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A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers

A Neural Link to Understanding Rosacea: Focusing on Flushing Triggers

A Neural Link to Understanding : Focusing on Triggers

B.D. Gray, DO,* K. Metzler-Wilson, PT, PhD,** K.W. Dawes, MD,*** T.E. Wilson, PhD****

*Intern, OhioHealth O’Bleness Hospital, Athens, OH **Assistant Professor of Neuroscience & Pharmacology, Marian University College of Osteopathic Medicine, Indianapolis, IN ***Dermatologist, Dawes Fretzin Clinical Research Group & Dawes Fretzin Dermatology Group, Indianapolis, IN ****Professor of Physiology, Marian University College of Osteopathic Medicine, Indianapolis, IN

Abstract Facial in rosacea can be triggered by events that do not normally cause sustained flushing. This review discusses why flushing was evolutionarily conserved, how facial flow increases, and how the process can go awry in rosacea. Known mechanisms of increased facial- blood flow associated with thermal/environmental, social/emotional, pharmaceutical/topicals, dietary, and physical-exercise trigger events are explored. Flushing triggers begin with neural (sympathetic, cranial , axon reflex, or sensory afferent) responses inducing (active vasodilation and/or reduced tonic vasoconstriction), fluid extravascularization, and increased vascular volume. Local inflammatory mediators can augment responses, but it is neural responses that initiate the process. We theorize that mechanistically understanding erythema will allow rosacea to be better tolerated and controlled.

Introduction are important, it is the neural events (sympathetic, which decrease associated with Rosacea is a chronic skin disorder most cranial nerve, axon reflex, and sensory afferent) rosacea but do not generally improve the that initiate the trigger. We refer the reader erythema. In contrast, neural (ganglionic, commonly characterized by erythema and α inflammatory lesions in the central region, to a number of excellent reviews and source cholinergic, and -adrenergic) antagonism which affects many people worldwide, including material that cover general information about strategies have been reported to reduce rosacea rosacea, inflammatory and pathological changes erythema.13-15 One interesting approach is the an estimated 16 million people in the United 6-12 α States.1 Disease classification often includes associated with it, and its potential treatment. use of an 2-adrenergic agonist (brimonidine gel), both subtypes and variants. Subtypes include Although etiology is unknown, current FDA- which has recently been approved for treatment of approved treatments in the United States include rosacea erythema. This class of drug can directly erythematotelangiectatic, papulopustular, α phymatous, and ocular rosacea; variants include metronidazole, azelaic acid gel, and doxycycline, cause some vasoconstriction via post-synaptic 2- granulomatous and neurogenic rosacea.2,3 Regardless of classification or whether all patients Table 1. Common rosacea triggers can be adequately classified, most patients present Category Examples Stimulus/Mechanism at some point with induced or permanent facial Sun UV,* local and whole-body heating flushing.4 Hot weather Local and whole-body heating Rosacea erythema, especially in the erythematotelangiectatic subtype, can change Wind Local heating and cooling, irritation, in intensity and is activated by trigger events. AVAs,** blood-pressure effect Erythema triggers vary among patients but can Thermal/ Hot bath, sauna Local and whole-body heating be grouped into categories related to thermal/ Environmental environmental, social/emotional, pharmaceutical/ Cold Local and whole-body cooling, AVAs, topicals, dietary, and exercise (Table 1). In a recent blood-pressure effect National Rosacea Society survey, more than 50% Indoor heat Local and whole-body heating of North American participants reported that Humidity Whole-body heating hot weather and baths, sun and wind exposure, emotional , consumption, and Embarrassment Mental stress exercise all trigger flushing and associated Psychological stress Arousal, blood-pressure effect symptomatology.5 Besides acute erythema, these Social/Emotional Anxiety Mental stress, blood-pressure effect episodes can cause local inflammation, , and painful burning or stinging sensations. Arousal, whole-body heating Chronic and repeated bouts of flushing and Variable associated inflammation can induce structural Skin-care products Irritation, allergic changes in the vasculature (e.g., telangiectasias) Pharmaceutical/Topical and connective , which add to disease signs Cosmetics Irritation, allergic and symptoms. Alcohol Direct effect, gustatory reflex This review addresses what is known about Spicy food Gustatory reflex the neural mechanisms underlying rosacea Heated foods and beverages Gustatory reflex erythema trigger events. We discuss why flushing Dietary was evolutionarily conserved, how blood flow Certain fruits and vegetables Variable, unknown mechanistically increases in facial skin, and how it Dairy Unknown can go awry in disorders such as rosacea. A review Aerobic exercise Whole-body heating with this particular focus, neural mechanisms of Exercise rosacea erythema triggers, has not been previously Resistance exercise Arousal, blood-pressure effect completed. Most mechanistic evaluations of * UV - ultraviolet rosacea have almost exclusively focused on the **AVA - arteriovenous anastomosis inflammatory aspects of the disease; while these

