Central efferent pathways mediating skin cooling-evoked sympathetic thermogenesis in brown adipose tissue

Control of thermoregulatory effectors by the autonomic nervous system is a critical component of rapid cold-defense responses, which are triggered by thermal information from the skin. However, the central autonomic mechanism driving thermoregulatory effector responses to skin thermal signals remains to be determined. Here, we examined the involvement of several autonomic brain regions in sympathetic thermogenic responses in brown adipose tissue (BAT) to skin cooling in urethane-chloralose-anesthetized rats by monitoring thermogenic [BAT sympathetic nerve activity (SNA) and BAT temperature], metabolic (expired CO(2)), and cardiovascular (arterial pressure and heart rate) parameters. Acute skin cooling, which did not reduce either rectal (core) or brain temperature, evoked increases in BAT SNA, BAT temperature, expired CO(2), and heart rate. Skin cooling-evoked thermogenic, metabolic, and heart rate responses were inhibited by bilateral microinjections of bicuculline (GABA(A) receptor antagonist) into the preoptic area (POA), by bilateral microinjections of muscimol (GABA(A) receptor agonist) into the dorsomedial hypothalamic nucleus (DMH), or by microinjection of muscimol, glycine, 8-OH-DPAT (5-HT(1A) receptor agonist), or kynurenate (nonselective antagonist for ionotropic excitatory amino acid receptors) into the rostral raphe pallidus nucleus (rRPa) but not by bilateral muscimol injections into the lateral/dorsolateral part or ventrolateral part of the caudal periaqueductal gray. These results implicate the POA, DMH, and rRPa in the central efferent pathways for thermogenic, metabolic, and cardiac responses to skin cooling, and suggest that these pathways can be modulated by serotonergic inputs to the medullary raphe.     

常用大鼠发热模型研究

目的探讨干酵母、2,4-二硝基酚、脂多糖（LPS）、细菌内毒素引起SD大鼠实验性发热的过程和特点,比较不同浓度外致热原对大鼠发热过程的影响。方法建立大鼠干酵母（2 g/kg、1 g/kg）、2,4-二硝基酚（30mg/kg、15 mg/kg）、LPS（100μg/kg、20μg/kg）、细菌内毒素（120 EU/kg、60 EU/kg）发热模型,记录不同时间点大鼠升温值,绘制各模型平均升温曲线,比较不同大鼠发热模型的发热特点。结果皮下注射干酵母混悬液,注射后2～3 h开始升温,6～7 h达峰值,升温持续20 h;皮下注射2,4-二硝基酚溶液,注射后20 min开始升温,1～1.5 h达峰值,升温持续3～5 h;腹腔注射LPS、细菌内毒素,注射后30 min开始升温,此后升温曲线表现为双相热或三相热,升温持续5～8 h。结论不同外致热原所致SD大鼠发热的过程和特点不同;外致热原浓度不同,所致大鼠发热过程和特点不同。解热试验中,应根据受试药物本身特点选用合适的大鼠发热模型。     

Unaltered norepinephrine-heart rate relationship in exercise with exogenous heat

We measured plasma norepinephrine (NE) concentration, an index of sympathetic nervous activity, and epinephrine (E), an index of adrenal medulla activity, in six normal young men during mild to severe exercise, with and without superimposed heat stress. The primary objective was to observe whether the normally close relationship between heart rate and log NE concentration in upset when heart rate at a given work load is increased by heat stress. Exercise, beginning at 50 W, was graded in 50-W increments lasting 10 min each up to 200 W, which lasted 5-10 min. Each subject went through the protocol twice, once with skin temperature kept low by a water-perfused suit and then with skin temperature raised to 38 degrees C. Exogenous heart stress raised log circulating NE concentration in proportion to the rise in heart rate at a given work load so that the usual relationship between these variables, previously observed during other stresses, was preserved. In contrast to some other stresses, heat stress had no added effect on E concentration, indicating that this stress during exercise raises sympathetic neural activity (as reflected in the rise in NE) without stimulating additional adrenal release of E.     

