Increase In Tail Skin Temperature Research Articles

Cerebral Lactate Participates in Hypoxia-induced Anapyrexia Through its Receptor G Protein-coupled Receptor 81

Hypoxia-induced anapyrexia is thought to be a regulated decrease in body core temperature (Tcore), but the underlying mechanism remains unclear. Recent evidence suggests that lactate, a glycolysis product, could modulate neuronal excitability through the G protein-coupled receptor 81 (GPR81). The present study aims to elucidate the role of central lactate and GPR81 in a rat model of hypoxia-induced anapyrexia. The findings revealed that hypoxia (11.1% O2, 2 h) led to an increase in lactate in cerebrospinal fluid (CSF) and a decrease in Tcore. Injection of dichloroacetate (DCA, 5 mg/kg, 1 μL), a lactate production inhibitor, to the third ventricle (3 V), alleviated the increase in CSF lactate and the decrease in Tcore under hypoxia. Immunofluorescence staining showed GPR81 was expressed in the preoptic area of hypothalamus (PO/AH), the physiological thermoregulation integration center. Under normoxia, injection of GPR81 agonist 3-chloro-5-hydroxybenzoic acid (CHBA, 0.05 mg/kg, 1 μL) to the 3 V, reduced Tcore significantly. In addition, hypoxia led to a dramatic increase in tail skin temperature and a decrease in interscapular brown adipose tissue skin temperature. The number of c-Fos+ cells in the PO/AH increased after exposure to 11.1% O2 for 2 h, but administration of DCA to the 3 V blunted this response. Injection of CHBA to the 3 V also increased the number of c-Fos+ cells in the PO/AH under normoxia. In light of these, our research has uncovered the pivotal role of central lactate-GPR81 signaling in anapyrexia, thereby providing novel insights into the mechanism of hypoxia-induced anapyrexia.

Excessive whole-body exposure to 28 GHz quasi-millimeter wave induces thermoregulation accompanied by a change in skin blood flow proportion in rats.

Limited information is available on the biological effects of whole-body exposure to quasi-millimeter waves (qMMW). The aim of the present study was to determine the intensity of exposure to increase body temperature and investigate whether thermoregulation, including changes in skin blood flow, is induced in rats under whole-body exposure to qMMW. The backs of conscious rats were extensively exposed to 28 GHz qMMW at absorbed power densities of 0, 122, and 237 W/m2 for 40 minutes. Temperature changes in three regions (dorsal and tail skin, and rectum) and blood flow in the dorsal and tail skin were measured simultaneously using fiber-optic probes. Intensity-dependent temperature increases were observed in the dorsal skin and the rectum. In addition, skin blood flow was altered in the tail but not in the dorsum, accompanied by an increase in rectal temperature and resulting in an increase in tail skin temperature. These findings suggest that whole-body exposure to qMMW drives thermoregulation to transport and dissipate heat generated on the exposed body surface. Despite the large differences in size and physiology between humans and rats, our findings may be helpful for discussing the operational health-effect thresholds in the standardization of international exposure guidelines.

Abdominal TRPV1 channel desensitization enhances stress-induced hyperthermia during social stress in rats.

In rats, stress-induced hyperthermia caused by social interaction depends on brown adipose tissue (BAT) thermogenesis and peripheral vasoconstriction. However, the peripheral mechanisms responsible for regulating the level of hyperthermia during social stress are still unknown. The transient receptor potential vanilloid 1 (TRPV1) subfamily, expressed in sensory and visceral neurons, can serve as a thermoreceptor. Here, we tested the hypothesis that the abdominal TRPV1 is essential in regulating stress-induced hyperthermia during social stress. Male Wistar rats received an intraperitoneal injection of Resiniferatoxin (RTX) - an ultra-potent capsaicin analog, (i.e., to desensitize the TRPV1 channels) or vehicle. Seven days later, we evaluated the effects of abdominal TRPV1 channels desensitization on core body temperature (CBT), brown adipose tissue (BAT) temperature, tail skin temperature, and heart rate (HR) of rats subjected to a social stress protocol. We found abdominal TRPV1 desensitization increased CBT and BAT temperature but did not change tail skin temperature and HR during rest. However, under social stress, we found that abdominal TRPV1 desensitization heightened the increase in CBT and BAT caused by stress. Also, it abolished the increase in tail skin temperature that occurs during and after social stress. TRPV1 desensitization also delayed the HR recovery after the exposure to the social stress. These results show that abdominal TRPV1 channels desensitization heightens stress-induced hyperthermia, causing heat dissipation during and after social stress, enabling optimal thermal control during social encounters.

