Cutaneous Vasoconstriction Research Articles

THE EFFECT OF CONCENTRIC AND ECCENTRIC CYCLING ON SKIN MICROVASCULATURE STRUCTURE AND FUNCTION IN INDIVIDUALS WITH HEART FAILURE: AN OPTICAL COHERENCE TOMOGRAPHY STUDY

INTRODUCTION Chronic heart failure (CHF) is associated with systemic vasoconstriction and exercise is an integral management strategy. Beneficial adaptations to exercise training in conduit arteries in CHF are well-established, but training-induced alteration in skin microvessels has not been explored, partly due to measurement limitations. Furthermore, the optimal type of exercise for individuals with CHF is not fully determined. This study utilised optical coherence tomography (OCT) to visualise, quantify and compare skin microvessel adaptations to eccentric (ECC) and concentric (CON) cycling interventions. METHODS Patients with CHF (EF<50%) were randomly assigned to either CON or ECC, and both groups underwent supervised training twice weekly for 16wks. Skin microvessel reactivity was measured at week 0 and week 16 using OCT responses to a local heating challenge alongside laser Doppler flowmetry (LDF). RESULTS Nineteen participants (CON n=9; ECC n=10, age 56.7±14.4yrs) completed the intervention. For OCT outcomes, there were no significant within group changes in skin local heating response from Wk0–Wk16 for either CON (Δdiameter: 14.2±3.3 µm vs 13.4±4.5 µm; Δvelocity: 107.6±31.8 µm.s-1 vs 106.4±36.4 µm.s-1; Δflow: 318.8±115.3 pl.s-1 vs 325.0±144.4 pl.s-1; Δdensity: 18.8±4.6% vs 16.5±2.6%) or ECC (Δdiameter: 13.5±4.0 µm vs 11.6±3.3 µm; Δvelocity: 105.9±33.6 µm.s-1 vs 126.3±29.6 µm.s-1; Δflow: 298.4±130.1 pl.s-1 vs 348.1±109.2 pl.s-1; Δdensity: 18.0±5.4% vs 17.5±2.1%), all P>0.050. There were no other differences between groups in response to training (all P>0.05). No significant differences were found in response to local heating by LDF (P>0.05). There were no differences in these variables between groups in response to training (all P>0.050) and no differences in LDF responses (P>0.050). CONCLUSIONS The 16-week cycle exercise program implemented in this study was insufficient to induce any evidence of microvascular adaptation in patients with CHF. Overcoming cutaneous microvascular vasoconstriction in CHF may require more aggressive exercise approaches than those which have induced adaptation in conduit and resistance arterioles.

Association Between Early Patient Characteristics and IgE-Mediated Allergy in the Perioperative Setting

BackgroundEarly recognition of perioperative anaphylaxis, a life-threatening, usually immunoglobulin E [IgE]-mediated, immediate hypersensitivity, is essential, but bedside diagnosis is not always straightforward as clinical presentation may vary. ObjectivesTo describe early characteristics of perioperative immediate hypersensitivity (POH), with a special attention on cutaneous phenotypes, and identify risk factors for IgE-mediated allergy. MethodsWe retrospectively analyzed data from adults with suspected POH who were investigated in two academic medical centers. Multivariable logistic regression was conducted to evaluate associations between patient, clinical, and paraclinical characteristics and IgE-mediated allergy. ResultsOut of 145 patients enrolled, 99 (68.3%) and 46 (31.7%) were respectively categorized in the IgE-mediated allergy and non-allergy groups. Cutaneous vasoconstriction phenotype (pallor, piloerection, thelerethism, sweating ± cyanosis) occurring within minutes (or even one minute) of drug-exposure, was strongly associated with IgE-mediated allergy (adjusted odds ratio [aOR]: 28.02, 95% confidence interval [CI]: 4.41-305.18). IgE-mediated allergy was always life-threatening in this setting. Other early factors associated with allergy were low end-tidal carbon dioxide (ETco2) ≤25mmHg (aOR: 5.45, 95%CI: 2.39-26.45), low mean arterial pressure (MAP) ≤60mmHg (aOR: 3.82, 95%CI: 1.28-17.31), and early cutaneous vasodilation (erythema, urticaria and/or angioedema) (aOR: 2.78, 95%CI: 0.73-20.54). Late cutaneous vasodilation following restoration of hemodynamics corroborated the diagnosis of allergy (aOR: 23.67, 95%CI: 4.94-205.09). The best-fit model including three readily available variables (cutaneous phenotype involving the three modalities [reference lack of cutaneous signs], low MAP and low ETco2) had an AUC of 0.91. ConclusionsCutaneous vasoconstriction phenotype is associated with the strongest risk of life-threatening allergy and may thus be regarded as pathognomonic of perioperative IgE-mediated anaphylaxis.