伤寒Vi多糖菌苗接种反应观察

本文报告了对我国首次成功的伤寒Ｖｉ多糖菌苗进行人体接种反应观察结果,接种对象为２０至５４岁无伤寒病史,近年无伤寒菌苗接种史的健康人,共６０名,以完全随机的方法分为两组,实验组注射３０μｇＶｉ多糖菌苗,对照组注射Ｖｉ多糖菌苗的稀释液。其结果３０名Ｖｉ多糖菌苗接种者注射后体温无中重反应发生,局部红肿仅有１例中反应。注射后对血压、心律没有影响。红细胞计数,白细胞计数均在正常范围,与接种前相比,无显著差异     

Central CO-heme oxygenase pathway raises body temperature by a prostaglandin-independent way.

Recently, the carbon monoxide (CO)-heme oxygenase pathway has been shown to play an important role in fever generation by acting on the central nervous system, but the mechanisms involved have not been assessed. Thus the present study was designed to determine whether prostagandins participate in the rise in body temperature (T(b)) observed after induction of the CO-heme oxygenase pathway in the central nervous system. Intracerebroventricular (ICV) injection of heme-lysinate (152 nmol/4 microl), which is known to induce the CO-heme oxygenase pathway, caused an increase in T(b) [thermal index (TI) = 5.3 +/- 0.5 degrees C. h], which was attenuated by ICV administration of the heme oxygenase inhibitor ZnDPBG (200 nmol/4 microl; TI = 2.5 +/- 1.7 degrees C. h; P < 0.05). No change in T(b) was observed after intraperitoneal injection of the cyclooxygenase inhibitor indomethacin (5 mg/kg), whereas indomethacin at the same dose attenuated the fever induced by ICV administration of lipopolysaccharide (LPS) (10 ng/2 microl) (vehicle/LPS: TI = 4.5 +/- 0.5 degrees C. h; indomethacin/LPS: TI = 1.7 +/- 1.0 degrees C. h; P < 0.05). Interestingly, indomethacin did not affect the rise in T(b) induced by heme-lysinate (152 nmol/4 microl) ICV injection (vehicle/heme: TI = 4.5 +/- 1.4 degrees C. h; indomethacin/heme: TI = 4.2 +/- 1.0 degrees C. h). Finally, PGE(2) (200 ng/2 microl) injected ICV evoked a rise in T(b) that lasted 1.5 h. The heme oxygenase inhibitor ZnDPBG (200 nmol/4 microl) failed to alter PGE(2)-induced fever. Taken together, these results indicate that the central CO-heme oxygenase pathway increases T(b) independently of prostaglandins.     

Fever and acute-phase response induced in rabbits by intravenous and intracerebroventricular injection of interleukin-6

We investigated the effect of human recombinant interleukin-6 (IL-6) on body temperature and acute-phase response, including changes in plasma levels of iron, zinc, copper, and fibrinogen and in circulating leukocyte count. The intravenous (IV) injection of IL-6 (2 micrograms/kg) produced a monophasic fever. The intracerebroventricular (ICV) injection of IL-6 produced a dose-dependent fever that developed gradually and remained elevated throughout the 5-h recording period. The IV injection of IL-6 decreased the plasma concentration of iron and zinc and increased the circulating leukocyte count. The ICV injection of IL-6 resulted in similar trace metal and leukocyte changes, and increased plasma levels of fibrinogen. These results show that IL-6 can cause fever when injected IV or ICV and induces some acute-phase responses through its action on peripheral target organs and in the central nervous system.     

Effects of hypothalamic microinjection of PGE2 on body temperature and sympathetic nervous activities in the rabbit

The febrile response and sympathetic nervous response to hypothalamic microinjections of prostaglandin E₂ (PGE₂) were investigated in anesthetized rabbits. Microninjection of PGE₂ (500–1000 ng) caused an increase in rectal temperature of more than 0.3°C in 13 of 50 loci in the preoptic and anterior hypothalamic area (PO/AH). At 8 of these 13 loci, PGE₂ elicited response patterns in the sympathetic nervous system, such as an increase in cutaneous sympathetic nervous activity and decrease in renal sympathetic nervous activity. This pattern of sympathetic nervous responses was induced with a simultaneous increase in rectal temperature of more than 0.5°C. The 8 loci were distributed in the preoptic area, especially in the vicinity of the supraoptic nucleus. Electrolytic lesions of this region were made bilaterally, and intracerebroventricular injection of PGE₂ (8 µg/kg) was found to inhibit fever and sympathetic activity. The results demonstrate that the action of PGE₂ is responsible for the response patterns of sympathetic twigs during fever. The preoptic area, especially in the vicinity of the supraoptic nucleus, is most sensitive to PGE₂ for the patternized response of sympathetic neurons and fever.     