Norepinephrine modulation of heat dissipation in female rats lacking estrogen.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine-ß-hydroxylase (DBH)-immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH-ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2-adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes.

Alleviation of Metabolic Disturbance by Substituting Kanjang High in Bacillus for Salt through Modulation of Gut Microbiota in Estrogen-Deficient Rats.

A high salt intake may exacerbate menopausal symptoms and substituting for different types of traditionally made kanjang (TMK; soy sauce) may prevent it. This study examined whether substituting salt with lyophilized TMK containing low and high Bacillus and biogenic amines in a high-fat diet might modulate the menopausal symptoms and the energy, glucose, and lipid metabolism in ovariectomized (OVX) rats. They were categorized into salt (Control), TMK with high Bacillus and low biogenic amines (HBLB), TMK with high Bacillus and high biogenic amines (HBHB), TMK with low Bacillus and low biogenic amines (LBLB), and TMK with low Bacillus and high biogenic amines (LBHB). Sham-operated rats consumed the same diet as the Control. HBLB, HBHB, and LBHB prevented increased tail skin temperature compared to the Control. HBHB and HBLB partially inhibited the increased weight gain and abdominal fat mass by reducing the food efficiency without changing the serum 17β-estradiol concentrations. Serum glucose and insulin concentrations and the insulin resistance index by the homeostatic model assessment for insulin resistance showed a positive association for weight gain. HBLB and HBHB decreased the serum malondialdehyde and tumor-necrosis factor-α levels. Hepatic triglyceride storage was lower in all TMK groups than in the Control, while hepatic glycogen accumulation was higher in the HBLB, HBHB, and LBHB groups than in the Control and LBLB groups. Accordingly, the mRNA expression of peroxisome proliferator-activated receptors-γ(PPAR-γ) was higher in the HBLB and HBHB groups compared to the Control, and that of fatty acid synthase was opposite to PPAR-γ expression. However, HBLB and HBHB improved dyslipidemia and insulin resistance compared to the Control, but their improvement did not reach that of the Normal-control. The acetic acid concentrations in the portal vein were lower in the LBLB than in the Control, while the butyric acid contents were higher in the LBHB and HBLB groups than in the Control. HBHB, HBLB, and LBHB elevated Akkermansia and Lactobacillus, and HBLB and LBLB increased Bacteroides and Ruminococcus compared to the Control. Polycyclic aromatic hydrocarbon degradation, bile acid synthesis, and unsaturated fatty acid biosynthesis were significantly higher in the HBLB group than in the Control group. In conclusion, substituting salts to TMK with a high Bacillus content regardless of the bioamine contents partially improved the menopausal symptoms and metabolic disturbance in estrogen-deficient animals.

Select panicogenic drugs and stimuli induce consistent increases in tail skin flushes and decreases in core body temperature.

Panic attacks (PAs) are episodes of intense fear or discomfort that are accompanied by a variety of both psychological and somatic symptoms. Panic induction in preclinical models (e.g. rats) has largely been assayed through flight and avoidance behavioral tests and cardiorespiratory activity. Yet, the literature pertaining to PAs shows that thermal sensations (hot flushes/heat sensations and chills) are also a common symptom during PAs in humans. Considering that temperature alterations are objectively measurable in rodents, we hypothesized that select panicogenic drugs and stimuli induce consistent changes in thermoregulation related to hot flushes and chills. Specifically, we challenged male rats with intraperitoneal injections of the GABAergic inverse agonist FG-7142; the α2 adrenoceptor antagonist yohimbine; the serotonin agonist D-fenfluramine, and 20% CO2 (an interoceptive homeostatic challenge). We assayed core body temperature and tail skin temperature using implanted radiotelemetry probes and tail thermistors/thermal imaging camera, respectively, and found that all challenges elicited rapid, high-amplitude (~7-9°C) increase in tail skin temperature and delayed decreases (~1-3°C) in core body temperature. We propose that thermal sensations such as these may be an additional indicator of a panic response in rodents and humans, as these panicogenic compounds or stimuli are known to precipitate PAs in persons with panic disorder.

