Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

Exposure of rats to 1-15 Gy gamma radiation (60Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.     

Involvement of prostaglandins and histamine in radiation-induced temperature responses in rats

Exposure of rats to 1-15 Gy of gamma radiation induced hyperthermia, whereas exposure to 20-150 Gy produced hypothermia. Since radiation exposure induced the release of prostaglandins (PGs) and histamine, the role of PGs and histamine in radiation-induced temperature changes was examined. Radiation-induced hyper- and hypothermia were antagonized by pretreatment with indomethacin, a cyclooxygenase inhibitor. Intracerebroventricular administration of PGE2 and PGD2 induced hyper- and hypothermia, respectively. Administration of SC-19220, a specific PGE2 antagonist, attenuated PGE2- and radiation-induced hyperthermia, but it did not antagonize PGD2- or radiation-induced hypothermia. Consistent with an apparent role of histamine in hypothermia, administration of disodium cromoglycate (a mast cell stabilizer), mepyramine (H1-receptor antagonist), or cimetidine (H2-receptor antagonist) attenuated PGD2- and radiation-induced hypothermia. These results suggest that radiation-induced hyperthermia is mediated via PGE2 and that radiation-induced hypothermia is mediated by another PG, possibly PGD2, via histamine.     

Characterization of alpha-adrenoceptors involved in central thermoregulation in rabbits

Intracerebroventricular (icv) injection of methyldopa induced body temperature changes in the rabbits. The dose of 100 micrograms/kg did not produce any significant change on body temperature whereas 250 micrograms/kg of the drug induced hyperthermia. Higher dose of 500 micrograms/kg produced initial hypothermia which was followed by hyperthermia. On further increase of the dose to 1 mg/kg, consistent hypothermia was evident. Prazosin, a specific post-synaptic alpha 1 adrenoceptor blocker, induced hypothermia whereas piperoxan (presynaptic alpha 2 antagonist) produced hyperthermia. The pretreatment with prazosin, blocked the hyperthermic response of methyldopa. The initial hypothermia by 500 micrograms/kg of methyldopa was also potentiated. The pretreatment with piperoxan completely blocked the hypothermia but had no effect on hyperthermic response of methyldopa. Pretreatment of rabbits with both prazosin and piperoxan completely blocked the hypothermia as well as hyperthermic response of methyldopa. Thus it appeared that both presynaptic alpha 2 and postsynaptic alpha 1 adrenoceptors are involved in central thermoregulation in rabbits.     

2-Deoxy-D-glucose prevents and nicotinamide potentiates 3, 4-methylenedioxymethamphetamine-induced serotonin neurotoxicity

Neurotoxicity induced by different substituted amphetamines has been associated with the exhaustion of intracellular energy stores. Accordingly, we examined the influence of 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glucose uptake and metabolism, and nicotinamide, an agent that improves energy metabolism, on 3, 4-methylenedioxymethamphetamine (MDMA)-induced 5-hydroxytryptamine (5-HT; serotonin) deficits. Administration of MDMA (15 mg/kg i.p.) produced a significant hyperthermia, whereas 2-DG caused a profound hypothermia that lasted throughout the experiment. When MDMA was given to 2-DG-treated rats, an immediate but transient hyperthermia occurred and was followed by a return to hypothermia. 2-DG had no effect on 5-HT concentrations in the frontal cortex, hippocampus, and striatum but prevented the neurotoxicity induced by MDMA. When rats were injected with 2-DG/MDMA and were warmed to prevent hypothermia, the protection afforded by 2-DG was abolished. Nicotinamide had no effect on body temperature of the rats, and the hyperthermia induced by the nicotinamide/MDMA treatment was similar to that of the saline/MDMA-treated rats. However, the long-term 5-HT deficits induced by MDMA were potentiated by nicotinamide in all the brain regions examined. Finally, no change on ATP concentrations in the frontal cortex, hippocampus, and striatum was observed up to 3 h after a single dose of MDMA. These results suggest that an altered energy metabolism is not the main cause of the neurotoxic effects induced by MDMA.     

