Sustained Hyperthermia Research Articles

Locomotor and reinforcing effects of pentedrone, pentylone and methylone in rats

The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025–0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5–10.0 mg/kg), pentedrone (0.5–10.0 mg/kg) or mephedrone (0.5–10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4–0.8 °C) was observed for four hours after 10.0 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone.This article is part of the Special Issue entitled ‘Designer Drugs and Legal Highs.’

Cardiovascular and thermoregulatory dysregulation over 24 h following acute heat stress in rats.

The influences of severe heat stroke (HS) on cardiovascular function during recovery are incompletely understood. We hypothesized that HS would elicit a heart rate (HR) increase persisting through 24 h of recovery due to hemodynamic, thermoregulatory, and inflammatory events, necessitating tachycardia to support mean arterial pressure (MAP). Core temperature (Tc), HR, and MAP were measured via radiotelemetry in conscious male Fischer 344 rats (n = 22; 282.4 ± 3.5 g) during exposure to 37°C ambient temperature until a maximum Tc of 42.0°C, and during recovery at 20°C ambient temperature through 24 h. Rats were divided into Mild, Moderate, and Severe groups based on pathophysiology. HS rats exhibited hysteresis relative to Tc with HR higher for a given Tc during recovery compared with heating (P < 0.0001). "Reverse" hysteresis occurred in MAP with pressure during cooling lower than heating per degree Tc (P < 0.0001). Mild HS rats showed tachycardia [P < 0.01 vs. control (Con)] through 8 h of recovery, elevated MAP (P < 0.05 vs. Con) for the initial 5 h of recovery, with sustained hyperthermia (P < 0.05 vs. Con) through 24 h. Moderate HS rats showed significant tachycardia (P < 0.01 vs. Con), normal MAP (P > 0.05 vs. Con), and rebound hyperthermia from 4 to 24 h post-HS (P < 0.05 vs. Con). Severe HS rats showed tachycardia (P < 0.05 vs. Con), hypotension (P < 0.01 vs. Con), and hypothermia for 24 h (P < 0.05 vs. Con). Severe HS rats showed 14- and 12-fold increase in heart and liver inducible nitric oxide synthase expression, respectively. Hypotension and hypothermia in Severe HS rats was consistent with inducible nitric oxide synthase-mediated systemic vasodilation. These findings provide mechanistic insight into hemodynamic and thermoregulatory impairments during 24 h of HS recovery.

Cardiovascular and thermoregulatory biomarkers of heat stroke severity in a conscious rat model.

Multiorgan failure is a catastrophic consequence of heat stroke (HS) and considered the underlying etiology of mortality. Identifying novel biomarkers capable of predicting the extent of HS-induced organ damage will enhance point-of-care triage and treatment. Conscious male F344 rats (n = 32) were radiotelemetered for continuous core temperature (Tc), heart rate, and arterial pressure measurement. Twenty-two animals were exposed to ambient temperature of 37°C to a maximum Tc of 41.9 ± 0.1°C. Rats were euthanized at 24 h of recovery for analysis of plasma biomarkers [cardiac troponin I (cTnI), blood urea nitrogen (BUN), alanine aminotransferase (ALT), albumin, glucose] and histology. Tc profiles observed during recovery stratified HS severity into Mild, Moderate, and Severe. Eleven (50%) animals exhibited an acute compensatory hemodynamic response to heat exposure and a monophasic Tc profile consisting of sustained hyperthermia (∼1°C). Five (23%) rats displayed hemodynamic challenge and a biphasic Tc profile with rapid return to baseline followed by rebound hyperthermia. All biomarkers were significantly altered from control values (P < 0.05). Four (18%) animals exhibited significant hemodynamic compromise during heat and a triphasic profile characterized by rapid cooling to baseline Tc, rebound hyperthermia, and subsequent hypothermia (∼35°C) through 24 h. cTnI showed a 40-fold increase over CON (P < 0.001) and correlated with BUN (r = 0.912) consistent with cardiorenal failure. Hypoglycemia correlated with ALT (r = 0.824) suggestive of liver dysfunction. Histology demonstrated myocardial infarction, renal tubular necrosis, and acute liver necrosis. Two (9%) animals succumbed during HS recovery. This study identified novel biomarkers that predict HS severity and organ damage during acute recovery that could provide clinical significance for identifying key biomarkers of HS pathogenesis.