Neural circuits of long-term thermoregulatory adaptations to cold temperatures and metabolic demands.

The mammalian brain controls heat generation and heat loss mechanisms that regulate body temperature and energy metabolism. Thermoeffectors include brown adipose tissue, cutaneous blood flow and skeletal muscle, and metabolic energy sources include white adipose tissue. Neural and metabolic pathways modulating the activity and functional plasticity of these mechanisms contributenot only to the optimization of function during acute challenges, such as ambient temperature changes, infection and stress, but also to longitudinal adaptations to environmental and internal changes. Exposure of humans to repeated and seasonal cold ambient conditions leads to adaptations in thermoeffectors such as habituation of cutaneous vasoconstriction and shivering. In animals that undergo hibernation and torpor, neurally regulated metabolic and thermoregulatory adaptations enable survival during periods of significant reduction in metabolic rate. In addition, changes in diet can activate accessory neural pathways that alter thermoeffector activity. This knowledge may be harnessed for therapeutic purposes, including treatments for obesity and improved means of therapeutic hypothermia.

Mechanistic involvement of noradrenergic neuronal neurotransmitter release in cutaneous vasoconstriction during autonomic dysreflexia in persons with spinal cord injury

IntroductionAutonomic dysreflexia (AD) is a potentially life-threatening consequence in high (above T6) spinal cord injury that involves multiple incompletely understood mechanisms. While peripheral arteriolar vasoconstriction, which controls systemic vascular resistance, is documented to be pronounced during AD, the pathophysiological neurovascular junction mechanisms of this vasoconstriction are undefined. One hypothesized mechanism is increased neuronal release of norepinephrine and co-transmitters. We tested this by examining the effects of blockade of pre-synaptic neural release of norepinephrine and co-transmitters on cutaneous vasoconstriction during AD, using a novel non-invasive technique; bretylium (BT) iontophoresis followed by skin blood flow measurements via laser doppler flowmetry (LDF). MethodsBretylium, a sympathetic neuronal blocking agent (blocks release of norepinephrine and co-transmitters) was applied iontophoretically to the skin of a sensate (arm) and insensate (leg) area in 8 males with motor complete tetraplegia. An nearby untreated site served as control (CON). Cutaneous vascular conductance (CVC) was measured (CVC = LDF/mean arterial pressure) at normotension before AD was elicited by bladder stimulation. The percent drop in CVC values from pre-AD vs. AD was compared among BT and CON sites in sensate and insensate areas. ResultsThere was a significant effect of treatment but no significant effect of limb/sensation or interaction of limb x treatment on CVC. The percent drop in CVC between BT and CON treated sites was 25.7±1.75 vs. 39.4±0.87, respectively (P = 0.004). ConclusionBretylium attenuates, but does not fully abolish vasoconstriction during AD. This suggests release of norepinephrine and cotransmitters from cutaneous sympathetic nerves is involved in cutaneous vasoconstriction during AD.

Hesperetin-7-O-glucoside/β-cyclodextrin Inclusion Complex Induces Acute Vasodilator Effect to Inhibit the Cold Sensation Response during Localized Cold-Stimulate Stress in Healthy Human Subjects: A Randomized, Double-Blind, Crossover, and Placebo-Controlled Study.

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with β-cyclodextrin (HEPT7G/βCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/βCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/βCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.

Nipple Vasospasm of Nursing Mothers.

Background: Nipple vasospasm is a painful cutaneous vasoconstriction that nursing mothers experience after breastfeeding. Case presentations: In this case series, we present the common features and management of nipple vasospasm in nursing mothers. Discussion: The diagnosis of vasospasm relies on the doubt of physician or the breastfeeding consultant and observation of the color change of the nipple. Persistent nipple and breast pain in breastfeeding is often attributed to Candida albicans; thus, many mothers receive antifungal therapy before the diagnosis. Conclusions: Timely diagnosis also prevents unnecessary antimicrobial treatments. Precise and rapid diagnosis is crucial, as pain is a risk factor for cessation of breastfeeding and its exclusivity.