Ontogeny of Glucose Metabolism in Sympathetic Ganglia of Chickens. Changes in the Carbon Fluxes to CO2, Lactate, and Tissue Constituents from 8 to 19 Days of Embryonic Age

Chains of sympathetic ganglia were excised from the lumbar region of white Leghorn chicken embryos, 8-19 days of age. The chains were incubated for 5 h at 36 degrees C in a bicarbonate-buffered physiological salt solution containing 5.55 mM unlabeled glucose and tracer amounts of glucose labeled either uniformly or at carbon-1 or carbon-6. Glucose uptake and labeled lactate output were both highest in ganglia from the youngest embryos studied and declined progressively with increasing age. The output of labeled CO2 rose to a peak rate at an incubation age of 10-12 days in the presence of either [U-14C]glucose or [1(-14)C]glucose, but changed relatively little with age in the presence of [6(-14)C]glucose. The incorporation of 14C into tissue constituents was fastest at 10-12 days with all three labeled glucoses. It is concluded that the hexosemonophosphate shunt is most active at an incubation age of 10-12 days, after glycolysis has greatly slowed. The literature on morphological and biochemical changes in the sympathetic ganglia during development is briefly reviewed and discussed in relation to the observed metabolic changes. The early high glycolytic rate may be related to the normal developmental delay in vascularization of the sympathetic chains.     

Brown fat UCP1 is not involved in the febrile and thermogenic responses to IL-1beta in mice

The activity of brown adipose tissue (BAT), a site of nonshivering metabolic thermogenesis, has been reported to increase after interleukin (IL)-1beta/lipopolysaccharide injection. To clarify the possible contribution of BAT thermogenesis to whole body febrile response, we investigated febrile and thermogenic response to IL-1beta using mice deficient in uncoupling protein-1 (UCP1), a key molecule for BAT thermogenesis. In wild-type (WT) mice, IL-1beta injection (5 microg/kg ip) increased body temperature (+1.82 degrees C at 20 min), decreased physical activity (-37% at 1 h), and produced a slight and insignificant rise (+15% at 1 h) in oxygen consumption (Vo(2)). Vo(2) dependent on metabolic thermogenesis (DeltaVO2 thermogenesis) calculated by correcting the effect of physical activity was increased after IL-1beta injection (726 +/- 200 ml x h(-1) x kg(-1) at 1 h). Almost the same responses were observed in UCP1-deficient mice, showing 638 +/- 87 ml x h(-1) x kg(-1) of DeltaVO2 thermogenesis at 1 h. In contrast, CL316,243, a selective activator of BAT thermogenesis, increased body temperature, decreased physical activity, and produced a significant rise in Vo2 in WT mice, showing 1,229 +/- 35 ml x h(-1) x kg(-1) of DeltaVO2 thermogenesis at 1 h. These changes were not observed in UCP1-deficient mice. These results, conflicting with a previously proposed idea of a role of BAT in fever, suggest a minor contribution of BAT thermogenesis to IL-1beta-induced fever. In support of this, we found no effect of IL-1beta on triglyceride content and UCP1 mRNA level in BAT, in contrast with apparent effects of CL316,243.     