Hypothermia in burns intensive care: use of the intravenous temperature management system Thermogard XP®

The care of the patient with major burns in the ICU is a complex and challenging task. They differ from the other critical care patient groups in several ways. One of the major challenges faced is confronting their hypermetabolic state and temperature management [1]. It is widely known that major burn injury is associated with the most profound of hypermetabolic responses to a pathological state. Hyperthermia that is non-infectious is a feature of the systemic inflammatory response to this. In burns intensive care, the disproportionate increase in metabolic rate to small rises in core temperature can have significant impact on resuscitation and prognosis. The pathophysiology of the hyperthermic response in major burn injury is poorly understood. It could be secondary to an infective etiology or a metabolic response to the systemic inflammation. Irrespective of the reason, sustained hyperthermia above 40°C can culminate in cellular injury and death [2]. The hypermetabolic response starts within the first 5 days of the major burn and can last for a year after the injury. Because of the ongoing systemic inflammatory stimulation, patients with major burns often have pyrexia and their thermoregulatory system reset at a higher baseline temperature around 38.5°C [3]. While therapeutic cooling is widely used in neuro intensive care in the management of hyperthermic brain-injured patients and in patients after out-of-hospital cardiac arrests, there is very scarce literature available on the management of hyperthermia in burns intensive care. We, in this article, would like to share our experience of using the intravascular temperature management system (IVTM) Thermoguard XP® in our unit to manage refractory hyperthermia in patients with major burns. We report the responses of two major burns patients to core intravascular thermoregulation during periods of severe hyperthermia (>40°C). Case 1 A 24-year-old male had sustained 80% mixed depth, total body surface area (TBSA) flame burns following a road traffic accident. He had no significant past medical history. Initial resuscitation including endotracheal intubation and fluid resuscitation was instituted in the nearby district general hospital and was transferred over to our burns ICU without much delay. On admission to the ICU, detailed assessment of the burn injuries revealed second-degree and third-degree burns involving the trunk, abdomen, back, upper and lower extremities. Initial temperature recorded was 34°C. He responded to external warming, which included nursing in a warm environment, use of warm air blanket and warm fluids. The patient underwent extensive escharatomies on the day of admission as a part of his initial resuscitation. He developed multiorgan failure requiring high inotropic support, renal replacement therapy and high FiO2. He developed hyperpyrexia (temperature >42°C) on day 11 post burn. Relevant microbiology investigations had demonstrated no obvious focus of ongoing infection. The hyperpyrexia was resistant to conventional active cooling (bladder/gastric lavage, hemofiltration, external cooling with cooling blanket). The hyperpyrexia was associated with marked tachycardia (heart rate >150 beats/minute) with increasing oxygen demands and hypotension with escalating inotropic support. Forced core thermoregulation was commenced due to instability attributed to high core temperature. The Thermogard XP® was inserted in the femoral vein, the target temperature was set at 37°C. Within 2 hours of initiating the IVTM, the core body temperature dropped by 3°c down to 39°C. It took a further 3 hours to stabilise at the target temperature of 37°C. The IVTM system was used for a period of 6 days. The objective measurements of pulse rate, blood pressure, respiratory rate and urine output were seen to improve in the presence of a normothermic state (Figure ​(Figure1).1). After a protracted and convoluted stay in the ICU, the patient was discharged to a ward after 38 days. Open in a separate window Figure 1 Response in vital parameters in the first 20 hours after initiating IVTM: case 1.

Chronic exposure to ethanol exacerbates MDMA-induced hyperthermia and exposes liver to severe MDMA-induced toxicity in CD1 mice