The role of the dorsolateral prefrontal cortex in control of skin sympathetic nerve activity in humans.

The dorsolateral prefrontal cortex (dlPFC) is primarily involved in higher order executive functions, with there being evidence of lateralization. Brain imaging studies have revealed its link to the generation of skin sympathetic nerve activity (SSNA), which is elevated in states of emotional arousal or anxiety. However, no studies have directly explored dlPFC influences on SSNA. Transcranial alternating current stimulation (-2 to 2mA, 0.08Hz, 100cycles) was applied between the left or right dlPFC and nasion via surface electrodes. Spontaneous bursts of SSNA were recorded from the common peroneal nerve via a tungsten microelectrode in 21 healthy participants. The modulation index was calculated for each stimulation paradigm by constructing cross-correlation histograms between SSNA and the sinusoidal stimulus. Stimulation of the dlPFC caused significant modulation of SSNA, but there was no significant difference in the median modulation index across sides. Stimulation also caused cyclic modulation of skin blood flow and sweat release. We have shown for the first time that stimulation of the dlPFC causes modulation of SSNA, also reflected in the effector-organ responses. This supports a role for the dlPFC in the control of SSNA, which likely contributes to the ability of emotions to bring about cutaneous vasoconstriction and sweat release.

Mediobasal hypothalamic neurons contribute to the control of brown adipose tissue sympathetic nerve activity and cutaneous vasoconstriction

The mediobasal hypothalamus (MBH) contains heterogeneous neuronal populations that regulate food intake and energy expenditure. However, the role of MBH neurons in the neural control of thermoeffector activity for thermoregulation is not known. This study sought to determine the effects of modulating the activity of MBH neurons on the sympathetic outflow to brown adipose tissue (BAT), BAT thermogenesis, and cutaneous vasomotion. Pharmacological inhibition of MBH neurons by local administration of muscimol, a GABAA receptor agonist, reduced skin cooling-evoked BAT thermogenesis, expired CO2, body temperature, heart rate, and mean arterial pressure, while blockade of GABAA receptors by nanoinjection of bicuculline in the MBH induced large increases in BAT sympathetic nerve activity (SNA), BAT temperature, body temperature, expired CO2, heart rate, and cutaneous vasoconstriction. Neurons in the MBH send projections to neurons in the dorsal hypothalamic area and dorsomedial hypothalamus (DMH), which excite sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) that control sympathetic outflow to BAT. The increases in BAT SNA, BAT temperature, and expired CO2 elicited by blockade of GABAA receptors in the MBH were reversed by blocking excitatory amino acid receptors in the DMH or in the rRPa. Together, our data show that MBH neurons provide a modest contribution to BAT thermogenesis for cold defense, while GABAergic disinhibition of these neurons produces large increases in the sympathetic outflow to BAT, and cutaneous vasoconstriction. Activation of glutamate receptors on BAT thermogenesis-promoting neurons of the DMH and rRPa is necessary for the increased sympathetic outflow to BAT evoked by disinhibition of MBH neurons. These data demonstrate neural mechanisms that contribute to the control of thermoeffector activity, and may have important implications for regulating body temperature and energy expenditure.

손 냉각과 압박이 조합된 항암 치료용 장갑이 손의 혈관 수축 및 국소 감각에 미치는 영향

This study investigated the combined effects of wrist compression and hand cooling on cutaneous vasoconstriction of the hands to develop chemotherapy gloves that alleviate side-effects of anti-cancer treatments. Eight healthy young females (23 ± 3 y in age, 162 ± 4 cm in height, 60 ± 8 kg in weight, 22.6 ± 3.0 kg•mSUP-2/SUP in body mass index, 29.0 ± 6.6 % body fat) participated in the following three experimental conditions: cooling only with 14℃ (CO), cooling & intermittent compression (CIC), and cooling & continuous compression (CCC). The results showed 1) no significant differences in finger skin blood flow(%) or finger skin temperature among the three conditions, 2) no significant difference in hand skin temperature between the CO and CCC or CIC conditions, and 3) no significant differences in overall thermal sensation or thermal comfort among the three conditions. However, subjects felt more wrist and hand pressure and tingle sensations in the CIC (pressure phase) and CCC conditions than in the CO condition (P0.001). In conclusion, we did not find any synergistic effects on hand skin vasoconstriction from adding wrist compression to hand cooling, and the pressure and tingling sensations were deteriorated by adding the compression band. Therefore, we suggest cooling the hands at 14oC during cancer treatments, rather than adding compression with cooling.