Energetic responses to cold temperatures in rats lacking forebrain-caudal brain stem connections

Hypothalamic neurons are regarded as essential for integrating thermal afferent information from skin and core and issuing commands to autonomic and behavioral effectors that maintain core temperature (T(c)) during cold exposure and for the control of energy expenditure more generally. Caudal brain stem neurons are necessary elements of the hypothalamic effector pathway and also are directly driven by skin and brain cooling. To assess whether caudal brain stem processing of thermal afferent signals is sufficient to drive endemic effectors for thermogenesis, heart rate (HR), T(c), and activity responses of chronic decerebrate (CD) and control rats adapted to 23 degrees C were compared during cold exposure (4, 8, or 12 degrees C) for 6 h. Other CDs and controls were exposed to 4 or 23 degrees C for 2 h, and tissues were processed for norepinephrine turnover (NETO), a neurochemical measure of sympathetic drive. Controls maintained T(c) for all temperatures. CDs maintained T(c) for the 8 and 12 degrees C exposures, but T(c) declined 2 degrees C during the 4 degrees C exposure. Cold exposure elevated HR in CDs and controls alike. Tachycardia magnitude correlated with decreases in environmental temperature for controls, but not CDs. Cold increased NETO in brown adipose tissue, heart, and some white adipose tissue pads in CDs and controls compared with their respective room temperature controls. These data demonstrate that, in neural isolation from the hypothalamus, cold exposure drives caudal brain stem neuronal activity and engages local effectors that trigger sympathetic energetic and cardiac responses that are comparable in many, but not in all, respects to those seen in neurologically intact rats.     

Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.     

The surgeon's mental load during decision making at various stages of operations

In surgeons while opening the wound, during the operation proper, closing the skin and immediately after the operation, the ECG was recorded telemetrically for 5-min periods. From the ECG recordings, indices reflecting cardiac arrhythmia and emotional level were calculated. It is concluded that the process of decision making during the vital stages of operations causes a fall in the CHRV (the coefficient of heart rate variability), S2 (the variance of R-R intervals) and VR (the variability range of R-R intervals). It seems that of the indices studied, the most suitable for evaluation of the degree of mental loading due to decision making processes are the CHRV and S2. During all the stages of surgery studied, and immediately after the operation, an increase in tonus of the sympathetic nervous system occurs in surgeons indicating a rise in emotional level.     

Can non-shivering thermogenesis in brown adipose tissue following NA injection be quantified by changes in overlying surface temperatures using infrared thermography?

We aimed to investigate whether infra red thermography (IRT) can be used to measure and quantify non-shivering thermogenesis (NST) in the short-tailed field vole Microtus agrestis, by directly comparing it with a standard method, i.e. metabolic response following Noradrenaline injection (NA). Mean skin surface temperature overlying Brown adipose tissue (BAT) depot was 0.82 degrees C higher than mean surface temperature that did not overly BAT. The difference in temperature increased by 1.26 degrees C after NA was administered. Mean skin surface temperature overlying BAT increased by 0.32 degrees C after NA was administered; however, surface temperature decreased by 1.32 degrees C after saline was administered. Mean skin surface temperature overlying BAT did not change significantly between warm and cold acclimated voles; in contrast metabolic peak following NA injection significantly increased in cold acclimated voles. There was no significant correlation between change in surface temperature after NA injection and metabolic peak following NA injection. The results of this study suggest that IRT is not a sensitive enough method to measure changes in NST capacity in BAT following NA injection, or to detect changes in NST capacity induced by cold acclimation. However, IRT can distinguish between skin surfaces overlying BAT and skin surfaces that do not.     

Some pathophysiological aspects of vibration-induced white finger

The level of sympathetic nervous activity was assessed by evaluating cardiovascular responses to a cold test in 63 vibration-exposed workers (50 subjects without vibration white finger (VWF) and 13 subjects at stages 1 and 2 of VWF) and in 41 controls. Blood pressure, heart rate, systolic time intervals and the skin temperature of the third finger of the right hand were monitored throughout the cold test period. Basal urinary excretion of free catecholamines and platelet aggregation indices both in vitro and in vivo were also determined in all subjects. Systolic time intervals such as electromechanical systole index (QS2I) and left ventricular ejection time index (LVETI) were found to be shorter in the vibration-exposed workers with and without VWF than in the controls, both at rest and during cold exposure and recovery (p less than 0.001). A significant inverse relationship between urinary free catecholamines and the duration of LVETI was observed under resting conditions (p less than 0.03). The recovery rate of the basal finger skin temperature after local cooling was slower in vibration workers with VWF than in those without VWF (p less than 0.05) and in the controls (p less than 0.001). Platelet aggregation indices were similar in all groups studied. The results suggest that the level of sympathetic nervous activity is higher in vibration-exposed workers than in controls. In subjects with VWF, sympathetic hyperactivity in combination with local factors such as vibration-induced hyperresponsiveness to cold of the digital vessels may be responsible for finger blanching attacks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central endothelin: effects on vasopressin and the arterial baroreflex in doxorubicin heart failure rats