GRAY, METZLER-WILSON, DAWES, WILSON Page 11 adrenergic receptors on vascular smooth muscle face during an embarrassing task corresponds to which includes neurovascular dysregulation but also reduces the release of neurotransmitters an increase in an index of skin blood flow in that and inflammation.12 The subsequent sections α 22 and modulators from these via 2- area. It is thought that embarrassment, and in of the review discuss the neural origins of these adrenergic receptors located presynaptically part , may be a remnant of appeasement erythema triggers based on patient-frequency on the adrenergic axon terminals. Our central display that is observed in some social animals.23 data and trigger categorization. theory is that if rosacea erythema triggers are In sum, flushing should be considered a normal mechanistically understood, better avoidance and physiological response that can aid in providing treatment plans as well as prevention strategies social cues and conveying emotion. Rosacea Erythema Trigger for those more susceptible to this disease state Facial flushing can also participate to a minor Mechanisms can evolve. In rosacea, no erythema trigger is universal.5 In extent in heat dissipation. Humans can lose heat the current review, we refer to triggers as having from the face and head but primarily rely on hairy major (>50% of survey respondents), moderate skin of the rest of the body for heat dissipation. Skin Blood Flow (25%-50%), and minor (<25%) incidence rates To understand the erythema associated with Both in glabrous skin (e.g., nose, ears) and other and will discuss only the major and moderate rosacea, an understanding of the physiology facial areas (e.g., , cheek), blood flow can triggers.5 Rosacea erythema triggers can be of skin blood flow and its measurement is increase during times in which heat dissipation is roughly categorized into five groups (Table 1), required. The advent of many noninvasive necessary, but because of hairy skin’s sheer surface with varied mechanisms of induction of facial indices of skin blood flow (e.g., laser-Doppler area and large blood flow capacity (up to 8 L/min), flushing and associated symptomatology. The flowmetry with both fixed probes and scanners, there is a much greater potential to offload heat 24-26 study of facial blood flow is made more difficult transcutaneous tissue oxygenation, in vivo video in hairy skin. In addition to differences in skin because certain mechanistic pharmacological microscopy, photoplethysmography) has allowed blood flow, there are also neural, anatomical, and 16- procedures (e.g., intradermal microdialysis) measurements of indices of facial blood flow. functional differences between the types of skin 18 cannot be completed in the human face for safety The ease of use of these devices has allowed (Table 2). Notably, there is vasomotor cranial- and ethical reasons. Glabrous skin also suffers for increased utilization, but most dermatology- nerve involvement in facial mucosa and skin but 27 transcutaneous drug delivery difficulties due focused studies do not appropriately control for not in peripheral glabrous and hairy skin. Thus, to its thick epidermal layer. Thus, the majority factors that affect skin blood flow independent for primary heat dissipation, humans rely not on of mechanistic in vivo studies are completed of their treatment paradigm. For instance, not facial flushing but on blood-flow changes in non- in the hairy skin of the , , or thigh. expressing laser-Doppler measures as cutaneous facial hairy skin. Nonetheless, a discussion of erythema triggers as vascular conductance (flux/mean arterial blood If facial flushing is normal during embarrassment they relate to forearm, leg, and palm skin with the pressure) is problematic because and heat-stress conditions, what constitutes a inclusion of face skin when available provides a increases flow independent of changes in luminal flushing disorder? There are a number of factors framework to investigate flushing mechanisms in diameter of the . This is especially 28 and disorders that can cause flushing. The the face and in individuals with rosacea. important as arterial blood-pressure-to-flow differential diagnosis of the rosacea patient who relationships are dissimilar between glabrous presents with flushing, sensitive skin and facial Thermal/Environmental and non-glabrous skin, and many trigger events 7 edema can be difficult. Rosacea’s most visible sign, Whole-body heat stress is a major rosacea flushing are sympathetic nervous system stimulants that facial erythema that fluctuates in intensity with trigger that induces a number of physiological increase arterial blood pressure.19, 20 trigger