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is an amphetamine derivative drug with entactogenic, empathogenic and hallucinogenic properties, commonly consumed at rave parties in a polydrug abuse pattern, especially with cannabis, tobacco and ethanol. Since both MDMA and ethanol may cause deleterious effects to the liver, the evaluation of their putative hepatotoxic interaction is of great interest, especially considering that most of the MDMA users are regular ethanol consumers. Thus, the aim of the present study was to evaluate, in vivo, the acute hepatotoxic effects of MDMA (10 mg/kg i.p.) in CD-1 mice previously exposed to 12% ethanol as drinking fluid (for 8 weeks). Body temperature was continuously measured for 12 h after MDMA administration and, after 24 h, hepatic damage was evaluated. The administration of MDMA to non pre-treated mice resulted in sustained hyperthermia, which was significantly increased in ethanol pre-exposed mice. A correspondent higher increase of hepatic heat shock transcription factor (HSF-1) activation was also observed in the latter group. Furthermore, MDMA administration resulted in liver damage as confirmed by histological analysis, slight decrease in liver weight and increased plasma transaminases levels. These hepatotoxic effects were also exacerbated when mice were pre-treated with ethanol. The activities of some antioxidant enzymes (such as SOD, GPx and Catalase) were modified by ethanol, MDMA and their joint action. The hepatotoxicity resulting from the simultaneous exposure to MDMA and ethanol was associated with a higher activation of NF-κB, indicating a pro-inflammatory effect in this organ. In conclusion, the obtained results strongly suggest that the consumption of ethanol increases the hyperthermic and hepatotoxic effects associated with MDMA abuse.

Monoamine Oxidase-B Mediates Ecstasy-Induced Neurotoxic Effects to Adolescent Rat Brain Mitochondria

3,4-Methylenedioxymethamphetamine (MDMA)-induced neurotoxicity and the protective role of monoamine oxidase-B (MAO-B) inhibition were evaluated at the mitochondrial level in various regions of the adolescent rat brain. Four groups of adolescent male Wistar rats were used: (1) saline control, (2) exposed to MDMA (4 x 10 mg/kg, i.p.; two hourly), (3) treated with selegiline (2 mg/kg, i.p.) 30 min before the same dosing of MDMA, and (4) treated with selegiline (2 mg/kg, i.p.). Body temperatures were monitored throughout the whole experiment. Animals were killed 2 weeks later, and mitochondria were isolated from several brain regions. Our results showed that "binge" MDMA administration causes, along with sustained hyperthermia, long-term alterations in brain mitochondria as evidenced by increased levels of lipid peroxides and protein carbonyls. Additionally, analysis of mitochondrial DNA (mtDNA) revealed that NDI nicotinamide adenine dinucleotide phosphate dehydrogenase subunit I and NDII (nicotinamide adenine dinucleotide phosphate dehydrogenase subunit II) subunits of mitochondrial complex I and cytochrome c oxidase subunit I of complex IV suffered deletions in MDMA-exposed animals. Inhibition of MAO-B by selegiline did not reduce hyperthermia but reversed MDMA-induced effects in the oxidative stress markers, mtDNA, and related protein expression. These results indicate that monoamine oxidation by MAO-B with subsequent mitochondrial damage may be an important contributing factor for MDMA-induced neurotoxicity.

G-CSF, but not corticosterone, mediates circulating neutrophilia induced by febrile-range hyperthermia

We previously showed that sustained exposure to febrile-range hyperthermia (FRH) for 24 h caused an increase in circulating granulocyte colony-stimulating factor (G-CSF) levels and a peripheral neutrophilia in mice (Hasday J, Garrison A, Singh I, Standiford T, Ellis G, Rao S, He JR, Rice P, Frank M, Goldblum S, and Viscardi R. Am J Pathol 162: 2005-2017, 2003). In this study, we utilized a conscious temperature-clamped mouse model to analyze the kinetics of G-CSF expression and peripheral neutrophil expansion and the contributions of FRH-induced G-CSF expression, glucocorticoid generation, and catecholamine-induced neutrophil demargination. In conscious mice housed at an ambient temperature of 34.5 degrees C, core temperature rapidly equilibrated at 39.5-40 degrees C. Peripheral neutrophil counts increased 2-fold after 24-h exposure to hyperthermia, peaked at 3.6-fold baseline levels after 36-h exposure to FRH, and returned to baseline levels after 42 h of sustained hyperthermia. Plasma G-CSF levels were increased by 6.8-fold after 24 h and peaked at 40-fold baseline levels after 36 h in the hyperthermic mice. Plasma corticosterone levels peaked at 3.3-fold baseline levels after 30-h sustained hyperthermia and returned to baseline by 42 h. Immunoneutralization of G-CSF blocked FRH-induced peripheral neutrophilia, but blockade of the glucocorticoid receptor with mifepristone failed to modify FRH-induced neutrophilia. Epinephrine induced similar increases in peripheral blood absolute neutrophil counts in euthermic mice (2.2-fold increase) and mice exposed to FRH for 36 h (1.8-fold increase). Collectively, these data suggest that FRH-induced expression of G-CSF drives the sustained peripheral neutrophilia that occurs during sustained (36 h) hyperthermia, whereas glucocorticoid generation and catecholamine-induced demargination play little role in this response.