Association of high-fat diet with neuroinflammation, anxiety-like defensive behavioral responses, and altered thermoregulatory responses in male rats

Overweight and obesity are a worldwide pandemic affecting billions of people. These conditions have been associated with a chronic low-grade inflammatory state that is recognized as a risk factor for a range of somatic diseases as well as neurodevelopmental disorders, anxiety disorders, trauma- and stressor-related disorders, and affective disorders. We previously reported that the ingestion of a high-fat diet (HFD; 45% fat kcal/g) for nine weeks was capable of inducing obesity in rats in association with increased reactivity to stress and increased anxiety-related defensive behavior. In this study, we conducted a nine-week diet protocol to induce obesity in rats, followed by investigation of anxiety-related defensive behavioral responses using the elevated T-maze (ETM), numbers of FOS-immunoreactive cells after exposure of rats to the avoidance or escape task of the ETM, and neuroinflammatory cytokine expression in hypothalamic and amygdaloid nuclei. In addition, we investigated stress-induced cutaneous thermoregulatory responses during exposure to an open-field (OF). Here we demonstrated that nine weeks of HFD intake induced obesity, in association with increased abdominal fat pad weight, increased anxiety-related defensive behavioral responses, and increased proinflammatory cytokines in hypothalamic and amygdaloid nuclei. In addition, HFD exposure altered avoidance- or escape task-induced FOS-immunoreactivity within brain structures involved in control of neuroendocrine, autonomic, and behavioral responses to aversive stimuli, including the basolateral amygdala (BLA) and dorsomedial (DMH), paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei. Furthermore, rats exposed to HFD, relative to control diet-fed rats, responded with increased tail skin temperature at baseline and throughout exposure to an open-field apparatus. These data are consistent with the hypothesis that HFD induces neuroinflammation, alters excitability of brain nuclei controlling neuroendocrine, autonomic, and behavioral responses to stressful stimuli, and enhances stress reactivity and anxiety-like defensive behavioral responses.

Physical Exercise-Induced Cardiovascular and Thermoregulatory Adjustments Are Impaired in Rats Subjected to Cutaneous Artery Denervation.

This study aimed to investigate the chronic effects of caudal artery denervation on morphometric parameters of the tail vascular smooth muscle and on physical exercise-induced thermoregulatory and cardiovascular adjustments in rats. Male Wistar rats were subjected to caudal artery denervation or the sham procedure. Approximately 26–28 days after these procedures, their thermoregulatory and cardiovascular parameters were evaluated at rest and during or following a fatiguing treadmill run. At the end of the experiments, the rats were euthanized, and samples of their tails were removed to evaluate morphometric parameters of the vascular smooth muscle surrounding the caudal artery. Denervated rats showed morphological adaptations, including increased arterial wall thickness and wall-to-lumen ratios. In resting rats and following the fatiguing exercise, caudal artery denervation barely affected the thermoregulatory and cardiovascular parameters evaluated. By contrast, caudal artery denervation attenuated the increase in tail skin temperature, decreased the spontaneous baroreflex sensitivity, and exacerbated the increases in mean arterial pressure in exercising rats. The increased wall-to-lumen ratio of denervated rats correlated negatively with the maximum tail skin temperature attained or cutaneous heat loss sensitivity but correlated positively with the maximum diastolic blood pressure attained during exercise. In conclusion, cutaneous denervation induces vascular remodeling characterized by morphological adaptations of the tail vascular smooth muscle. This vascular remodeling likely underlies the impaired tail heat loss and blood pressure adjustments in denervated rats subjected to physical exercise. Therefore, we have highlighted the importance of cutaneous vascular innervation integrity in thermal and cardiovascular control in stress-challenged rats. In this sense, our findings advance the understanding of thermoregulatory and cardiovascular system reactions after a sustained cutaneous vascular innervation injury, which is essential for the treatment of some diseases, such as Parkinson's disease and type 1 and type 2 diabetes mellitus.

Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer's disease-induced estrogen deficient rats.

Intermittent fasting may be an effective intervention to protect against age-related metabolic disturbances, although it is still controversial. Here, we investigated the effect of intermittent fasting on the deterioration of the metabolism and cognitive functions in rats with estrogen deficiency and its mechanism was also explored. Ovariectomized rats were infused with β-amyloid (25-35; Alzheimer's disease) or β-amyloid (35-25, Non-Alzheimer's disease; normal cognitive function) into the hippocampus. Each group was randomly divided into two sub-groups: one with intermittent fasting and the other fed ad libitum: Alzheimer's disease-ad libitum, Alzheimer's disease-intermittent fasting, Non-Alzheimer's disease-ad libitum, and Non-Alzheimer's disease-intermittent fasting. Rats in the intermittent fasting groups had a restriction of food consumption to a 3-h period every day. Each group included 10 rats and all rats fed a high-fat diet for four weeks. Interestingly, Alzheimer's disease increased tail skin temperature more than Non-Alzheimer's disease and intermittent fasting prevented the increase. Alzheimer's disease reduced bone mineral density in the spine and femur compared to the Non-Alzheimer's disease, whereas bone mineral density in the hip and leg was reduced by intermittent fasting. Fat mass only in the abdomen was decreased by intermittent fasting. Intermittent fasting decreased food intake without changing energy expenditure. Alzheimer's disease increased glucose oxidation, whereas intermittent fasting elevated fat oxidation as a fuel source. Alzheimer's disease and intermittent fasting deteriorated insulin resistance in the fasting state but intermittent fasting decreased serum glucose levels after oral glucose challenge by increasing insulin secretion. Alzheimer's disease deteriorated short and spatial memory function compared to the Non-Alzheimer's disease, whereas intermittent fasting prevented memory loss in comparison to ad libitum. Unexpectedly, cortisol levels were increased by Alzheimer's disease but decreased by intermittent fasting. Intermittent fasting improved dyslipidemia and liver damage index compared to ad libitum. Alzheimer's disease lowered low-density lipoprotein cholesterol and serum triglyceride levels compared to Non-Alzheimer's disease. In conclusion, Alzheimer's disease impaired not only cognitive function but also disturbed energy, glucose, lipid, and bone metabolism in ovariectomized rats. Intermittent fasting protected against the deterioration of these metabolic parameters, but it exacerbated bone mineral density loss and insulin resistance at fasting in Alzheimer's disease-induced estrogen-deficient rats. Impact statement Intermittent fasting was evaluated for its effects on cognitive function and metabolic disturbances in a rat model of menopause and Alzheimer's disease. Intermittent fasting decreased skin temperature and fat mass, and improved glucose tolerance with decreasing food intake. Intermittent fasting also prevented memory loss: short-term and special memory loss. Therefore, intermittent fasting may prevent some of the metabolic pathologies associated with menopause and protect against age-related memory decline.

Hypothermia induced by inhibition of fatty acid metabolism in anesthetized rats: contributions of the forebrain and vagal afferents.

2-Mercaptoacetate (MA) is an antimetabolic drug that inhibits the utilization of fatty acids as an energy source. The intravenous injection of MA (1.2 mmol·kg-1) elicited an increase in tail skin temperature and a decrease in body core temperature in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats, although administration of the same amount of NaCl did not. The respiratory exchange ratio was significantly higher after administration of MA than that after the saline treatment. On the other hand, heat production was increased by either the MA- or NaCl-injection, suggesting a nonspecific effect caused by the hyperosmolality of the solutions. These results indicate that the MA-induced hypothermia was caused by an increase in heat loss but not by a decrease in heat production. The amplitudes of heat loss responses to MA in rats fasted overnight were significantly smaller than those in fed ones, suggesting a mechanism for suppression of heat loss in the fasted state. Rats pretreated with vagotomy, capsaicin-induced desensitization of sensory nerve fibers or decerebration did not exhibit the MA-induced hypothermic responses. It is possible that the MA-induced heat loss and hypothermia were mediated by the vagal afferents and required the forebrain for the full expression of the responses.