events, is defined by its pathophysiology, changes to improve the body’s ability to dissipate Also problematic is comparing groups and sites without skin-blood-flow standardization, as Table 2. Characteristic differences between types of absolute values are uninterpretable unless density Type Neural Anatomical Functional of blood vessels and other parameters are known – and in non-invasive studies, these are always Adrenergic vasoconstrictor Surface loops Heat dissipation unknown. Combined with the neural and trigger foci Cholinergic-related discussed above, understanding the physiological vasodilator Hairy mechanisms of skin blood flow, its assessment, Cholinergic sudomotor Tissue insulation and the control factors that govern responses and then applying these concepts to rosacea will provide new insights into this complex disease Adrenergic pilomotor whose etiology is still for the most part unknown. Adrenergic vasoconstrictor Surface capillary loops Grip and dexterity Facial Flushing Facial flushing is common in many mammals for Glabrous Cholinergic sudomotor Arteriovenous display (act of attracting attention or showing anastomoses (AVAs) emotion) and heat dissipation. Humans have retained the capacity to increase blood flow to Cranial nerves Surface capillary loops Display show emotion, such as flushing (blushing) in response to an embarrassing event or in response Adrenergic vasoconstrictor to frustrating circumstances. The questions of where, when, and why blushing occurs are difficult to answer. Charles Darwin said of blushing, “…a Cholinergic-related Arteriovenous Heat dissipation Facial rather curious question why, in most cases the face, vasodilator? anastomoses (AVAs) ears, and alone redden.”21 He hypothesized Cholinergic sudomotor that blushing could be due to generations of focus on the human face, possibly because of its role in communication. Highlighting this Adrenergic pilomotor? phenomenon, focused attention on a part of the

Page 12 A NEURAL LINK TO UNDERSTANDING ROSACEA: FOCUSING ON FLUSHING TRIGGERS 5 α heat. Notably, there are sympathetically proinflammatory photoproducts, such as DNA- conditions, 2C-adrenergic receptors are located mediated increases in rate and cardiac repair enzymes, TNF-α, and other cytokines.52,53 in the Golgi apparatus membrane. Then, with output; vasoconstriction of renal, splanchnic, and Photoproducts associated with tryptophan, mitochondrial ROS stimulation, such as during vasculatures; and vasodilation of another chromophore, increase expression of local cooling, the Golgi apparatus migrates to the skin to facilitate environmental heat transfer.29 COX-2 and thereby catalyze erythema, producing the cell surface and fuses with the existing cell 52 α Glabrous, hairy, and facial skin are under tonic PGE2 and PGE3 during UVB exposure. UVA membrane. This increases 2-adrenergic receptor sympathetic vasoconstrictor tone, as evidenced travels deeper into the skin and thus affects the density, which allows for greater vasoconstrictor by the release of vasoconstriction with ganglionic dermal layer to a greater extent. UVA damage per quanta of norepinephrine released from blockade or presynaptic release inhibitor and is perfusion- and O2-dependent, which heavily sympathetic nerves. To our knowledge, the local the existence of basal skin sympathetic nerve implicates a reactive oxygen species (ROS) cooling response in facial skin has not been activity.20,30-37 All skin types appear to utilize a mechanism.54 Finally, both UVB and UVA described. Facial skin could be different in that release of vasoconstrictor tone to increase skin exposures upregulate both vascular endothelial it has a higher density of sensory afferents, which blood flow during a whole-body heat stress. growth factor and toll-like receptor (TLR) could lead to an augmented counteracting of Peripheral hairy but not glabrous skin also pathways, which could mediate and vasodilation depending on pain and other sensory employs a cholinergic-related active vasodilator cytokine synthesis and secretion.55,56 This latter afferent vasoactive releases.42,59,60 Whether system.32,38 Although peripheral hairy skin has effect may sensitize the skin for subsequent UV- sensory afferent or other neural control of facial functional β-adrenergic receptors, it appears that exposure responses. Whether these UV processes blood flow during local cold stress is altered in facial skin may be more reliant on these receptors are altered in facial compared to peripheral hairy rosacea needs further clarification. during stress.39- 41 It is unknown if facial skin and glabrous skin or in rosacea, however, remains Wind is listed as a distinct and major rosacea also relies on the same cholinergic-related active to be determined. flushing trigger, but the specific temperature is vasodilator mechanism that peripheral hairy skin 5 Whole-body cold stress, a moderate rosacea not accounted for in most surveys. Cold-wind does. Schwab and colleagues identified marked flushing trigger, induces a number of physiological responses may be related to local and whole- vasodilation in affected