Elevation of Ambient Room Temperature has Differential Effects on MDMA-Induced 5-HT and Dopamine Release in Striatum and Nucleus Accumbens of Rats

3,4-Methylenedioxymethamphetamine (MDMA) produces acute dopamine and 5-HT release in rat brain and a hyperthermic response, which is dependent on the ambient room temperature in which the animal is housed. We examined the effect of ambient room temperature (20 and 30 degrees C) on MDMA-induced dopamine and 5-HT efflux in the striatum and shell of nucleus accumbens (NAc) of freely moving rats by using microdialysis. Locomotor activity and rectal temperature were also evaluated. In the NAc, MDMA (2.5 or 5 mg/kg, i.p.) produced a substantial increase in extracellular dopamine, which was more marked at 30 degrees C. 5-HT release was also increased by MDMA given at 30 degrees C. In contrast, MDMA-induced extracellular dopamine and 5-HT increases in the striatum were unaffected by ambient temperature. At 20 degrees C room temperature, MDMA did not modify the rectal temperature but at 30 degrees C it produced a rapid and sustained hyperthermia. MDMA at 20 degrees C room temperature produced a two-fold increase in activity compared with saline-treated controls. The MDMA-induced increase in locomotor activity was more marked at 30 degrees C due to a decrease in the activity of the saline-treated controls at this high ambient temperature. These results show that high ambient temperature enhances MDMA-induced locomotor activity and monoamine release in the shell of NAc, a region involved in the incentive motivational properties of drugs of abuse, and suggest that the rewarding effects of MDMA may be more pronounced at high ambient temperature.

Serotonin neurotoxins--past and present.

Autoxidation pathways and redox reactions of dihydroxytryptamines (5,6- and 5,7-DHT) and of 6-hydroxydopamine (6-OH-DA) are illustrated, and their potential role in aminergic neurotoxicity is discussed. It is proposed that certain aspects of the cytotoxicity of 6-OH-DA and of the DHTs, namely redox cycling of their quinone- and quinoneimine-intermediates as a source of free radicals, may also apply to quinoidal reactive intermediates and to glutathionyl- or cysteinyl conjugates ("thioether adducts") of o-dihydroxylated (catechol-like) metabolites of certain substituted amphetamines (of methylenedioxymethamphetamine (MDMA) and of methylenedioxyamphetamine (MDA)). Despite similarities in their primary interaction with the plasmalemmal (serotonergic transporter/dopamine transporter, SERT/DAT) and vesicular monoamine transporters (VMAT2), MDMA and fenfluramine (N-ethyl-meta-trifluoromethamphetamine, Fen) differ substantially in many aspects of their metabolism, pharmacokinetics, pharmacology, and neurotoxicology profile; the consequences of these differences for neuronal response patterns and long-term survival prospects are not yet fully understood. However, sustained hyperthermia appears to be a critical factor in these differences. Methodological requirements for adequate detection and description of pre- and postsynaptic forms of drug-induced neurotoxicity are exemplified using recently published accounts. The inclusion of microglial markers into research strategies has widened contemporary pathogenetic concepts on methamphetamine (MA)-induced neurotoxicity as an example of inflammatory neurodegeneration, thus complementing the traditional ROS and RNS-dependent stress models. Amphetamine-type neurotoxicity studies may assist in elaborating of preventive strategies for human neurodegenerative disorders.

Repeated administration of the anorectic factor prolactin-releasing peptide leads to tolerance to its effects on energy homeostasis.

Central administration of a single dose of prolactin-releasing peptide (PrRP) causes a reduction in both fast-induced and nocturnal food intake and body weight gain. The aim of this study was to examine the effect of repeated administration of PrRP on energy homeostasis, including a measure of the expression of the mitochondrial uncoupling protein-1 (UCP-1) in brown adipose tissue. Conscious, free-feeding animals received central injections of PrRP (4 nmol icv) or vehicle. A single injection at 1000 caused a sustained hyperthermia over the 4-h test period and an increase in the expression of UCP-1 mRNA. Repeated, twice daily injection caused a reduction in body weight gain greater than that seen in pair-fed animals for the first 48-72 h. After 72 h, the animals became refractory to the actions of PrRP. The pair-fed group showed a reduction in UCP-1 mRNA expression at 48 h, which was reversed by PrRP treatment. This study indicates that PrRP exerts its effects on energy homeostasis in the short-medium term by reducing food intake and increasing energy expenditure.