Progenitor cell injury after irradiation to the developing brain can be modulated by mild hypothermia or hyperthermia

Ionizing radiation induced acute cell death in the dentate gyrus subgranular zone (SGZ) and the subventricular zone (SVZ). Hypomyelination was also observed. The effects of mild hypothermia and hyperthermia for 4 h after irradiation (IR) were studied in postnatal day 9 rats. One hemisphere was irradiated with a single dose of 8 Gy and animals were randomized to normothermia (rectal temperature 36 degrees C for 4 h), hypothermia (32 degrees C for 4 h) or hyperthermia (39 degrees C for 4 h). Cellular injury, e.g. chromatin condensation and nitrotyrosine formation, appeared to proceed faster when the body temperature was higher. Caspase-3 activation was more pronounced in the hyperthermia group and nuclear translocation of p53 was less pronounced in the hypothermia group 6 h after IR. In the SVZ the loss of nestin-positive progenitors was more pronounced (48%) and the size was smaller (45%) in the hyperthermia group 7 days post-IR. Myelination was not different after hypo- or hyperthermia. This is the first report to demonstrate that hypothermia may be beneficial and that hyperthermia may aggravate the adverse side-effects after radiation therapy to the developing brain.     

Thermic response of selective muscarinic agonists and antagonists in rat

Effect of some selective agonists and antagonists of cholinergic M receptor subtypes on rectal temperature was investigated in rats at an ambient temperature of 25 degrees +/- 2 degrees C. Centrally administered acetylcholine (ACh) induced transient hypothermia, whereas the muscarinic M1 receptor agonists, arecholine (ip) and McN-A-343 (McN) (icv), induced sustained and dose-related hypothermia. However, the nonspecific muscarinic receptor agonist, oxotremorine, and physostigmine, induced hypothermia at a lower dose and hyperthermia, accompanied by tremors, at higher doses. The muscarinic M2 receptor agonist, carbachol (icv) also produced a dose-related dual effect, hyperthermia and hypothermia being induced by the lower and higher doses, respectively. The M1 receptor antagonists, scopolamine (ip) and pirenzepine (icv), induced hyperthermia, whereas the M2 receptor antagonists, gallamine (icv) and AF-DX 116 (AFDX) (ip), produced hypothermia. The hypothermic effects of ACh. arecholine, McN, physostigmine, oxotremorine and carbachol were attenuated by scopolamine and pirenzepine. However, although scopolamine also inhibited the hyperthermic and tremorogenic effects of the higher dose of oxotremorine, it had a synergistic effect with the hyperthermia-inducing higher dose of physostigmine. AFDX attenuated the hyperthermic effect of the lower dose of carbachol, indicating that it was M2 receptor-mediated. Hemicholinium, an ACh synthesis inhibitor, had a transient hypothermic effect followed by slight hyperthermia. However, it markedly antagonized the hypothermic effects of gallamine and AFDX, indicating that their effects were dependent upon the availability of neuronal ACh. The results indicate that cholinergic hypothermia is a function of central muscarinic M1 receptors, with the M2 receptors serving as automodulators.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of kainic acid on core temperature and cytokine levels in the brain

Excitotoxic brain injury is associated with hyperthermia, and there are data showing beneficial effects of hypothermia on neurodegeneration and that hyperthermia facilitates the neurodegeneration. Cytokines are inflammatory proteins that seem to be involved in the neuroinflammation associated with epilepsy. Core temperature changes caused by the epileptogenic glutamate analogue kainic acid (KA) were investigated in relation to changes in levels of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and the endogenous interleukin-1 receptor antagonist (IL-1ra). The temperature was measured every 10 min during the first hour, and at 90 and 120 min, and hourly until 8 h after KA-injection (10 mg/kg). The cytokines were measured in the hypothalamus, a site of temperature regulation, and in hippocampus, cerebellum, and frontal cortex. KA induced a brief hypothermia followed by hyperthermia. IL-1beta levels were increased after KA-administration in all brain regions examined and, excepting hippocampus, returned to baseline levels at 24 h. The hippocampal IL-1ra levels were significantly increased at 24 h, whereas no changes in IL-6 levels were observed. The changes in IL-1beta levels and in ratios between the levels of the three cytokines, may account for some of the temperature changes and the behavioural manifestations induced by KA.     

