results support the hypothesis that the hyperthermic response to opioids is mediated by the mu receptor and the hypothermic response is mediated by the kappa receptor in rats. The POAH is a primary functional area in Tb, but not in analgesic, responses to opioids, whereas the PAG is a sensitive area for analgesic, but not for Tb, responses to opioids.
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PMID:Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain. 910 37

Previous studies demonstrated that intracerebroventricular (icv) injection of a kappa opioid receptor agonist decreased, and a mu agonist increased, body temperature (Tb) in rats. A dose-response study with the selective kappa antagonist nor-binaltorphimine (nor-BNI) showed that a low dose (1.25 nmol, icv) alone had no effect, although a high dose (25 nmol, icv) increased Tb. It was hypothesized that the hyperthermia induced by nor-BNI was the result of the antagonist blocking the kappa opioid receptor and releasing its inhibition of mu opioid receptor activity. To determine whether the Tb increase caused by nor-BNI was a mu receptor-mediated effect, we administered the selective mu antagonist CTAP (1.25 nmol, icv) 15 min after nor-BNI (25 nmol, icv) and measured rectal Tb in unrestrained rats. CTAP significantly antagonized the Tb increase induced by icv injection of nor-BNI. Injection of 5 or 10 nmol of CTAP alone significantly decreased the Tb, and 1.25 nmol of nor-BNI blocked that effect, indicating that the CTAP-induced hypothermia was kappa-mediated. The findings strongly suggest that mu antagonists, in blocking the basal hyperthermia mediated by mu receptors, can unmask the endogenous kappa receptor-mediated hypothermia, and that there is a tonic balance between mu and kappa opioid receptors that serves as a homeostatic mechanism for maintaining Tb.
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PMID:The dynamic relationship between mu and kappa opioid receptors in body temperature regulation. 1625 20

Salvinorin (Sal) A is a naturally occurring, selective kappa opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxymethyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed approximately 3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5'-O-(3-[(35)S]thio)triphosphate binding and was approximately 5- and approximately 7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three kappa agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05-1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting approximately 3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1-5 mg/kg s.c.). In addition, MOM-Sal B (0.5-5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.
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PMID:2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A. 1808 45

Beta-lactam antibiotics are the only clinically approved drugs which directly increase glutamate uptake. They activate the glutamate transporter subtype 1 (GLT-1), the protein responsible for 90% of glutamate uptake in the mammalian brain. The capacity of GLT-1 to clear extracellular glutamate suggests that glutamate transporter activators be explored for therapeutic approaches to clinical conditions caused by increased glutamatergic transmission. One of the most common drug effects mediated by increased glutamatergic signaling is opioid tolerance. Therefore, we tested the hypothesis that a beta-lactam antibiotic (ceftriaxone), by increasing glutamate uptake, prevents tolerance to hypothermia induced by a kappa opioid receptor agonist (U-50,488H). A single injection of U-50,488H (20mg/kg, s.c.) caused significant hypothermia in rats. Tolerance to the hypothermic effect of U50,488H was induced by injecting U50,488H (20mg/kg) twice daily for 7days. Pretreatment with ceftriaxone (200mg/kg, i.p.) for 7days did not alter the acute hypothermic response to U50,488H (20mg/kg) but did prevent tolerance to U50,488H-induced hypothermia. Central administration of dl-threo-beta-benzyloxyaspartic acid (TBOA) (0.2micromol, i.c.v.), a glutamate transporter inhibitor, abolished the effect of ceftriaxone. These results identify a functional interaction between ceftriaxone and U50,488H in vivo and provide pharmacological evidence that a beta-lactam antibiotic abolishes tolerance to hypothermia induced by a kappa opioid receptor agonist.
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PMID:Beta-lactam antibiotic prevents tolerance to the hypothermic effect of a kappa opioid receptor agonist. 1864 97

We have previously shown the involvement of central endothelin (ET) mechanisms in morphine analgesia and tolerance. Here we investigated the interaction of centrally administered endothelin ET(A) receptor antagonist, BMS182874, with DAMGO (micro opioid receptor agonist), SNC80 (delta opioid receptor agonist), U50,488H (kappa opioid receptor agonist), and oxycodone (micro and kappa opioid receptor agonist) towards antinociception, tolerance to antinociception and body temperature. Antinociception was determined using tail-flick latency method. BMS182874 (50microg, i.c.v.) treatment alone did not produce analgesia or change in body temperature. However, BMS182874 significantly enhanced antinociception response of DAMGO (66.75%), SNC80 (62.40%), U50,488H (55.38%), and oxycodone (61.72%). Chronic treatment with DAMGO, SNC80, U50,488H or oxycodone, induced tolerance to antinociception. Treatment with BMS182874 restored antinociceptive effect in mice that were tolerant to DAMGO, SNC80, U50,488H as well as oxycodone. Antinociceptive response of DAMGO, SNC80, U50,488H, and oxycodone in tolerant mice treated with BMS182874 was significantly higher (44.55%, 37.48%, 43.02%, and 56.08%, respectively) compared to tolerant mice treated with vehicle. Body temperature decreased with DAMGO, SNC80, U50,488H, and oxycodone; tolerance did not develop to hypothermic effect and BMS182874 did not affect DAMGO, SNC80, U50,488H, or oxycodone induced changes in body temperature. Opioid-antagonist naloxone, completely blocked antinociceptive effect of DAMGO, SNC80, U50,488H or oxycodone and potentiation of antinociception by BMS182874. It is concluded that BMS182874 potentiated antinociception and restored antinociceptive effect in mice tolerant to micro, delta and kappa selective, as well as a non-selective opioid receptor agonist. Therefore, endothelin ET(A) receptor antagonists could be useful in the restoration of antinociceptive effect during tolerance to opiates.
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PMID:Effect of endothelin-A receptor antagonist on mu, delta and kappa opioid receptor-mediated antinociception in mice. 2030 44

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. Pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.
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PMID:Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss. 3184 84


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