Programmable microchip monitoring of post-stroke pyrexia: effects of aspirin and paracetamol on temperature and infarct size in the rat

Background: Recent studies have demonstrated spontaneous and prolonged hyperthermia following stroke in both humans and rodents. However, a full characterization of these pyretic changes and the effects of anti-pyretic drugs on outcome is not available. Methods: The aims of this study were to monitor conscious body temperature ( n=10 per group) using programmable microchips for up to 24 h in rats following either permanent (p) or 90 min transient (t) middle cerebral artery occlusion (MCAO) or sham surgery, and to evaluate the relationship to hypothalamic damage. Also, the effects of anti-pyretic drug therapy on body temperature and infarct volume were evaluated in animals treated with vehicle, optimal doses of either aspirin or paracetamol (250 mg/kg i.p.) following pMCAO ( n=10 per group). Results: At 1 h, body temperature significantly ( P<0.01) increased to 38.6±0.2 °C following tMCAO and 38.9±0.1 °C following pMCAO compared with sham-operated animals (37.1±0.1 °C). Sustained hyperthermia (≥38.1 °C) was observed for up to 24 h following pMCAO but approached baseline within 30 min (37.6±0.2 °C) following tMCAO with reperfusion. The post-stroke pyrexia was related to the degree of ischemia where hypothalamic damage was observed in (80%) of the animals undergoing pMCAO and (0%) in the tMCAO group ( P<0.05). Treatment with paracetamol (250 mg/kg i.p.) significantly attenuated ( P<0.05) but did not normalize core body temperature up to 2 h (38.2±0.4 °C) compared with vehicle treated animals (39.3±0.1 °C). Aspirin had no effect on temperature under these conditions. Hypothalamic damage and lesion volume were not different between animals treated with paracetamol (253.3±8.5 mm 3), aspirin (264.0±11.6 mm 3) or vehicle (274.4±8.2 mm 3). Conclusions: This study is the first to demonstrate the utility of programmable microchips to monitor serial changes in post-stroke hyperthermia. The sustained post-stroke pyrexia and negative effects of antipyretic treatment may be attributed to the extensive hypothalamic injury suggesting that better pharmacologic approaches to reduce body temperature should be identified and evaluated for brain protection in severe experimental stroke.

A neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) to rats results in a long-term defect in thermoregulation.

3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") administration to rats produces damage to cerebral 5-HT nerve endings; however, the long-term functional consequences of this damage are poorly understood. To confirm that MDMA administration produces a long-term effect on thermoregulation and investigate the mechanisms involved. Male Dark Agouti rats were injected with a neurotoxic dose of MDMA (12.5 mg/kg i.p.). Five to 6 weeks later, they were exposed to high ambient temp (30 degrees C) for 60 min followed by a return to normal temp (20 degrees C), with rectal temperature being measured under both conditions. Further groups of MDMA-pretreated rats were challenged with 8-OH-DPAT and their temperature response measured. MDMA administration produced acute hyperthermia. Rectal temperature had normalised 24 h later and was similar to saline-injected controls over the following 15 days. MDMA administration produced a 37% loss in hypothalamic 5-HT content 18 days later. When MDMA-pretreated rats were subjected to high ambient temperature 33 days posttreatment, they displayed both a faster rise in rectal temperature and sustained hyperthermia when returned to normal conditions. There was no difference in their hypothermic response to the 5-HT1A agonist 8-OH-DPAT. A neurotoxic dose of MDMA resulted in impaired thermoregulation when rats were exposed to high ambient temperature. 5-HT1A receptor mechanisms were unaltered. Impaired serotonergic function following MDMA presumably alters the neurotransmitter balance, thereby compromising thermoregulation. Heavy recreational users of MDMA may also have impaired thermoregulation and thus be at greater risk of an acute adverse response to MDMA in a hot crowded dance environment.