Possible mechanisms of hypothermia after inhibition of the median or dorsal raphe nucleus of freely moving rats.

We previously reported that tetrodotoxin (TTX) perfusion into the median raphe nucleus (MRN), which contains the cell bodies of serotonin (5-HT) neurons, induced a considerable body temperature reduction under normal and low ambient temperatures (23 and 5°C, respectively) in freely moving rats but showed no such effect under high ambient temperature (35°C). In the present study, we aimed to determine the mechanism(s) of body temperature reduction after TTX perfusion into the MRN by measuring tail skin temperature (an index of heat loss), heart rate (an index of heat production), and locomotor activity (Act) under normal ambient temperature (23°C). We performed similar experiments in the dorsal raphe nucleus (DRN), another area containing cell bodies of 5-HT neurons, to compare any functional differences with the MRN. TTX perfusion into the MRN or DRN induced significant hypothermia (from 37.4±0.2 to 33.7±0.4°C or from 37.4±0.1 to 34.5±0.4°C, respectively; P<0.001) with increased tail skin temperature (from 26.1±0.8 to 31.1±1.3°C or from 26.3±0.9 to 31.7±0.4°C, respectively; P<0.001), but no change in heart rate. However, TTX perfusion into the MRN or DRN differentially affected Act. TTX perfusion into the MRN induced hyperactivity (from 10.7±4.6 to 67.6±25.1 counts/min; P<0.01), whereas perfusion into the DRN induced immobility. Thus, the 5-HT projections from the MRN and DRN may play similar roles in thermoregulation, both in the heat production system and in the heat loss system, but their roles in the regulation of Act might be distinct and opposite.

Anxiogenic CO2 stimulus elicits exacerbated hot flash-like responses in a rat menopause model and hot flashes in postmenopausal women.

As longitudinal studies determined that anxiety is a strong risk factor for hot flashes, we hypothesized that an anxiogenic stimulus that signals air hunger (hypercapnic, normoxic gas) would trigger an exacerbated hot flash-associated increase in tail skin temperature (TST) in a rat ovariectomy (OVEX) model of surgical menopause and hot flashes in symptomatic postmenopausal women. We also assessed TST responses in OVEX serotonin transporter (SERT) rats that models a common polymorphism that is associated with increased climacteric symptoms in postmenopausal women and increases in anxiety traits. OVEX and sham-OVEX rats (initial experiment) and wildtype and SERT OVEX rats (subsequent experiment) were exposed to a 5-minute infusion of 20% carbon dioxide (CO2) normoxic gas while measuring TST. Postmenopausal women were given brief 20% and 35% CO2 challenges, and hot flashes were self-reported and objectively verified. Compared to controls, OVEX rats had exacerbated increases in TST, and SERT OVEX rats had prolonged TST increases following CO2. Most women reported mild/moderate hot flashes after CO2 challenges, and the hot flash severity to CO2 was positively correlated with daily hot flash frequency. The studies demonstrate that this anxiogenic stimulus is capable of inducing cutaneous vasomotor responses in OVEX rats, and eliciting hot flashes in postmenopausal women. In rats, the severity of the response was mediated by loss of ovarian function and increased anxiety traits (SERT), and, in women, by daily hot flash frequency. These findings may provide insights into anxiety-related triggers and genetic risk factors for hot flashes in thermoneutral environments.

2-Deoxy-D-glucose-induced hypothermia in anesthetized rats: Lack of forebrain contribution and critical involvement of the rostral raphe/parapyramidal regions of the medulla oblongata.