areas in all subtypes changes to increase tissue insulation and decrease body cooling responses. Wind causes direct skin- of rosacea but did not resolve the vasoactive 5 environmental heat loss. Passive cold stress temperature changes via convective cooling and 42 Additional substance(s) or the origin(s) thereof. does not change cardiac output but causes may also cause irritation and thus induce sensory research is needed to determine whether changes systemic vasoconstriction, thereby increasing afferent responses similar to local cooling. Wind in facial vasodilator mechanisms are implicated in 57,58 vascular resistance and arterial blood pressure. may also dry superficial skin layers, leading to rosacea during whole-body heating. Despite this pressure increase, both peripheral a disruption of the skin barrier. If a hot or cold Local skin heating, also a major rosacea flushing hairy and glabrous skin undergo pronounced wind causes a great enough skin-temperature trigger, induces vasodilation that is sympathetic- decreases in cutaneous vascular conductance change, it may locally exacerbate or attenuate independent but requires adrenergic innervation during whole-body cooling. Peripheral hairy skin skin-blood-flow responses per change in internal for complete expression.5,43-45 This vasodilation normally remains vasoconstricted throughout temperature.61 Another possible cold-wind occurs in a biphasic manner in peripheral hairy a cold stress; however, skin with arteriovenous outcome, if applied directly to the face, is a skin, where the initial vasodilation is primarily anastomoses (e.g., glabrous skin) can oscillate “diving” reflex response that results in decreased due to an axon reflex and the later vasodilation to a between constricted and relaxed states. This heart rate and increased arterial blood pressure.62 nitric-oxide-mediated response.46 Local-heating- cyclical response has been termed the “hunting Experimental “diving” reflex procedures decrease induced vasodilation occurs in facial skin but is reaction,” as it is thought to increase flow to aid skin sympathetic nerve activity to peripheral not consistently observed in peripheral glabrous in dexterity and prevent tissue freezing without glabrous and hairy skin; this reduction in skin.47 Facial (i.e., forehead and cheek) axon reflex losing extraordinary amounts of heat.26 Thus, in vasoconstriction coupled with increased arterial responses follow hairy skin’s biphasic vasodilation response to whole-body cooling, arteriovenous pressure could lead to increased skin blood pattern but are unique in that standard topical anastomosis-rich areas such as the nose, ears, and flow.63,64 Little is known about wind or convective anesthetic protocols are not successful in blunting lips can increase blood flow, although responses cooling, outside the “diving” reflex, in facial skin. the initial, axon-reflex-associated vasodilation.47 in other areas of the face are less clear. Facial Similarly, possible changes in rosacea have yet to Guzman-Sanchez identified increased local heat skin’s absolute vasoconstriction in response to be determined. sensitivities in both erythematotelangiectatic and cooling may also be blunted or absent because papulopustular rosacea.48 This result is consistent many facial locations such as the forehead do not Social/Emotional with an upregulation of the heat-activated appear to contain a high density of cutaneous Emotional stress and anxiety are both major 5 transient receptor potential vanilloid-1 (TRPV1) vasoconstrictor nerves.36 Thus, it is possible that rosacea flushing triggers. Embarrassment is channel in erythematotelangiectatic rosacea and there are regional arteriovenous anastomosis often not precisely delineated in rosacea surveys, greater nerve-fiber densities in all subtypes of responses and less opposition to the increases in but it is a very common cause of increased rosacea.42,49 Thus, it is possible that the face has arterial blood pressure. This could be a mechanism blood flow in facial skin (see Facial Flushing a greater axon-reflex component compared to to decrease blood flow in some facial skin while section) and is likely related to emotional peripheral hairy and glabrous skin and that this increasing skin blood flow to other facial areas stress. The precise mechanisms of emotional- response is heightened in rosacea-affected areas.50 during whole-body cooling. It is possible that the stress-induced flushing are poorly understood. arteriovenous anastomosis response is altered in One theory relates to a catecholamine surge Ultraviolet (UV) exposure associated with 5 patients with rosacea, possibly due to changes in (likely neural due to timing) and associated sunlight is another major rosacea flushing trigger. the neural control of this response. b-adrenergic vasodilation. Peripheral hairy skin This stimulus is likely multifactorial, involving also possesses β-adrenergic receptors but not in whole-body and local heating mechanisms Local cooling can also be a moderate rosacea 5 a great enough density to induce erythema in resulting from UV-induced heat gain