Quantification of catecholamine neurotransmitters released from cutaneous vasoconstrictor nerve endings in men with cervical spinal cord injury.

Control of cutaneous circulation is critically important to maintain thermoregulation, especially in individuals with cervical spinal cord injury (CSCI) who have no or less central thermoregulatory drive. However, the peripheral vasoconstrictor mechanism and capability have not been fully investigated after CSCI. Post- and presynaptic sensitivities of the cutaneous vasoconstrictor system were investigated in 8 CSCI and 7 sedentary able-bodied (AB) men using an intradermal microdialysis technique. Eight doses of norepinephrine (NE, 10-8 to 10-1 M) and five doses of tyramine (TY, 10-8, 10-5 to 10-2 M) were administered into the anterior right and left thigh, respectively. Endogenous catecholamines, noradrenaline, and dopamine, collected at the TY site, were determined by high-performance liquid chromatography with electrochemical detection. Regardless of vasoconstrictor agents, cutaneous vascular conductance decreased dose-dependently and responsiveness was similar between the groups (NE: Group P = 0.255, Dose P = 0.014; TY: Group P = 0.468, Dose P < 0.001), whereas the highest dose of each drug induced cutaneous vasodilation. Administration of TY promoted the release of noradrenaline and dopamine in both groups. Notably, the amount of noradrenaline released was similar between the groups (P = 0.819), although the concentration of dopamine was significantly greater in individuals with CSCI than in AB individuals (P = 0.004). These results suggest that both vasoconstrictor responsiveness and neural functions are maintained after CSCI, and dopamine in the skin is likely to induce cutaneous vasodilation.

Raynaud's Phenomenon: A Brush Up!

Raynaud's Phenomenon: A Brush Up!

Control of blood pressure in the cold: differentiation of skin and skeletal muscle vascular resistance.

What is the central question of this study? Why does blood pressure increases during cold air exposure? Specifically, what is the contribution of skin and skeletal muscle vascular resistance during whole body versus isolated face cooling? What is the main finding and its importance? Whole-body cooling caused an increase in blood pressure through an increase in skeletal muscle and cutaneous vascular resistance. However, isolated mild face cooling caused an increase in blood pressure predominately via an increase in cutaneous vasoconstriction. The primary aim of this investigation was to determine the individual contribution of the cutaneous and skeletal muscle circulations to the cold-induced pressor response. To address this, we examined local vascular resistances in the cutaneous and skeletal muscle of the arm and leg. Thirty-four healthy individuals underwent three different protocols, whereby cold air to clamp skin temperature (27°C) was passed over (1) the whole-body, (2) the whole-body, but with the forearm pre-cooled to clamp cutaneous vascular resistance, and (3) the face. Cold exposure applied to the whole body or isolated to the face increased mean arterial pressure (all, P<0.001) and total peripheral resistance (all, P<0.047) compared to thermal neutral baseline. Whole-body cooling increased femoral (P<0.005) and brachial artery resistance (P<0.003) compared to thermoneutral baseline. Moreover, when the forearm was pre-cooled to remove the contribution of cutaneous resistance (P=0.991), there was a further increase in lower arm vasoconstriction (P=0.036) when whole-body cooling was superimposed. Face cooling also caused a reflex increase in lower arm cutaneous (P=0.009) and brachial resistance (P=0.050), yet there was no change in femoral resistance (P=0.815) despite a reflex increase in leg cutaneous resistance (P=0.010). Cold stress causes an increase in blood pressure through a change in total peripheral resistance that is largely due to cutaneous vasoconstriction with face cooling, but there is additional vasoconstriction in the skeletal muscle vasculature with whole-body cooling.