Postischemic Spontaneous Hyperthermia and Its Effects in Middle Cerebral Artery Occlusion in the Rat

This study examined the time course and effects of postischemic spontaneous hyperthermia after transient and permanent focal ischemia. Rats underwent a 90-min, 120-min, or permanent middle cerebral artery occlusion (MCAO). Body temperatures started rising 15–20 min after MCAO and reached 39–40.5°C during the first hour. Sustained hyperthermia was observed during the rest of the first 24 h. In another experiment, rats were subjected to the same interventions, but a normothermic body temperature was maintained. Spontaneous hyperthermia significantly increased the infarct volumes measured 48 h after MCAO in all groups. Reperfusion 2 h after the onset of ischemia was not beneficial in the hyperthermic animals in contrast to the normothermic group. We also examined the effect of spontaneous hyperthermia on the temporal progression of infarcted and penumbral areas 4, 12, or 48 h after MCAO. During spontaneous hyperthermia, penumbral areas became infarcted areas more rapidly, which was most expressed at 4 h. These findings demonstrate that severe spontaneous hyperthermia can occur in rats after MCAO and that it not only increases the infarct volumes in both transient and permanent ischemia, but also accelerates the incorporation of penumbral areas into necrotic areas, which significantly decreases the window of opportunity for therapeutic interventions.

Cyclo-oxygenase mediation of endotoxin-induced fever, anterior and posterior pituitary hormone release, and hypothalamic c-Fos expression in the prepubertal pig

Prepubertal pigs (n = 8) treated with bacterial endotoxin (20 micrograms lipopolysaccharide; LPS) exhibited a sustained (4 h) hyperthermia, increased plasma concentrations of cortisol, prolactin, growth hormone and vasopressin, but no change in adrenaline or noradrenaline levels was observed. All these effects were prevented or attenuated when the animals were pretreated intravenously with the cyclo-oxygenase inhibitor indomethacin (IND; 2 mg/kg). Similarly, in pigs (n = 3 per treatment) given IND, LPS or IND + LPS, parallel changes in the neuronal expression of c-Fos were observed in hypothalamic regions concerned with thermoregulation, neurohypophysial secretion, and the control of pituitary-adrenocortical function. The stimulatory action of LPS in the median preoptic, supraoptic and paraventricular nuclei was prevented by IND, whereas IND given alone was without effect. These findings suggest that inducible cyclo-oxygenase pathways are responsible for the febrile and neuroendocrine effects of endotoxin in this species.

Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament

The present experiments were designed to study under what circumstances middle cerebral artery (MCA) occlusion by an intraluminal filament technique leads to hyperthermia and what the mechanisms are. We found that permanent MCA occlusion by this technique lead to a rise in body (core) temperature to 39.0–39.5°C during the first 2–4 h, and to sustained hyperthermia thereafter (38.5–39.0°C). After2 h of transient MCA occlusion hyperthermia could only be avoided if anesthesia (with control of temperature) was maintained for 2 h of ischemia and 1 h of recirculation or, in unanesthetized animals, if external cooling was maintained for 2 h of ischemia and 2 h of recirculation. Control of temperature only during ischemia did not prevent a postischemic rise in temperature. One hour of MCA occlusion had less effect on body temperature. Results are presented which suggest that the hyperthermia observed is due to an interference, by the intraluminal filament, of circulation to hypothalamic centers regulating body temperature. It is speculated that the hyperthermia induced may blunt or obliterate the effect of drugs, normally considered to ameliorate brain damage due to focal ischemia.

Hyperthermia-associated changes in Fos protein in the median preoptic and other hypothalamic nuclei of the pig following intravenous administration of prostaglandin E 2

Changes in body temperature and hypothalamic Fos production were investigated in pigs injected intravenously with prostaglandin E 2 (PGE 2, 20 μg/kg). PGE 2 produced a sustained ( 150min) hyperthermia (0.7–1°C) and significant increases in Fos labelling in the supraoptic and paraventricular nuclei. In addition, PGE 2 induced Fos production in the median preoptic nucleus, a region previously demonstrated to be involved in thermoregulation in this species.

Apnea and rapid eye movement sleep excess in the piglet during recovery from hyperthermia.