The effect of alpha-interferon, cyclosporine A, and radiation-induced immune suppression on morphine-induced hypothermia and tolerance

An interconnection between the immune and the central nervous systems has been suggested by investigators studying the actions of several types of immune modifying agents and procedures upon opiate related phenomena. These studies have included the effects of altering immune system function by administration of either alpha-interferon, cyclosporine or radiation exposure upon naloxone-precipitated opiate withdrawal and upon opioid antinociceptive effects. The present study extends these earlier investigations by examining the effect of immune modulation upon opiate induced hypothermia. The results demonstrate that interferon and cyclosporine have no effects on baseline temperature or morphine induced hypothermia, while irradiation exposure elicits hyperthermia without affecting morphine-induced hypothermia. Finally, neither cyclosporine nor irradiation affect the development of tolerance to morphine induced hypothermia, while a single injection of the immune system modifier interferon was able to prevent the development of such tolerance. These observations suggest that yet another opiate-related phenomenon may be regulated at least in part by the immune system. These results together with our previous findings are further evidence of a link between the immune system and the CNS mediated through the opioid system. In addition, these studies further support our earlier hypothesis that "Interferon" is one of the endogenous substances which serves to prevent the development of tolerance and dependence to endogenous opioids.     

Spinal heat shock protein (70) expression: effect of spinal ischemia,hyperthermia (42 degrees C)/hypothermia (27 degrees C), NMDA receptor activation and potassium evoked depolarization on the induction

The present study shows that anoxic neuronal depolarization or NMDA receptor activation are potent stimuli for inducing spinal neuronal heat shock protein 70 (Hsp70). Spinal hyperthermia, despite its significant glutamate releasing effect, induced only glial Hsp70 upregulation. No significant increase in spinal Hsp70 expression after potassium depolarization was seen. Transient spinal ischemia (6 min) was induced by the inflation of a 2F Fogarty catheter placed into descending thoracic aorta during concurrent hypotension (40 mmHg). To determine the onset of anoxic depolarization extracellular concentration of K+ was measured in the lumbar dorsal horn using a microelectrode. Spinal hyperthermia (42 degrees C) or hypothermia (27 degrees C) was induced using a heat exchanger placed in the paravertebral subcutaneous space overlying Th5-S4 spinal segments. To measure extracellular concentration of glutamate during hyperthermia a loop dialysis catheter was implanted into lumbar intrathecal space. Receptor specific (NMDA, 3 microg) or non-specific (KCl, 10 microl, 1M) neuronal depolarization was induced using previously implanted intrathecal catheters. After ischemia, temperature manipulations or drug injections animals survived for 4 or 24h. Animals were then terminally anesthetized and perfusion fixed for Hsp70 immunohistochemistry. After spinal ischemia or NMDA administration a neuronal Hsp70 expression was seen at 24h. After spinal hyperthermia only glial expression was seen at 4h. Hyperthermia significantly increased CSF glutamate concentration, however, MK-801 (a non-competitive NMDA receptor antagonist) pretreatment failed to block Hsp70 expression. After hypothermia or potassium depolarization only minimal or no Hsp70 expression was seen in glial cells. Exposure of neuronal tissue to a specific stimuli may lead to intervals of increased resistance to subsequent neurotoxic/ischemic insult. The intervening biochemistry of this protection has been attributed to a family of molecules referred to as HSP. In the present study, we demonstrate that short-lasting anoxic depolarization or activation of NMDA receptor are the most potent stimuli for spinal neuronal Hsp70 induction. This effect corresponds with the observed ischemic tolerance state induced by short-lasting preconditioning spinal ischemia.     

Characterization of dopamine receptors involved in central thermoregulation in rabbits.