in addition flushing trigger. In peripheral hairy skin, locally 39 these areas. Sudomotor activity to peripheral to the unique activity of UV radiation itself. It is applied cold produces biphasic vasomotor glabrous skin increases during embarrassment, unclear whether UVA (320-400) or UVB (290- responses. An initial vasoconstriction is followed but less is known about the response in skin 320 nm) triggers symptoms. Although UVA by a transient vasodilation and then a prolonged blood flow. Validating these observations, mental 46 The mechanisms by which is the dominant component of solar radiation, vasoconstriction. stress increases peripheral glabrous and hairy local cooling causes these vascular changes, 65,66 it requires greater energy to induce a minimal skin sympathetic nerve activity. Mental stress 51 with the exception of α erythema dose. DNA is a chromophore, a 2C-adrenergic receptor also increases supraorbital-skin sympathetic UV-photon absorber, and in response to UVB- translocation, are unclear but likely involve nerve activity, and this increase is accentuated photon bombardment it creates a number of local sensory afferents. Under thermoneutral 67 in those with erythematotelangiectatic rosacea. GRAY, METZLER-WILSON, DAWES, WILSON Page 13 However, Drummond and Su did not observe Spicy-food consumption is also classified as a rosacea, often resulting in exaggerated responses; differences in an index of forehead-skin blood moderate rosacea flushing trigger and may utilize over time, persistent erythema, inflammation, flow in those with rosacea while performing a TRPV1-channel mechanism similar to that of and telangiectasia can develop. Highlighting embarrassing tasks; this is despite those with the oral sensation of heat.5 The classic response these blood-vessel changes, using capillaroscopy, rosacea reporting greater embarrassment and to spicy products is capsaicin-mediated, although Rosina and colleagues described increases in vessel 68 diameters, vessel tortuosity, and telangiectasia intensity of blushing compared to controls. other chemicals that are perceived as spicy could 86 There may be differences in neural responses also be involved. Kashima and Hayashi observed in rosacea-affected areas. Flushing triggers to mental stress vs. embarrassing tasks, but it is increases in an index of skin blood flow throughout are numerous and individualized but can be possible that rosacea symptoms are due in part to the face with oral capsaicin administration.74 grouped into thermal/environmental, social/ emotional, pharmaceutical/topical, dietary, and supraorbital-nerve overactivity or altered issues of Capsaicin-induced vasodilation occurs via exercise-related items. These erythema triggers perception. TRPV1-receptor stimulation, which causes begin with neural events such as sympathetic flushing through the gustatory parasympathetic Pharmaceutical/Topical 30 nervous system, cranial nerve, axon reflex, or vasodilator pathway. This reflex response via a sensory afferent responses. The nervous system, in Certain cosmetics, skin care products, and topical cranial nerve is different from acute or chronic addition to affecting inflammation, both directly medications applied to the face are classified as topical capsaicin administration75,76 As described 5 and indirectly controls blood-vessel diameter moderate rosacea flushing triggers. Defining previously, the increase in TRPV1-receptor gene and thus blood flow. The facial vasculature is this category’s mechanism of action is difficult expression in erythematotelangiectatic rosacea innervated by post-synaptic sympathetic fibers because of the plethora of potential skin care could provide a potential mechanism whereby and cranial nerves and is affected by axon reflexes, products, but it most likely results from either rosacea may result in hyperactive gustatory-reflex sensory nerves, and locally released paracrine skin irritation or an allergic reaction to the responses.49 substances. Because ganglionic blockade, product. Sensory afferent nerves sense skin intradermal botulinum toxin A, and adrenergic irritation, while the wheal and flair response Physical Exercise blockade have been reported to reduce flushing, of a typical allergic reaction involves an axon Physical exercise is another major rosacea flushing potential roles for the sympathetic nervous reflex. It is also possible that these irritations trigger.5 On surveys, this concept is often referred system are implicated.15,30,31,87-89 Individuals with could not only increase skin blood flow but also to as “carrying and lifting” (resistive exercise) or rosacea appear to have overactive supraorbital compromise the skin barrier, leading to increased “walking, running, bicycling” (aerobic exercise). sympathetic responses to mental and physical transepithelial water loss and inflammation. This Physical stress increases arousal, which increases stress, which further implicates this mechanism. disrupted and inflamed facial skin barrier in skin sympathetic-nerve activity to peripheral Cranial nerves participate in cutaneous vasodilation via such