This investigation tested the hypothesis that artificially induced mild hyperthermia and recovery from hyperthermia in the developing newborn piglet (2-10 d of age) alter sleep state patterns and respiratory control. Continuous measurements of sleep state, respiratory pattern, carbon dioxide production and oxygen consumption were made before, during, and after a 3-h period of sustained hyperthermia. During hyperthermia, rectal temperatures were raised a mild 1-1.5 degree C above normal, well below the levels likely to cause severe physiologic distress in this species. This resulted in a disruption of the sleep state pattern characterized by a decrease in duration of rapid eye movement (REM) episodes, whereas immediately afterwards, during recovery, the amount of REM sleep increased. In some cases the amount of REM sleep in recovery more than doubled the basal level. Apneas were rarely observed during hyperthermia, but in recovery there was an increase in the total amount of time spent in apnea in both REM and non-rapid eye movement sleep states with a predominance in the REM state. Arousal responses to chemostimulation were not affected at this time. We conclude that the sleeping newborn piglet does indeed show marked changes in sleep state pattern (particularly REM sleep) and in the amount of apnea recorded during and immediately after only a mild increase in core temperature.

5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine

1. The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-HT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-1, i.p.) protected only the hippocampus. 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection. 4. Injection of PCA (5 mg kg-1, i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content. Chlormethiazole did prevent the hyperthermia induced by PCA (5 mg kg-1), while the lower dose of PCA (2.5 mg kg-1) did not produce a change in body temperature.5. Neither chlormethiazole nor dizocilpine prevented the neurotoxic loss of hippocampal or cortical 5-HT neurones measured 4 days following administration of fenfluramine (25 mg kg-1, i.p.).6. In general, chlormethiazole and dizocilpine were effective antagonists of the 5-HT-mediated behaviours of head weaving and forepaw treading which appeared following injection of all three neurotoxins.7. Both chlormethiazole and dizocilpine have previously been shown to prevent the neurotoxic effects ofa high dose of methamphetamine on cerebral 5-HT and dopamine pathways. These drugs also prevent MDMA-induced neurotoxicity of 5-HT pathways, but not that induced by injection of PCA or fenfluramine. This suggests that the mechanisms of neurotoxic damage to 5-HT pathways produced by substituted amphetamines cannot be identical. The monoamine loss does not appear to result from the hyperthermia produced by the neurotoxic compounds.

Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs.

We examined effects of hyperthermia on cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) in anesthetized, newborn pigs (2-5 days old). CBF and CMRO2 were measured during normothermia (38 degrees C) and during hyperthermia induced by body heating (42 degrees C). During normothermia, total CBF was 32 +/- 3 ml.min-1.100 g-1 (n = 9), and CMRO2 was 1.34 +/- 0.08 ml O2.100 g-1.min-1 (n = 7). During hyperthermia, total CBF increased by 97 +/- 23% and CMRO2 by 65 +/- 24%. We also examined whether cerebral resistance vessels were responsive under these conditions. During hyperthermia, total CBF was 63 +/- 6 ml.min-1.100 g-1, and CMRO2 was 2.13 +/- 0.27 ml O2.100 g-1.min-1. During sustained hyperthermia, intravenous injection of 5 mg/kg of indomethacin decreased total CBF by 45 +/- 7% (n = 9), and CMRO2 fell by 55 +/- 10% (n = 5). We conclude that 1) hyperthermia increases CBF and CMRO2, and 2) the dilated cerebrovascular bed during hyperthermia still is responsive to a constrictor stimulus.

Molecular cloning of sequences encoding the human heat-shock proteins and their expression during hyperthermia

Plasmids containing cDNA copies of mRNAs induced in HeLa cells by heat shock have been isolated and characterized. In vitro translation of RNAs selected by hybridization to plasmid DNAs identified sequences representing the three major classes ∗∗ ∗∗ The 89-kDa hsp referred to in this manuscript was described as 80 kDa in our previous publication (Hickey and Weber, 1982a). This protein is the same as the 90-kDa stress protein of HeLa cells (Welch and Feramisco, 1982; Welch et al., 1983). (89, 70 and 27-kDa) of heat-shock proteins (hsp) and a 60-kDa minor hsp. Plasmids with inserts specific for the 27, 60, and 70-kDa hsp each hybridize with a single discrete size class of heat-inducible mRNA. Plasmids specific for the 89-kDa protein, however, hybridize with either a 2.7-or 2.95-kb mRNA species. Both mRNAs are coordinately induced during heat shock. We show that the characteristic pattern of induction and repression of each class of hsp during sustained hyperthermia is the result of changes in the steady state level of each mRNA.