Effect of aging on cardiovascular responses to cold stress in humans

Abstract Cold exposure increases the risk of adverse events related to cardiovascular causes, especially in the elderly. In this review, we focus on recent findings concerning the impact of aging on the regulatory mechanisms of cold-induced cardiovascular responses. In response to cold exposure, the initial physiological thermoregulation in healthy young persons, such as cutaneous vasoconstriction to reduce heat loss, is attenuated in older individuals, resulting in a reduced ability of the older persons to maintain body temperature in cold environment. Impaired sympathetic skin response, reduced noradrenergic neurotransmitter synthesis, insufficient noradrenergic transmitters, and altered downstream signaling pathways inside the vascular smooth muscle may be among the underlying mechanisms for the maladaptive vasoconstrictive response to cold stress in the elderly. The increase in blood pressure during cold exposure in young persons may be further augmented in aging adults, due to greater central arterial stiffness or diminished baroreflex sensitivity with aging. Cold stress raises myocardial oxygen demand caused by increased afterload in both young and old adults. The elderly cannot adjust to meet the increased oxygen demand due to reduced left ventricular compliance and coronary blood flow with advancing age, rendering the elderly more susceptible to hypothermia-induced cardiovascular complications from cold-related diseases. These age-associated thermoregulatory impairments may further worsen patients' health risk with existing cardiovascular diseases such as hypertension, coronary artery disease, and heart failure. We searched PubMed for papers related to cold stress and its relationship with aging, and selected the most relevant publications for discussion.

Topical Analgesic Containing Methyl Salicylate and L-Menthol Accelerates Heat Loss During Skin Cooling for Exercise-Induced Hyperthermia

Hyperthermia impairs physical performance and, when prolonged, results in heat stroke or other illnesses. While extensive research has investigated the effectiveness of various cooling strategies, including cold water immersion and ice-suit, there has been little work focused on overcoming the cutaneous vasoconstriction response to external cold stimulation, which can reduce the effectiveness of these treatments. Over-the-counter (OTC) topical analgesics have been utilized for the treatment of muscle pain for decades; however, to date no research has examined the possibility of taking advantage of their vasodilatory functions in the context of skin cooling. We tested whether an OTC analgesic cream containing 20% methyl salicylate and 6% L-menthol, known cutaneous vasodilators, applied to the skin during skin cooling accelerates heat loss in exercise-induced hyperthermia. Firstly, we found that cutaneous application of OTC topical analgesic cream can attenuate cold-induced vasoconstriction and enhance heat loss during local skin cooling. We also revealed that core body heat loss, as measured by an ingestible telemetry sensor, could be accelerated by cutaneous application of analgesic cream during ice-suit cooling in exercise-induced hyperthermia. A blunted blood pressure response was observed during cooling with the analgesic cream application. Given the safety profile and affordability of topical cutaneous analgesics containing vasodilatory agents, our results suggest that they can be an effective and practical tool for enhancing the cooling effects of skin cooling for hyperthermia.

Laser speckle contrast imaging and laser Doppler flowmetry reproducibly assess reflex cutaneous vasoconstriction.

Reproducibility of the reflex cutaneous vasoconstriction response is currently unknown. Our aim was to determine the test-retest reproducibility of laser speckle contrast imaging (LSCI) and varying sampling depths of laser Doppler flowmetry (LDF) in response to whole-body cooling. Over two studies, nine and fourteen healthy, young adults underwent a 40-min cooling bout over two separate experiments. Participants were cooled from 34.0°C to 30.5°C and held at a 30.5°C plateau for 10-min prior to rewarming. Throughout the cooling bout, changes in blood flow were measured as LSCI flux and LDF flux for Study 1 and LDF flux by three different LDF sampling depths in Study 2. Test-retest reproducibility and reliability were evaluated by the coefficient of variation (CV) and intraclass correlation coefficients (ICC), respectively. Vasoconstriction was presented as cutaneous vascular conductance (CVC=flux/mean arterial pressure) and expressed as a percent change from baseline (%ΔCVCBASELINE). For Study 1, test-retest reproducibility displayed good reproducibility for LSCI (CV: <9.0%) and good-to-moderate for LDF (CV: <17.0%) throughout the cooling bout and at plateau (LSCI CV: 1.0%; LDF CV: 1.9%). For Study 2, all Doppler depths displayed good reproducibility during the cooling bout (CV: <9.0%) and at plateau (CV: 0.9-2.0%). Only LSCI demonstrated reliability across both studies (ICC: 0.58-0.88). A reduced vasoconstriction response was measured with the shallowest penetration in the skin (LSCI: 26±0.9%ΔCVCBASELINE) compared to the Doppler with the deepest penetration (35±0.6%ΔCVCBASELINE, p<0.001). Although Dopplers better discriminate the reflex cutaneous vasoconstriction response, LSCI exhibits greater test-retest reproducibility and reliability, and thus may be more suitable for longitudinal assessments.