responses as axon and rosacea appears to be involved in the increased glabrous and hairy skin as well as facial areas 27 susceptibility to contact and a more independent of changes in metabolism.36,65,77-80 gustatory reflexes. Individuals with rosacea vigorous response to cutaneous irritation.69 Issues The level of effort, but not the amount of muscle may also have altered facial axon reflexes, which could contribute to these augmented reflex associated with rosacea-induced disruption of the mass engaged in the effort, determines the increase 50 responses. When activated, sensory nerves facial skin barrier and how this relates to topicals in peripheral skin sympathetic-nerve activity 79,81,82 release local vasodilator agents (e.g., CGRP and require further research. in response to resistive exercise. Exercise ATP) and can stimulate keratinocytes, sweat task visualization and direct motor-cortex Dietary glands, and mast cells, releasing substances such stimulation increase peripheral skin sympathetic- as prostaglandins, bradykinin, and . Consumption of alcohol (ethanol) is a major nerve activity, indicating that feedback from 5 Prostaglandins, bradykinin, and histamine are rosacea flushing trigger. Alcohol is associated the exercising muscle is not needed to increase potent vasodilators, increase vascular permeability, with small amounts of cutaneous vasodilation, sympathetic activity.83,84 Individuals with rosacea 70 and produce edema. Although still unknown, it especially in the face and periphery. The have augmented supraorbital skin sympathetic- is possible that individuals with rosacea release vasodilation effect is thought to be due to the direct nerve activity to resistive exercise.67 Thus, it is more of these or are sensitized to inflammatory 71 effect of ethanol on vascular smooth muscle. possible that this sympathetic-outflow increase is substances. The current understanding of the Facial flushing is pronounced in individuals with part of the reason for erythema in these patients. pathophysiology of rosacea, including the aldehyde dehydrogenase inactivation due to a The responses of peripheral skin sympathetic- inflammatory cascade involving TLR2 and serine point mutation, but this mutation likely does not nerve activity in rosacea are unknown, and thus protease KLK5 expression and abnormal forms account for alcohol’s potential trigger effect in it is unknown if the augmented responses are of cathelicidin peptides (LL-37 and FA-29), is 72 9,42,90 most individuals with rosacea. It is possible that limited to the face or reflect a global response. described in detail elsewhere. While this either individuals with rosacea are more sensitive inflammatory cascade is important, the neural to cutaneous vasodilation or that the ethanol Aerobic exercise causes an internally generated events initiate these processes. Over time, these induces a gustatory flushing response similar to heat stress. Thus, similar to whole-body heat erythema triggers can also lead to structural that of hot drinks or spicy foods. stress, widespread sympathetically mediated and functional adaptations that characterize the increases in skin blood flow conduct heat to the disease. Understanding these neural links and Hot drinks are classified as a moderate rosacea skin for dissipation. A few caveats associated physiological responses to erythema triggers 5 flushing trigger. Originally it was thought that with aerobic exercise-induced heat stress vs. may help to focus future rosacea treatments on the trigger was related to the in coffee environmental or passive heat stress: 1) There is mechanistically stopping disease progression or tea, but more recent investigations identified an anticipatory or feed-forward aspect of exercise, earlier and potentially in a more individualized 73 an oral-cavity heat effect. Wilkin suggested where peripheral skin sympathetic-nerve activity manner by targeting mechanisms of each that heat draining from the oral cavity into increases prior to the generation and sensation patient’s specific triggers, allowing rosacea to be the jugular heats carotid-artery blood via of heat stress; and 2) internally generated heat better tolerated and controlled. 73 a countercurrent system. While some heat (exercise heat stress) can occur more rapidly than 84,85 exchange occurs between vessels, it is more likely passive heat stress. Further research is needed Acknowledgements that the very warm temperatures (60 °C) cause to determine whether changes in sympathetic or Pilot work67 was conducted through funding a reflex vasodilation as occurs in other gustatory other neural responses during aerobic exercise are 27 from the National Rosacea Society. reflexes. This level of heat stimulates TRPV1 implicated in rosacea. receptors on warm sensory afferents, which could lead to a cranial-nerve reflex response. It is unclear to what extent individuals with rosacea Perspectives and Conclusions Flushing is a normal facial physiologic process have abnormal gustatory reflexes. that becomes hyperactive in individuals with

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