Turning down the body heat: A novel mechanism for TRPV1 antagonist-induced hyperthermia.

While effective analgesics, TRPV1 antagonists can dangerously alter thermoregulation. In this issue of Neuron, Huang et al.1 demonstrate that interaction with the S4-S5 linker of TRPV1 determines whether an antagonist affects core body temperature, with promising implications for analgesic development.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

Antipyretic and antinociceptive potential of Ricinus communis L. and Withania somnifera L. hydroalcoholic extracts in Wistar rats: A comparative study.

The present study was designed to evaluate the antipyretic and antinociceptive activities of R. communis leaves and W. somnifera roots hydroalcoholic extracts in Wistar rats. To assess the antipyretic activity, Brewer's yeast suspension was used to induce hyperthermia. Antinociceptive activity was observed using acetic acid-induced abdominal writhing, formalin-induced paw licking reflex and heat-induced pain models. R. communis and W. somnifera extracts were used at 150, 250 and 500mg/kg. Results showed that administration of both plants significantly (p<0.001) lowered rectal temperature (°C) in a dose-dependent manner from 1h to 4h of study. R. communis and W. somnifera extracts showed a dose-dependent reduction in abdominal writhing induced by acetic acid and decreased the paw licking reflex in formalin-induced nociceptive response. In the heat test, R. communis and W. somnifera extracts exhibited significant (p<0.001) analgesic effects evidenced as an increase in latency time. However, R. communis exhibited prominent antipyretic and antinociceptive activities at 250 and 500mg/kg as compared to W. somnifera. Conclusively, R. communis and W. somnifera could be a potential source of antipyretic and analgesic agents which require further studies.

Hard Boiled: Alcohol Use as a Risk Factor for MDMA-Induced Hyperthermia: a Systematic Review.

Although MDMA (ecstasy) is a relatively safe recreational drug and is currently considered for therapeutic use for the treatment of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), recreational MDMA use occasionally elicits hyperthermia and hyponatremia, sometimes with a fatal outcome. Specific risk factors for both adverse effects are profuse sweating while vigorously dancing under unfavorable conditions such as high ambient temperatures and insufficient fluid suppletion which result in dehydration. Concomitant use of MDMA and alcohol is highly prevalent, but adds to the existing risk, because alcohol facilitates the emergence of MDMA-induced adverse events, like hyperthermia, dehydration, and hyponatremia. Because of potential health-related consequences of concomitant use of MDMA and alcohol, it is important to identify the mechanisms of the interactions between alcohol and MDMA. This review summarizes the main drivers of MDMA-induced hyperthermia, dehydration, and hyponatremia and the role of concomitant alcohol use. It is shown that alcohol use has a profound negative impact by its interaction with most of these drivers, including poikilothermia, exposure to high ambient temperatures, heavy exercise (vigorous dancing), vasoconstriction, dehydration, and delayed initiation of sweating and diuresis. It is concluded that recreational and clinical MDMA-users should refrain from concomitant drinking of alcoholic beverages to reduce the risk for adverse health incidents when using MDMA.

The Effect of Early Sedation With Dexmedetomidine on Body Temperature in Critically Ill Patients.

OBJECTIVES: Previous case series reported an association between dexmedetomidine use and hyperthermia. Temperature data have not been systematically reported in previous randomized controlled trials evaluating dexmedetomidine. A causal link between dexmedetomidine administration and elevated temperature has not been demonstrated. DESIGN: Post hoc analysis. SETTING: Four ICUs in Australia and New Zealand. PATIENTS: About 703 mechanically ventilated ICU patients. INTERVENTIONS: Early sedation with dexmedetomidine versus usual care. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean daily body temperature. Secondary outcomes included the proportions of patients with body temperatures greater than or equal to 38.3°C and greater than or equal to 39°C, respectively. Outcomes were recorded for 5 days postrandomization in the ICU. The mean daily temperature was not different between the dexmedetomidine (n = 351) and usual care (n = 352) groups (36.84°C ± sd vs 36.78°C ± sd; p = 0.16). Over the first 5 ICU days, more dexmedetomidine group (vs usual care) patients had a temperature greater than or equal to 38.3°C (43.3% vs 32.7%, p = 0.004; absolute difference 10.6 percentage points) and greater than or equal to 39.0°C (19.4% vs 12.5%, p = 0.013; absolute difference 6.9 percentage points). Results were similar after adjusting for diagnosis, admitting temperature, age, weight, study site, sepsis occurrence, and the time from dexmedetomidine initiation to first hyperthermia recorded. There was a significant dose response relationship with temperature increasing by 0.30°C ±0.08 for every additional 1 µg/kg/hr of dexmedetomidine received p < 0.0002. CONCLUSIONS: Our study suggests potentially important elevations in body temperature are associated with early dexmedetomidine sedation, in adults who are mechanically ventilated in the ICU.