Intracerebroventricularly administered dopamine produced dose dependent hyperthermia in rabbits. Haloperidol, a D1 receptor blocker produced consistent hypothermia, whereas D2 receptor blocker metoclopramide produced hyperthermia, pretreatment with haloperidol competitively blocked the hyperthermic response of dopamine. Pretreatment with metoclopramide augmented the onset and peak response of dopamine. It is suggested that D1 receptors are involved in producing hyperthermia and D2 receptors in hypothermia.     

The effects of morphine and various narcotic antagonist type analgesics on body temperature in rats

ED50s were determined for morphine, nalorphine, butorphanol and pentazocine induced hyperthermia in rats. Morphine produced a significant hyperthermia with the doses of 5–160 mg.kg in rats. The peak hyperthermic effect was found 1 hr after 5–20 mg/kg doses of morphine. Nalorphine, butorphanol and pentazocine produced biphasic effects on rectal temperature. Initially they produced a dose-dependent hyperthermia and later hypothermia. In a comparison of the hyperthermic ED50's of morphine, nalorphine, butorphanol and pentazocine it was found that butorphanol is more active than the others (ED50s were 4.7, 4.3, 0.54 and 11.5 mg/kg respectively). The narcotic antagonist naloxone significantly inhibited both morphine and antagonist type analgesic induced hyperthermia. These results suggests that a different mechanism(s) is involved in the hyperthermic actions of antagonist type analgesics and agonist drugs.     

Blood flow in the emissary veins of the human head during hyperthermia

The direction of the blood flowing in the emissary veins (vena emissaria mastoidea and v. e. partietalis) was recorded in human subjects during moderate hyperthermia and hypothermia. During hyperthermia the blood flowed rapidly from skin to brain. During hypothermia either no flow could be detected or the blood flowed slowly from brain to skin. On two fresh cadavers the calvaria was removed with the scalp adhering. Gentle massaging of the scalp produced abundant drops of blood on the inner surface of the bone each time the scalp was massaged, thus showing that cutaneous blood can flow inward through the bone. These results support the hypothesis of selective brain cooling in hyperthermic humans by offering a possible mechanism.     

NPY Y1 receptor antagonist prevents NPY-induced torpor-like hypothermia in cold-acclimated Siberian hamsters

Siberian hamsters (Phodopus sungorus) undergo bouts of daily torpor during which body temperature decreases by as much as 20 degrees C and provides a significant savings in energy expenditure. Natural torpor in this species is normally triggered by winterlike photoperiods and low ambient temperatures. Intracerebroventricular injection of neuropeptide Y (NPY) reliably induces torporlike hypothermia that resembles natural torpor. NPY-induced torporlike hypothermia is also produced by intracerebroventricular injections of an NPY Y1 receptor agonist but not by injections of an NPY Y5 receptor agonist. In this research, groups of cold-acclimated Siberian hamsters were either coinjected with a Y1 receptor antagonist (1229U91) and NPY or were coinjected with a Y5 receptor antagonist (CGP71683) and NPY in counterbalanced designs. Paired vehicle + NPY induced torporlike hypothermia in 92% of the hamsters, whereas coinjection of Y1 antagonist + NPY induced torporlike hypothermia in 4% of the hamsters. In contrast, paired injections of vehicle + NPY and Y5 antagonist + NPY induced torporlike hypothermia in 100% and 91% of the hamsters, respectively. Although Y5 antagonist treatment alone had no effect on body temperature, Y1 antagonist injections produced hyperthermia compared with controls. Both Y1 antagonist and Y5 antagonist injections significantly reduced food ingestion 24 h after treatment. We conclude that activation of NPY 1 receptors is both sufficient and necessary for NPY-induced torporlike hypothermia.     