Endothelin 1 (ET-1) is increased in heart failure, both in plasma and within the central nervous system. Centrally, ET-1 induces sympathetic hyperactivity and arginine vasopressin (AVP) secretion. Both sympathetic activity and AVP secretion are regulated by the arterial baroreflex, which is typically impaired in heart failure. We hypothesized that central blockade of ETA receptors (ETAR) alters the baroreflex response of heart rate, renal sympathetic nerve activity (RSNA), and plasma AVP levels in a cardiomyopathic model of heart failure. Female Sprague-Dawley rats received weekly intraperitoneal injections of doxorubicin 2.5 mg x kg(-1) (doxorubicin heart failure, doxo-HF) or saline vehicle (control). After 8 weeks, they were instrumented, conditioned to the study environment, and then studied in the awake, non-restrained state. Baseline mean arterial pressure (MAP), RSNA, and plasma osmolality were similar in both groups, but heart rate (p<0.02), left ventricular pressure (p<0.001), and plasma AVP (p<0.01) were higher in the doxo-HF group. ET-1 dose dependently increased MAP, but the rise was significantly attenuated in doxo-HF rats at all doses. Baseline baroreflex control of heart rate and RSNA was similar in both groups. ETAR blockade with 4 nmol BQ123 i.c.v. significantly decreased both the upper plateau (p<0.05) and the range (p<0.05) of the baroreflex response of both heart rate and RSNA in doxo-HF but not in control rats. Despite higher basal plasma levels of AVP, ET-1 evoked a rise in plasma AVP of 13.6+/-3.2 pg x mL(-1) in doxo-HF compared with 0.4+/-0.4 pg x mL(-1) in control rats (p<0.001). To account for the blunted pressor response to ET-1 in the doxo-HF rats, gain of AVP release was calculated as DeltaAVP/DeltaMAP and was also found to be significantly greater in the doxo-HF rats (p<0.001). BQ123 prevented the rise in AVP and restored the gain in doxo-HF rats to that seen in controls. Thus, central ETAR contribute to the sympathoexcitation and AVP responses observed in heart failure due to doxorubicin cardiomyopathy.     

Cardiac Autonomic Nervous System Activation and Metabolic Profile in Young Children: The ABCD Study

Background

In adults, increased sympathetic and decreased parasympathetic nervous system activity are associated with a less favorable metabolic profile. Whether this is already determined at early age is unknown. Therefore, we aimed to assess the association between autonomic nervous system activation and metabolic profile and its components in children at age of 5–6 years.

Methods

Cross-sectional data from an apparently healthy population (within the ABCD study) were collected at age 5–6 years in 1540 children. Heart rate (HR), respiratory sinus arrhythmia (RSA; parasympathetic activity) and pre-ejection period (PEP; sympathetic activity) were assessed during rest. Metabolic components were waist-height ratio (WHtR), systolic blood pressure (SBP), fasting triglycerides, glucose and HDL-cholesterol. Individual components, as well as a cumulative metabolic score, were analyzed.

Results

In analysis adjusted for child’s physical activity, sleep, anxiety score and other potential confounders, increased HR and decreased RSA were associated with higher WHtR (P< 0.01), higher SBP (p<0.001) and a higher cumulative metabolic score (HR: p < 0.001; RSA: p < 0.01). Lower PEP was only associated with higher SBP (p <0.05). Of all children, 5.6% had 3 or more (out of 5) adverse metabolic components; only higher HR was associated with this risk (per 10 bpm increase: OR = 1.56; p < 0.001).

Conclusions

This study shows that decreased parasympathetic activity is associated with central adiposity and higher SBP, indicative of increased metabolic risk, already at age 5–6 years.     