Epidural analgesia, intrapartum hyperthermia, and neonatal brain injury: a systematic review and meta-analysis.

BACKGROUND: Epidural analgesia is associated with intrapartum hyperthermia, and chorioamnionitis is associated with neonatal brain injury. However, it is not known if epidural hyperthermia is associated with neonatal brain injury. This systematic review and meta-analysis investigated three questions: (1) does epidural analgesia cause intrapartum hyperthermia, (2) is intrapartum hyperthermia associated with neonatal brain injury, and (3) is epidural-induced hyperthermia associated with neonatal brain injury? METHODS: PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched from inception to January 2020 using Medical Subject Headings (MeSH) terms relating to epidural analgesia, hyperthermia, labour, and neonatal brain injury. Studies were reviewed independently for inclusion and quality by two authors (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach). Two meta-analyses were performed using the Mantel-Haenszel fixed effect method to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Forty-one studies were included for Question 1 (646 296 participants), 36 for Question 2 (11 866 021 participants), and two studies for Question 3 (297 113 participants). When the mode of analgesia was randomised, epidural analgesia was associated with intrapartum hyperthermia (OR: 4.21; 95% CI: 3.48-5.09). There was an association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54-2.3.06). It was not possible to quantify the association between epidural-induced hyperthermia and neonatal brain injury. CONCLUSIONS: Epidural analgesia is a cause of intrapartum hyperthermia, and intrapartum hyperthermia of any cause is associated with neonatal brain injury. Further work is required to establish if epidural-induced hyperthermia is a cause of neonatal brain injury.

Risperidone and 5-HT2A Receptor Antagonists Attenuate and Reverse Cocaine-Induced Hyperthermia in Rats.

BACKGROUND: Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. METHODS: Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. RESULTS: Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. CONCLUSIONS: Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

TRPV1 is crucial for thermal homeostasis in the mouse by heat loss behaviors under warm ambient temperature.

Thermal homeostasis in mammalians is a self-regulating process by which biological systems maintain an internal thermal stability, even under different temperature conditions; however, the molecular mechanisms involved under warm ambient temperature remain unclear. Here, we aimed to clarify functional significance of transient receptor potential vanilloid receptor 1 (TRPV1) under warm ambient temperature. TRPV1 KO mice exhibited transient hyperthermia when exposed to 30.0 and 32.5 °C, whereas wild-type (WT) mice did not. TRPV1 KO mice exhibited prolonged and prominent hyperthermia upon exposure to 35.0 °C, whereas WT mice showed transient hyperthermia. Hyperthermia also occurs in WT mice that received intracerebroventricular injection of TRPV1 antagonist AMG9810 upon exposure to 35.0 °C. Heat loss behaviors, sleeping and body licking, were deficient in TRPV1 KO mice exposed to warm temperatures. Therefore, the present results indicate that central TRPV1 is crucial for maintaining a constant body temperature via the initiation of heat loss behaviors under warm ambient temperature.

Hyperthermia Increases Neurotoxicity Associated with Novel Methcathinones.

Hyperthermia is one of the severe acute adverse effects that can be caused by the ingestion of recreational drugs, such as methcathinones. The effect of hyperthermia on neurotoxicity is currently not known. The primary aim of our study was therefore to investigate the effects of hyperthermia (40.5 °C) on the neurotoxicity of methcathinone (MC), 4-chloromethcathinone (4-CMC), and 4-methylmethcathinone (4-MMC) in SH-SY5Y cells. We found that 4-CMC and 4-MMC were cytotoxic (decrease in cellular ATP and plasma membrane damage) under both hyper- (40.5 °C) and normothermic conditions (37 °C), whereby cells were more sensitive to the toxicants at 40.5 °C. 4-CMC and 4-MMC impaired the function of the mitochondrial electron transport chain and increased mitochondrial formation of reactive oxygen species (ROS) in SH-SY5Y cells, which were accentuated under hyperthermic conditions. Hyperthermia was associated with a rapid expression of the 70 kilodalton heat shock protein (Hsp70), which partially prevented cell death after 6 h of exposure to the toxicants. After 24 h of exposure, autophagy was stimulated by the toxicants and by hyperthermia but could only partially prevent cell death. In conclusion, hyperthermic conditions increased the neurotoxic properties of methcathinones despite the stimulation of protective mechanisms. These findings may be important for the understanding of the mechanisms and clinical consequences of the neurotoxicity associated with these compounds.