A review of terms for regulated vs. forced,neurochemical-induced changes in body temperature

Deviations of the body temperature of homeothermic animals may be regulated or forced. A regulated change in core temperature is caused by a natural or synthetic compound that displaces the set-point temperature. A forced shift occurs when an excessive environmental or endogenous heat load, or heat sink, exceeds the body's capacity to thermoregulate but does not affect set-point. A fever is the paradigm of a regulated increase in body temperature, but the term fever has acquired a strict pathological definition over the past two decades. Consequently, other forms of nonpathological, regulated elevations in body temperature have generally been classified as hyperthermia; and decreases in core temperature--either forced or regulated--have generally been classified as hypothermia. Since the terms hyperthermia and hypothermia fail to distinguish a regulated vs. a forced temperature change, a confusion of terms has been created in the literature. It would appear that “resisted or unregulated hyperthermia” and “hypothermia,” respectively, are appropriate terms for describing a forced increase and decrease in core temperature. A nonpathological but regulated elevation in temperature may be defined as unresisted or regulated hyperthermia, whereas a regulated decrease in temperature may be termed unresisted or regulated hypothermia. This simple scheme appears to be the most practical means for distinguishing between forced and regulated changes in core temperature.     

Acute effects of a parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mouse body temperature

The parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given in single systemic doses (i.p.) to mice produced marked hyperthermia, and subsequent long-lasting hypothermia. Administration of MPTP or its oxidized product, 1-methyl-4-phenylpyridinium ion, MPP+, via i.c.v. resulted in only hypothermia. In contrast, i.p. MPP+ administration resulted in only hyperthermia. The MPTP-induced hyperthermia (i.p.) was blocked by quaternary derivatives of anti-cholinergic agents, atropine and scopolamine, but not by the tertiary-derivative of atropine. Duration of this hyperthermic effect was potentiated by neostigmine. Pretreatment with 1-deprenyl did not prevent hypothermia, but nomifensine partially or clorgyline completely prevented the effect without preventing MPTP-induced hyperthermia. The thermic effects by MPTP, unlike its neurotoxicity for the nigrostriatal DA system, may not require metabolism to MPP+. These results indicate that peripheral cholinergic functions are responsible for the MPTP-induced hyperthermia, whereas its hypothermic effect may be centrally mediated via dysregulation of the various neuron systems.     

Structure activity relationship studies with hypothalamic peptide hormones. II. Effects of thyrotropin releasing hormone analogs on morphine-induced responses in mice

The effects of several analogs of thyroliberin (TRH), that have a chloro-acetyl substituent at the amino terminus, on locomotor depressant, locomotor stimulant, hyperthermic and hypothermic response to morphine were determined in the mouse. These compounds included N-(chloroacetyl)-L-phenylalanylpyrrolidine (ClAc-Phe-Pyrr), N-[m-(chloroacetyl)benzoyl]-L-phenylalanylpyrrolidine] (mClAcBz-Phe-Pyrr), N-[m-(chloroacetyl)benzoyl]-L-alanyl-L-phenylalanylpyrrolidine (mClAcBz-Ala-Phe-Pyrr), N-[p-(chloroacetyl)benzoyl]-L-alanyl-L-phenylalanyl-pyrrolidine (pClAcBz-Ala-Phe-Pyrr), N-(chloroacytyl)-L-alanyl-L-phenylalanyl-L-prolineamide(ClAc-Ala-Phe-Pro-NH₂), N-[m-(chloroacetyl)-benzoyl]-L-phenylalanyl-L-prolineamide (mClAcBz-Phe-Pro-NH₂), N-[p-(chloroacetyl)benzoyl]-L-phenylalanyl-L-prolineamide (pClAcBz-Phe-Pro-NH₂). Since TRH is metabolized to cyclo (His-Pro) and the latter is shown to possess TRH like activity, an analog cyclo (Phe-Pro) was also used. Administration of morphine to mice at 10 mg/kg ip produced hyperthermia and depression in locomotor activity, while at 80 mg/kg ip, hypothermia and stimulation in locomotor activity were observed. Intracerebral injection of the following peptides (10 μg each per mouse) administered 10 min prior to morphine injection antagonized locomotor depression, hyperthermia, locomotor stimulation and hypothermia induced by an appropriate dose of morphine: mClAcBz-Phe-Pyrr, pClAcBz-Ala-Phe-Pyrr, ClAcAla-Phe-Pro-NH₂, pClAcBz-Phe-Pro-NH₂, cyclo (Phe-Pro) and TRH. The compounds which had no effect on low dose or high dose morphine induced responses included pGlu-Phe-Pyrr, mClAcBz-Ala-Phe-Pyrr, and mClAcBz-Phe-Pro-NH₂. One compound, namely ClAc-Phe-Pyrr, antagonized morphine-induced locomotor stimulation and hypothermia but did not affect locomotor depression and hyperthermia produced by morphine. None of these peptides had any effect on the body temperature or the locomotor activity of normal mice. Many of the active compounds were previously shown to possess extremely weak or no activity in releasing thyrotropin from the pituitary. It is concluded that several of these analogs of TRH possess CNS activity in antagonizing morphine effects, and that a lack of relationship exists between the CNS and endocrine activity of these peptides.     