Site-Specific Regulation of Stress Responses Along the Rostrocaudal Axis of the Insular Cortex in Rats.

The insular cortex (IC) has been described as a part of the central network implicated in the integration and processing of limbic information, being related to the behavioral and physiological responses to stressful events. Besides, a site-specific control of physiological functions has been reported along the rostrocaudal axis of the IC. However, a functional topography of the IC in the regulation of stress responses has never been reported. Therefore, this study aimed to investigate the impact of acute restraint stress in neuronal activation at different sites along the rostrocaudal axis of the IC. Furthermore, we evaluated the involvement of IC rostrocaudal subregions in the cardiovascular responses to acute restraint stress. We observed that an acute session of restraint stress increased the number of Fos-immunoreactive cells in the rostral posterior region of the IC, while fewer activated cells were identified in the anterior and caudal posterior regions. Bilateral injection of the non-selective synaptic inhibitor CoCl2 into the anterior region of the IC did not affect the blood pressure and heart rate increases and the sympathetically mediated cutaneous vasoconstriction to acute restraint stress. However, synaptic ablation of the rostral posterior IC decreased the restraint-evoked arterial pressure increase, whereas tachycardia was reduced in animals in which the caudal posterior IC was inhibited. Taken together, these pieces of evidence indicate a site-specific regulation of cardiovascular stress response along the rostrocaudal axis of the IC.

A Foundation for the Neural Control of Viral Fever

Fever, an acute‐phase neurally‐regulated increase in body temperature, is thought to be an adaptive response to optimize host defenses against invading pathogens. However, fever can be an unpleasant symptom of infection and excessive fever (&gt;41oC) can cause irreversible protein denaturation and result in tissue damage, seizure, coma and death. Common therapeutic approaches to fever include the use of non‐steroidal anti‐inflammatory drugs and cyclooxygenase inhibitors, however these approaches are ineffective for reducing prostaglandin‐independent fevers, can interfere with adaptive and innate immune defenses and are contraindicated for use in some viral infections, including SARS‐CoV2. Although research over the past couple of decades has defined the fundamental central nervous system (CNS) pathways necessary for the lipopolysaccharide model of bacterial fever, the CNS circuits mediating viral fevers are almost completely unknown. Double‐stranded RNA is an intermediary in viral replication and serves as a pathogen‐associated molecular pattern that elicits the acute phase responses to viral infection. Systemic administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic double stranded RNA, mimics the acute phase responses to viral infection. Neurons in the rostral raphe pallidus area (rRPa) and the dorsomedial hypothalamus play important roles in the control of the sympathetic outflow to thermoeffectors, therefore we hypothesized that neurons in these areas would be essential for fever elicited by a model of viral fever, intravenous (iv) poly I:C. Female and male Sprague Dawley rats anesthetized with urethane and α‐chloralose (for BAT sympathetic nerve recording, n=3) or isoflurane (for cutaneous vasoconstriction experiments, n=3) received iv poly I:C (1mg/kg for experiments with sympathetic nerve recording, or 500μg/kg for experiments for cutaneous vasoconstriction). Systemically administered poly I:C increased BAT SNA (+601 ± 161% baseline), BAT temperature (TBAT; +3.1 ± 0.8°C), and expired CO2 (+0.9 ± 0.2%). Poly I:C also elicited CVC, as observed by reductions in paw or tail skin temperature (TPAW/TTail) (‐2.6 ± 1.2°C). A nanoinjection of the ionotropic glutamate receptor antagonists, AP5 and CNQX in the rRPa reversed poly I:C‐evoked increases in BAT SNA (‐596 ± 128% baseline), TBAT (‐1.3 ± 0.2°C), and expired CO2 (‐0.5 ± 0.1%). Nanoinjection of AP5 and CNQX into the DMH reversed the polyI:C‐evoked reduction in TPAW/TTail (+2.8 ± 1.1°C). These data suggest that the activity of neurons in the rRPa and the DMH are necessary for poly I:C‐induced activation of BAT thermogenesis and cutaneous vasoconstriction. These data define critical components of the neural circuits for poly I:C‐induced fever, highlight differences between the neural circuitry mediating bacterial fever and viral fever, and provide a foundation for elucidating additional brain mechanisms responsible for viral fever.