Systemic or central administration of 2-deoxy-d-glucose (2DG), a competitive inhibitor of glucose utilization, induces hypothermia in awake animals and humans. This response is mediated by the central nervous system, though the neural mechanism involved is largely unknown. In this study, I examined possible involvement of the forebrain, which contains the hypothalamic thermoregulatory center, and the medullary rostral raphe/parapyramidal regions (rRPa/PPy), which mediate hypoxia-induced heat-loss responses, in 2DG-induced hypothermia in urethane-chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. The intravenous injection of 2DG (250mgkg(-1)) elicited an increase in tail skin temperature and decreases in body core temperature and the respiratory exchange ratio, though it did not induce any significant change in the metabolic rate. These results indicate that the hypothermic response was caused by an increase in heat loss, but not by a decrease in heat production and that it was accompanied by a decrease in carbohydrate utilization and/or an increase in lipid utilization as energy substrates. Complete surgical transection of the brainstem between the hypothalamus and the midbrain had no effect on the 2DG-induced hypothermic responses, suggesting that the hindbrain, but not the forebrain, was sufficient for the responses. However, pretreatment of the rRPa/PPy with the GABAA receptor blocker bicuculline methiodide, but not with vehicle saline, greatly attenuated the 2DG-induced responses, suggesting that the 2DG-induced hypothermia was mediated, at least in part, by GABAergic neurons in the hindbrain and activation of GABAA receptors on cutaneous sympathetic premotor neurons in the rRPa/PPy.

Activation of Brainstem and Hypothalamic Areas Related to Increased Tail Skin Temperature in Ovariectomized Rats

Hot flushes are usually treated with estrogen replacement in postmenopausal women but the neural pathways involved are poorly understood. We investigated the activation of brain areas associated with the increase in tail skin temperature in an animal model of menopause. Female Wistar rats were ovariectomized (OVX) and implanted with subcutaneous capsules containing 17ß‐estradiol (E2) (OVX+E2) or corn oil (OVX). Tail skin temperature (TST) was recorded during two hours at ambient temperature at 3, 7 and 14 days after surgery. On day 15th, rats were perfused and the brains were processed for immunohistochemistry. Neuronal activity was evaluated by counting the number of Fos‐immunoreactive (ir) cells. On day 14 after ovariectomy, the TST in OVX rats was higher than in OVX+E2 rats. All the brain areas examined exhibited significantly more Fos‐ir cells in OVX than OVX E2 rats. In the brainstem, OVX rats displayed more Fos/tyrosine hydroxylase doubled‐labeled neurons in the A1, A2 and locus coeruleus compared with OVX+E2 rats. OVX rats exhibited more Fos‐ir neurons than OVX+E2 rats in the rostral preoptic area (POA), anteroventral periventricular nucleus (AVPV), and median preoptic nucleus (MnPO) in the preoptic area and in the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus. Moreover, there was a high correlation between the TST and Fos expression in the A1, A2, AVPV and POA. Thus, ovariectomy gradually increases TST and induces neuronal activation in the brainstem, preoptic area and hypothalamus. Fos expression in neurons of the A1, A2, AVPV, and POA is directly correlated with TST, suggesting these brain areas are associated with the thermoregulatory effects of estrogen. &#x0D; Financial support: CNPQ, FAPEMIG, CAPES

Hypoxia-induced hypothermia mediated by GABA in the rostral parapyramidal area of the medulla oblongata

Hypoxia evokes a regulated decrease in the body core temperature (Tc) in a variety of animals. The neuronal mechanisms of this response include, at least in part, glutamatergic activation in the lateral preoptic area (LPO) of the hypothalamus. As the sympathetic premotor neurons in the medulla oblongata constitute a cardinal relay station in the descending neuronal pathway from the hypothalamus for thermoregulation, their inhibition can also be critically involved in the mechanisms of the hypoxia-induced hypothermia. Here, I examined the hypothesis that hypoxia-induced hypothermia is mediated by glutamate-responsive neurons in the LPO that activate GABAergic transmission in the rostral raphe pallidus (rRPa) and neighboring parapyramidal region (PPy) of the medulla oblongata in urethane–chloralose-anesthetized, neuromuscularly blocked, artificially ventilated rats. Unilateral microinjection of GABA (15nmol) into the rRPa and PPy regions elicited a prompt increase in tail skin temperature (Ts) and decreases in Tc, oxygen consumption rate (VO2), and heart rate. Next, when the GABAA receptor blocker bicuculline methiodide (bicuculline methiodide (BMI), 10pmol) alone was microinjected into the rRPa, it elicited unexpected contradictory responses: simultaneous increases in Ts, VO2 and heart rate and a decrease in Tc. Then, when BMI was microinjected bilaterally into the PPy, no direct effect on Ts was seen; and thermogenic and tachycardic responses were slight. However, pretreatment of the PPy with BMI, but not vehicle saline, greatly attenuated the hypothermic responses evoked by hypoxic (10%O2–90%N2, 5min) ventilation or bilateral microinjections of glutamate (5nmol, each side) into the LPO. The results suggest that hypoxia-induced hypothermia was mediated, at least in part, by the activation of GABAA receptors in the PPy.