Activation of peripheral serotonin2 receptors induces hypothermia in mice

The effects of peripherally administered serotonin (5-HT) on the rectal temperature were investigated. 5-HT i.p. induced a dose-dependent hypothermia in mice. The hypothermic effects of 5-HT were strongly antagonized by the 5-HT1 and 5-HT2 receptor antagonist methysergide and the 5-HT2 receptor antagonist ketanserin. However, the 5-HT1 receptor antagonist pindolol and the 5-HT3 receptor antagonist ICS 205-930 were without effect. In addition, the peripheral 5-HT2 receptor antagonist xylamidine strongly reduced 5-HT-induced hypothermia. These results indicate that the activation of the peripheral 5-HT2 receptors induces hypothermia, although the central 5-HT2 receptors have been suggested to relate to hyperthermia.     

胆囊收缩素8对大鼠大脑皮质细胞钙调素和蛋白激酶C活性的影响

 为阐明中枢神经系统中胆囊收缩素 8(CCK8)受体的信号传递机制 ,以分离的大鼠大脑皮质神经细胞为材料 ,观察了CCK8对细胞内钙调素 (CaM)、3′ ,5′ 环腺苷酸 (cAMP)、蛋白激酶C(PKC)活性的影响 研究结果表明 ,CCK8可刺激大脑皮质细胞CaM、PKC活性的增加 ,并有剂量依赖关系 但CCK8在 10 -12 ～ 10 -6mol L范围内 ,细胞内cAMP含量无显著变化 利用受体亚型L 364,718和L 365,2 60的研究表明 ,两种拮抗剂均可抑制CCK8引起的CaM和PKC活性变化 ,但两者IC50 不同 对于CaM ,CCKB 受体拮抗剂L 365,2 60的IC50 比CCKA 受体拮抗剂L 364,718低 4 0倍 ;而对于PKC ,L 365,2 60的IC50 比L 364,718低 60倍 因此认为 ,CCK8主要是通过CCKB 受体介导了CaM和PKC活性的变化     

Histamine and histamine receptors: behavioral thermoregulation in the salamander Necturus maculosus

Low doses (0.01, 0.1 mg/kg, i.p.) of histamine (HA) caused selection of significantly lower temperatures, and higher doses (0.5, 1.0 mg/kg) increased temperatures by mudpuppies in linear thermal gradients. Injection of the HA precursor, L-histidine (500 mg/kg) produced an increase in the temperatures selected. Results from injections of HA H1-receptor agonist (2-pyridylethylamine) and antagonist (pyrilamine), and H2-receptor agonist (dimaprit) and antagonist (cimetidine) had significant effects on thermoregulation; H1-receptors may mediate behavioral hyperthermia and H2-receptors behavioral hypothermia. Responses to these histaminic compounds are significantly influenced by the time of day at which the responses are measured and by season and acclimation temperature. The equivalent behavioral responses in both endotherms and ectotherms to agents which produce physiological hyperthermia and hypothermia are probably behavioral hypothermia ("cold seeking") and behavioral hyperthermia ("heat seeking"), respectively.