Torpor and ultradian rhythms require an intact signalling of the sympathetic nervous system

During entrance into torpor heart and respiration rates are greatly reduced in parallel with the reduction of metabolic rate, suggesting an involvement of parasympathetic control. We compared the effect of parasympathetic inhibition with the effect of sympathetic inhibition on spontaneous torpor behaviour in the Djungarian hamster. Hamsters were acclimated to short photoperiod and displayed their standard torpor pattern as observed from T_b records. Parasympathetic inhibition was achieved by a subcutaneous implant of 21-day release pellets with Atropine and the sympathetic noradrenergic pathway was inhibited with a single injection of 6-Hydroxydopamine. Atropine treatment did not affect the occurrence and quality of spontaneous daily torpor at all. However, the reversible sympathetic inhibition by 6-Hydroxydopamine injection resulted in a complete disappearance of torpor for about 6 days. These results conclude that the onset of daily torpor requires an intact noradrenergic signalling of the sympathetic nervous system. We further observed that parasympathetic as well as sympathetic blockade resulted in an immediate abolishment of ultradian rhythms of body temperature. This suggests that the expression of ultradian oscillations in body temperature require a continued interaction of sympathetic and parasympathetic activity.     

Temporal adjustments in sympathoadrenal activity in rats with obesity-producing hypothalamic knife cuts

Sympathoadrenal activity was assessed in adult rats with obesity-producing hypothalamic knife cuts prior to and after the onset of gross obesity by measuring urinary excretion of norepinephrine and epinephrine and by determining rates of norepinephrine turnover in selected organs. Urinary excretion of norepinephrine, as an index of overall sympathetic nervous system activity, was approximately doubled throughout the 4-week study in knife-cut rats, as was intake of the high-fat diet. Three days after knife-cut surgery (before the onset of gross obesity) rates of norepinephrine turnover (ng X organ-1 X hr-1) were 23-33% lower in three of the four organs examined than in the corresponding organs of control rats; rates of norepinephrine turnover were depressed in pancreas, interscapular brown adipose tissue, and abdominal white adipose tissue and unchanged in hearts. Four weeks after surgery when gross obesity was evident, rates of norepinephrine turnover were accelerated in heart (+82%) and pancreas (+63%), but remained low in interscapular brown adipose tissue (-27%) and abdominal white adipose tissue (-28%). Adrenal medullary activity, assessed by urinary excretion of epinephrine, was suppressed within the 1st day after knife-cut surgery and remained suppressed for several weeks. Brown adipose tissue and white adipose tissue appear to be selectively excluded from the generalized activation of the sympathetic nervous system in adult hyperphagic rats with obesity-producing hypothalamic knife cuts. Activation of the sympathetic nervous system was associated with reciprocal suppression of adrenal medullary responses in knife-cut rats.     

A subsidiary fever center in the medullary raphé?

In fever, as in normal thermoregulation, signals from the preoptic area drive both cutaneous vasoconstriction and thermogenesis by brown adipose tissue (BAT). Both of these responses are mediated by sympathetic nerves whose premotor neurons are located in the medullary raphé. EP3 receptors, key prostaglandin E2 (PGE2) receptors responsible for fever induction, are expressed in this same medullary raphé region. To investigate whether PGE2 in the medullary raphé might contribute to the febrile response, we tested whether direct injections of PGE2 into the medullary raphé could drive sympathetic nerve activity (SNA) to BAT and cutaneous (tail) vessels in anesthetized rats. Microinjections of glutamate (50 mM, 60-180 nl) into the medullary raphé activated both tail and BAT SNA, as did cooling the trunk skin. PGE2 injections (150-500 ng in 300-1,000 nl) into the medullary raphé had no effect on tail SNA, BAT SNA, body temperature, or heart rate. By contrast, 150 ng PGE2 injected into the preoptic area caused large increases in both tail and BAT SNA (+60 +/- 17 spikes/15 s and 1,591 +/- 150% of control, respectively), increased body temperature (+1.8 +/- 0.2 degrees C), blood pressure (+17 +/- 2 mmHg), and heart rate (+124 +/- 19 beats/min). These results suggest that despite expression of EP3 receptors, neurons in the medullary raphé are unable to drive febrile responses of tail and BAT SNA independently of the preoptic area. Rather, they appear merely to transmit signals for heat production and heat conservation originating from the preoptic area.