Thermoregulatory responses elicited by microinjection of l-glutamate and its interaction with thermogenic effects of GABA and prostaglandin E2 in the preoptic area

The aim of the present study was to investigate the thermoregulatory effects of neuronal activation with sodium l-glutamate (glutamate) in the preoptic area (POA) of the hypothalamus and to examine its possible interaction with the thermogenic effects of GABA and prostaglandin E2 (PGE2). Unilateral microinjection of glutamate (5nmol) into the lateral POA or its vicinity elicited a prompt increase in tail skin temperature and simultaneous decreases in the O2 consumption rate (VO2), heart rate, and colonic temperature in urethane–chloralose-anesthetized rats. A central subpopulation of these sites at around the level of bregma was also responsive to the thermogenic and tachycardic effects of GABA (30nmol). Although the microinjection of GABA into nearby sites elicited no direct effect, it greatly attenuated the hypothermic effects of glutamate subsequently administered to the same site. These results suggest that activation of the lateral POA elicited heat-loss responses and that its central part provided a tonic inhibitory drive toward heat production and tail vasoconstriction. On the other hand, the microinjection of glutamate elicited initial small decreases and subsequent large increases in VO2 and heart rate in the rostromedial POA. However, no thermoregulatory response was elicited by the microinjection of glutamate at sites where the microinjection of PGE2 (35fmol) elicited thermogenic, tachycardic and hyperthermic responses. These results may suggest that the rostromedial POA contained two glutamate-responsive cell groups that had opposite influences on thermoregulation and that the locus that was highly sensitive to the thermogenic effect of PGE2 was unreactive to glutamate. Collectively, activation of neurons in the lateral POA and rostromedial POA evoked distinct thermoregulatory responses.

Sinoaortic denervation prevents enhanced heat loss induced by central cholinergic stimulation during physical exercise

The present study investigated whether the effects of central cholinergic stimulation on thermoregulation during exercise are modulated by arterial baroreceptors. Wistar rats were submitted to sinoaortic denervation (SAD) or sham denervation (SHAM) and then fitted with a chronic guide cannula into the lateral cerebral ventricle. After 2 weeks, a catheter was implanted into the ascending aorta, and a temperature sensor was implanted into the peritoneal cavity. Two days later, the rats were submitted to exercise on a treadmill at 18 m/min until fatigued. Thermoregulatory and cardiovascular responses were measured after injection of 2 μL of 10 mM physostigmine (Phy) or 0.15 M NaCl solution (Sal) into the cerebral ventricle. In SHAM rats, Phy injection induced a greater exercise-induced increase in blood pressure and lower increase in heart rate than Sal treatment. In the SAD group, the attenuation of heart rate in response to Phy was blocked despite an exaggerated increase in blood pressure. SHAM rats treated with Phy had a higher increase in tail skin temperature compared to Sal injection (31.9 ± 0.4 °C Phy-SHAM vs. 30.1 ± 0.6 °C Sal-SHAM, 5 min after injection; p < 0.05), resulting in a lower exercise-induced increase in core temperature. In contrast, SAD blocked the Phy injection effects in thermoregulatory responses during exercise (tail temperature: 30.1 ± 1.2 °C Phy-SAD vs. 29.5 ± 1.2 °C Sal-SAD, 5 min, p = 0.65). Therefore, we conclude that the enhancement of cutaneous heat loss induced by central cholinergic stimulation during exercise is mediated primarily by arterial baroreceptors.