Systemic Interleukin‐1β Elicits Cyclooxygenase‐Independent Fever

Interleukin‐1β (IL‐1β) induces neuroimmune responses that help to fight infections. IL‐1β‐induced fever is not abolished by cyclooxygenase (COX) inhibitors used to treat inflammation and the neural pathways responsible for COX‐independent fever are still unknown. Considering that neurons that reside in the rostral raphe pallidus area (rRPa) and in the dorsomedial hypothalamus (DMH) play a key role in the control of thermoeffectors, we hypothesized that neurons in these areas contribute to COX‐independent fever elicited by intravenous (iv) IL‐1β. Female and male Sprague Dawley rats were anesthetized with urethane and α‐chloralose (ur/ch) or isoflurane (iso) and treated with saline or indomethacin, prior to receiving iv IL‐1β. Systemic IL‐1β increased brown adipose tissue (BAT) sympathetic nerve activity (SNA) (+2852 ± 2020% baseline (BL), p = 0.003), BAT temperature (TBAT; +2.6 ± 1.3°C, p &lt; 0.001), expired CO2 (+1.0 ± 0.4%, p &lt; 0.001), core body temperature (TCORE; +0.6 ± 0.2°C, p &lt; 0.001), heart rate (HR; +102 ± 42 bpm, p &lt; 0.001), mean arterial pressure (MAP; +11 ± 7 mmHg, p = 0.002), and paw temperature (TPAW; ‐6.9 ± 1.2°C, p &lt; 0.001), which is an index of cutaneous vasoconstriction (CVC). Indomethacin did not prevent IL‐1β‐evoked increases in BAT SNA (+2545 ± 756% BL, p &lt; 0.001), TBAT (+2.9 ± 1.3°C, p &lt; 0.001), expired CO2 (+1.2 ± 0.6%, p = 0.003), TCORE (+0.9 ± 0.5°C, p = 0.005), HR (+117 ± 47 bpm, p &lt; 0.001), MAP (+27 ± 20 mmHg, p = 0.01), or TPAW (‐5.9 ± 3.4°C, p = 0.02). Nanoinjection of muscimol in the rRPa prevented IL‐1β‐evoked increases in BAT SNA (p &lt; 0.01), TBAT (p &lt; 0.01), expired CO2 (p &lt; 0.01) and TCORE (p &lt; 0.01), but not in HR (p = 0.08), in comparison to the group that received IL‐1β only. Nanoinjection of muscimol in the rRPa in indomethacin‐pretreated rats prevented IL‐1β‐evoked increases in BAT SNA (p &lt; 0.01), TBAT (p &lt; 0.01), expired CO2 (p &lt; 0.01), TCORE (p &lt; 0.01), and TPAW (p = 0.03), but not in HR (p = 0.12), in comparison to an indomethacin‐pretreated group that received IL‐1β. Nanoinjections of glutamate receptor antagonists in the DMH markedly reduced IL‐1β‐evoked increases in BAT SNA (‐838 ± 542% BL, p = 0.03), TBAT (‐1.1 ± 0.4°C, p = 0.003), expired CO2 (‐0.4 ± 0.1%, p = 0.009) and HR (‐38 ± 20 bpm, p = 0.01), and reduced MAP (‐4 ± ‐2 mmHg, p = 0.02). Plasma PGE2 levels following iv IL‐1β were significantly higher (by ~3 fold) in rats that were not anesthetized when receiving IL‐1b (263.1 ± 136.4 pg/ml) compared to all other groups of rats that were maintained under anesthesia for 2 h (ur/ch anesthetized, saline pretreated: 96.7 ± 30.8 pg/ml, p = 0.007, or indomethacin pretreated: 119.7 ± 51.9 pg/ml, p = 0.02; iso anesthetized, saline pretreated: 82.5 ± 21.2 pg/ml, p = 0.003, or indomethacin‐pretreated: 108.4 ± 39.1 pg/ml, p = 0.01). Therefore, we suggest that the anesthetics used inhibited the systemic production of PGE2. Together, our data suggest that a glutamatergic input to the DMH is necessary for providing the excitatory drive for increasing BAT thermogenesis and tachycardia in response to circulating IL‐1β, likely via rRPa neurons. Additionally, IL‐1β‐evoked CVC requires activation of neurons in the rRPa. These data define critical components of the neural circuit for systemic IL‐1β‐induced fever and provide a foundation for elucidating additional brain mechanisms responsible for COX‐independent fever.