Behavioral and physiological responses to intraperitoneal injection of zymosan in chicks.

Zymosan is a cell wall component of the yeast Saccharomyces cerevisiae and produces severe inflammatory responses in mammals. When zymosan is peripherally injected in mammals, it induces several behavioral and physiological changes including anorexia and hyperthermia. However, to our knowledge, behavioral and physiological responses to zymosan have not yet been clarified in birds. Therefore, the purpose of the present study was to determine if intraperitoneal injection of zymosan affects food intake, voluntary activity, cloacal temperature, plasma corticosterone (CORT) and glucose concentrations, and splenic gene expression of cytokines in chicks (Gallus gallus). Intraperitoneal injection of zymosan (2.5 mg) significantly decreased food intake, voluntary activity, and plasma glucose concentration, and increased plasma CORT concentration. The injection of 0.5 mg zymosan significantly increased cloacal temperature, while 2.5 mg zymosan had a tendency to increase it. Finally, 2.5 mg zymosan significantly increased the splenic gene expression of interleukin-1ß (IL-1ß), IL-6, IL-8, interferon-γ, and tumor necrosis factor-like cytokine 1A. The present results suggest that zymosan would be one of components which induces nonspecific symptoms including anorexia, hypoactivity, hyperthermia, and stress responses, under fungus infection in chicks.

Death of an apprentice bodybuilder following 2,4-dinitrophenol and clenbuterol intake.

We present the case of a 17-year-old man, who died after 2,4-dinitrophenol (DNP) and clenbuterol consumption, which he likely took for physical enhancement. Forensic post-mortem examination revealed a yellowish skin colour and nonspecific signs of asphyxia. Analytical confirmation of the intoxication was obtained in blood and urine, with high levels of DNP and clenbuterol. Both of these substances are used by bodybuilders as DNP enhance lipolysis and clenbuterol has anabolic properties, but their toxicity is underestimated. DNP uncouples oxidative phosphorylation, leading to thermogenesis and even relatively small doses can cause fatal hyperthermia. Clenbuterol is a ß2 agonist that causes electrolyte disturbances (hypokalemia and hyperglycemia mostly) and death have been described through coronary vasospasm. Given the circumstances in which the body was found and toxicological results, we believe the cause of death to be fatal hyperthermia from DNP intake. These substances are illegal in many countries, but easily bought online. Through this availability, the last decades have seen an increase of fatal intoxications. Websites selling them are regularly closed by French public authorities and Interpol, but unfortunately it seems insufficient.

Antipyretic and antitumor effects of a purified polysaccharide from aerial parts of Tetrastigma hemsleyanum.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrastigma hemsleyanum Diels et Gilg (Sanyeqing) is traditionally used as a folk medicine for the treatments of inflammation, high fever, hepatitis and cancer, and can improve the immune function of the patient. It belongs to the family of Vitaceae, and is mainly distributed in southeast China (Yunnan province) and can be found in India (Andaman Islands), Myanmar, Thailand, Vietnam, Malaysia and Indonesia in the valleys with 1100-1300 m above the sea level. AIM OF THE STUDY: The present study aimed to characterize the chemical properties of a purified polysaccharide extracted from the aerial part of Tetrastigma hemsleyanum (SYQP) and investigate its antipyretic and antitumor effects in mice models. MATERIALS AND METHODS: Water-soluble crude polysaccharides from the aerial parts of Tetrastigma hemsleyanum were extracted and fractionated by DEAE and gel permeation chromatography. Homogeneity, molecular weight, monosaccharide composition, and FTIR analysis were performed to characterize the SYQP. Antipyretic effect of SYQP was examined using Brewer's yeast induced hyperthermia test. Antitumor effect was investigated using H22 tumor bearing mice. The serum cytokines were determined to evaluated the biological activities of SYQP. RESULTS: SYQP was composed of galacturonic acid (GalA), glucose (Glc), mannose (Man), arabinose (Ara), galactose (Gal), and rhamnose (Rha) with a molar ratio of 11.3:7.1:2.5:1.0:0.9:0.5 and it had an average molecular weight of 66.2 kDa. The oral administration of SYQP at 200 and 400 mg/kg could markedly suppress the hyperthermia of mice induced by Brewer's yeast and decrease the production of cytokines especially prostaglandin E2 (PGE2) in the serum of mice. SYQP inhibited the growth of H22 tumor in mice with inhibitory rate of 39.9% at the administration dose of 200 mg/kg and increased the production of cytokines such as tumor necrosis factor-alpha (TNF-a) and interferon γ (IFN-γ). Experimental results showed that the preventive administration of SYQP before lipopolysaccharide (LPS) reduced the high cytokine levels such as IL-6, IL-10 and IFN-γ, indicating that SYQP might act as a competitor with LPS to interact with toll like receptor 4 (TLR4), which further regulated the secretion of cytokines. CONCLUSION: The anti-inflammatory and antitumor activities of SYQP might be related to its regulation of host immune function by controlling the secretion of cytokines.

Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis.

Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation - by protons - is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and - via the acido-antithermogenic and acido-antivasoconstrictor reflexes - modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist's potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed.

The acute toxic and neurotoxic effects of 3,4-methylenedioxymethamphetamine are more pronounced in adolescent than adult mice.

3,4-methylenedioxymethamphetamine (MDMA) recently achieved breakthrough status from the Food and Drug Administration (FDA) for post-traumatic stress disorder (PTSD). However, evidence indicates that exposure to toxic doses of MDMA can lead to long-lasting dysregulation of brain monoaminergic neurotransmitters, primarily from studies conducted in young adult rodents. To date, there is a paucity of data on whether toxic doses of MDMA can differentially affect neurotransmitter systems in adolescents and mature adults, which is an important question as adolescents and adults may be differentially vulnerable to MDMA abuse. In the current study, adolescent (6-7 weeks of age) and mature adult (16-18 weeks of age) male, Swiss-Webster mice were exposed to MDMA (20 mg/kg) using a binge-like dosing regimen (4 administrations spaced every 2 h). Acute lethality, acute hyperthermia, and acute decreases in body weight following MDMA administration were more pronounced in adolescent than adult mice. Likewise, acute loss of striatal dopamine neurochemistry was also exacerbated in adolescents, as determined by high-pressure liquid chromatography coupled to electrochemical detection. Exposure to MDMA induced greater turnover of dopamine into its major metabolite dihydroxyphenylacetic acid (DOPAC) in adolescents, but not in adults, suggesting a novel mechanism through which adolescents may show increased vulnerability to the acute toxic and neurotoxic effects of MDMA, or conversely that mature adults show greater protection. These data caution that MDMA exposure in adolescence may be particularly dangerous and that the therapeutic window for MDMA may differ between adolescents and mature adults.

Drug-associated hyperthermia: A longitudinal analysis of hospital presentations.

WHAT IS KNOWN AND OBJECTIVE: Hyperthermia occurs when heat accumulation surpasses the body's ability for heat dissipation. Many drugs can affect thermoregulation through mechanisms including altering the neurotransmitters that cause increased heat production or decreased heat loss and may, therefore, be associated with hyperthermia. This study aimed to examine hospitalizations and emergency department (ED) presentations due to hyperthermia and to investigate the potential association with drug therapy. METHODS: A retrospective analysis of ED presentations and hospitalizations due to hyperthermia in all four major hospitals in Tasmania, Australia, between July 2010 and December 2018 was performed. Data of patients aged ≥18 years were extracted from the hospital digital medical records and analysed for the prevalence, trends and various potential risk factors for hyperthermia, such as age, environmental temperature and drug therapy. RESULTS: This study included 224 patients. The data illustrated a trend with time, albeit not statistically significant, towards increasing hospital presentations due to hyperthermia. Antiepileptics (P = .03) and furosemide (P = .04) were the most frequently used drugs in patients with primary hyperthermia. The high use of levothyroxine in the study population (6.7%) stood out compared with the estimated national average (2.1%). Various drug classes associated with hyperthermia were used significantly more in the age group ≥60 years, suggesting polypharmacy in the elderly as a contributing factor for hyperthermia. WHAT IS NEW AND CONCLUSION: This study reports a possible association of some drugs, particularly diuretics (furosemide), antiepileptics and levothyroxine, with hyperthermia. Healthcare professionals should be aware of the increasing prevalence of hyperthermia and the possible involvement of drugs.