Nitric oxide mediates noradrenaline-induced hypothermic responses and opposes prostaglandin E 2-induced fever in the rostromedial preoptic area

Noradrenaline (NA) microinjected into the rostromedial preoptic area (POA) elicits heat loss responses and opposes prostaglandin E 2-induced fever. Here, I tested the hypothesis that local synthesis and release of nitric oxide (NO) mediates the NA-induced effects. The unilateral microinjection of the NO donor sodium nitroprusside (SNP, 8.4 nmol), but not that of saline solution, into the NA-sensitive site elicited an increase in tail skin temperature and decreases in the whole-body O 2 consumption rate, heart rate, and colonic temperature simultaneously in urethane–chloralose-anesthetized rats. Pretreatment with SNP greatly attenuated the thermogenic, tachycardic, and hyperthermic effects of prostaglandin E 2 (140 fmol) microinjected into the same site. Furthermore, the NA-induced hypothermic responses were largely blocked by a prior microinjection of an NO synthase inhibitor N G-monomethyl- l-arginine ( l-NMMA, 5 nmol), but not by that of its inactive enantiomer, N G-monomethyl- d-arginine ( d-NMMA, 5 nmol), at the same site. These results suggest that the hypothermic and antipyretic effects of NA are mediated by NO in the rostromedial POA.

Preventive effect of oral estetrol in a menopausal hot flush model

Objective To evaluate the efficacy of estetrol (E4) in alleviating hot flushes in an experimental animal model considered representative for menopausal vasomotor symptoms.Methods Recording of the thermal responses in the tail skin of morphine-dependent ovariectomized rats after morphine withdrawal by administration of naloxone. Six groups of rats were treated orally for 8 days as follows: vehicle (negative) control; E4: 0.1, 0.3, 1.0 and 3.0 mg/kg/day; and, as active (positive) control, ethinylestradiol 0.3 mg/kg/day. On day 8, tail skin temperature was recorded at baseline and for 60 min at 5-min intervals following naloxone administration.Results In control animals, tail skin temperature increased sharply by about 4.5°C after naloxone treatment and reverted to baseline by 60 min. Estetrol suppressed the tail skin temperature increase in a dose-dependent fashion. The highest dose of E4 tested (3 mg/kg/day) was equipotent to a 10-fold lower dose of ethinylestradiol. Both fully suppressed tail skin temperature changes.Conclusion Estetrol is effective in alleviating hot flushes in an experimental animal model considered representative for studying menopausal hot flushes (vasomotor symptoms). In this model, the potency of estetrol is 10-fold lower compared to ethinylestradiol.

Effects of the 5-HT 2A antagonist mirtazapine in rat models of thermoregulation

Thermoregulation is a complex intercommunicative function requiring coordination between core body temperature (CBT), the central nervous system, and peripheral vasculature. In menopausal women, dysregulation of thermoregulatory mechanisms leads to hot flushes and night sweats. A previous study in ovariectomized (OVX) rats has suggested that mirtazapine can alleviate thermoregulatory dysfunction by blocking 5-HT 2A receptor signaling. This is in opposition to other work in which 5-HT 2A receptor blockade appeared to exacerbate thermoregulatory dysfunction in OVX rats. Thus, the goals of the present study were to reexamine the effects of mirtazapine on temperature regulation in OVX rat models and explore further the role of 5-HT 2A receptor blockade. Mirtazapine exhibited potent functional antagonism (EC 50 = 0.62 nM) at the cloned human 5-HT 2A receptor. In the morphine-dependent model of thermoregulatory dysfunction, mirtazapine (10 mg/kg, i.p.) induced an increase in tail-skin temperature (TST) prior to naloxone administration. In the telemetry model, mirtazapine (0.3–3 mg/kg, i.p.) caused an increase in TST. However, at the highest dose tested (10 mg/kg, i.p.), mirtazapine induced a small but significant decrease in TST followed by an increase in TST. To examine this finding further, mirtazapine's effect on CBT was determined. Administration of mirtazapine (1–3 mg/kg, i.p.) resulted in a slight decrease in CBT but at the 10 mg/kg dose a dramatic decrease (− 3.6 °C) in CBT was observed. These data support the concept that 5-HT 2A receptors play a role in temperature regulation but that functional blockade of these receptors by mirtazapine is not a likely mechanism for restoring thermoregulatory processes in OVX rats.