Site‐specific regulation of emotional stress responses along the rostrocaudal axis of the insular cortex in rats

The insular cortex (IC) has been described as part of the central network implicated in the behavioral and physiological responses to emotional stress. Besides, it has been reported a site‐specific control of physiological functions along the rostrocaudal axis of the IC. Nevertheless, evaluation of a functional topography of the IC in the regulation of the responses to stressful stimuli has never been documented. Therefore, this study aimed to investigate the impact of acute restraint stress in neuronal activation at different sites along the rostrocaudal axis of the IC in rats. Furthermore, we evaluated the involvement of IC rostrocaudal subregions in the cardiovascular responses to acute restraint stress. For this, male Wistar rats (60‐days‐old) were used. The restraint stress was performed by placing the animals in a cylindrical plastic tube for 60 minutes. For the cardiovascular study, different set of animals had cannula‐guide bilaterally implanted into the anterior, rostral posterior of caudal posterior subregions of the IC; and the non‐selective synaptic inhibitor CoCl2(1mM/100nL) was microinjected 10 min before the restraint onset. We observed that acute restraint stress increased the number of Fos‐immunoreactive cells in the rostral posterior region of the IC (t=2.95, df=14, P=0.0106), while fewer activated cells were identified in the anterior (t=2.44, df=14, P= 0.0276) and caudal posterior (t=2.27, df=14, P=0.0388) regions. Treatment of the anterior region of the IC with CoCl2 did not affect the blood pressure (F(1,15)=0.90, P&gt;0.05) and heart rate (F(1,15)=0.3, P&gt;0.05) increases and the sympathetically‐mediated cutaneous vasoconstriction (F(1,15)=2.23, P&gt;0.05) evoked by restraint stress. However, synaptic ablation of the rostral posterior IC decreased the restraint‐evoked arterial pressure increase (F(1,21)=5.3, P=0.0313), but without affecting the tachycardia (F(1,21)=4.1, P=0.0561) and the reduction in tail skin temperature (F(1,21)=0.05, P&gt;0.05). Besides, bilateral microinjection of CoCl2 into the caudal posterior IC decreased the tachycardia to restraint stress (F(1,17)=11.3, P=0.0036), but without affecting the blood pressure (F(1,17)= 0.2, P&gt;0.05) and tail skin temperature (F(1,17)= 1.4, P&gt;0.05) responses. Taken together, these findings indicate a site‐specific regulation of stress response along the rostrocaudal axis of the IC.

Neural circuits mediating circulating interleukin-1β-evoked fever in the absence of prostaglandin E2 production

Infectious diseases and inflammatory conditions recruit the immune system to mount an appropriate acute response that includes the production of cytokines. Cytokines evoke neurally-mediated responses to fight pathogens, such as the recruitment of thermoeffectors, thereby increasing body temperature and leading to fever. Studies suggest that the cytokine interleukin-1β (IL-1β) depends upon cyclooxygenase (COX)-mediated prostaglandin E2 production for the induction of neural mechanisms to elicit fever. However, COX inhibitors do not eliminate IL-1β-induced fever, thus suggesting that COX-dependent and COX-independent mechanisms are recruited for increasing body temperature after peripheral administration of IL-1β. In the present study, we aimed to build a foundation for the neural circuit(s) controlling COX-independent, inflammatory fever by determining the involvement of brain areas that are critical for controlling the sympathetic outflow to brown adipose tissue (BAT) and the cutaneous vasculature. In anesthetized rats, pretreatment with indomethacin, a non-selective COX inhibitor, did not prevent BAT thermogenesis or cutaneous vasoconstriction (CVC) induced by intravenous IL-1β (2 µg/kg). BAT and cutaneous vasculature sympathetic premotor neurons in the rostral raphe pallidus area (rRPa) are required for IL-1β-evoked BAT thermogenesis and CVC, with or without pretreatment with indomethacin. Additionally, activation of glutamate receptors in the dorsomedial hypothalamus (DMH) is required for COX-independent, IL-1β-induced BAT thermogenesis. Therefore, our data suggests that COX-independent mechanisms elicit activation of neurons within the DMH and rRPa, which is sufficient to trigger and mount inflammatory fever. These data provide a foundation for elucidating the brain circuits responsible for COX-independent, IL-1β-elicited fevers.