Skin Heating Research Articles

Cold-induced vasodilation in abstinent smokers with and without a 12-hour nicotine patch.

This study was designed to identify the effects of a 12-h nicotine patch administration on cold induced vasodilation (CIVD) in healthy young chronic smokers following 16 h of abstinence from smoking. Two laser Doppler probes and temperature thermocouples were placed on the dorsal part of the distal phalanx of the middle and ring fingers of 7 smokers (>12 cigarettes/day). Following 16 h of abstinence from smoking, smokers were tested with and without administration of a 21mg transdermal nicotine patch (NicoDerm® ). Each participant's right hand was immersed in cold (~5°C) water for 40 min. Cutaneous vascular conductance (CVC) was calculated from non-invasive arterial finger blood pressure and skin blood flow and expressed as a percentage of peak CVC observed during hand skin heating to 44°C. For comparison purposes, the CIVD response of a non-smoking cohort without nicotine patch (n = 10) was also examined. Baseline CVC was similar in smokers and non-smokers (27.8 ± 12.6 CVC % peak). The initial vasoconstriction during cold-water immersion decreased skin blood flow to 4.0 ± 3.9 CVC % peak in both smokers and non-smokers. The onset of CIVD in smokers (4.5 ± 1.5 min) was delayed compared to non-smoker (3.3 ± 0.8 min, p < .05). The area under the CVC %peak-time curve during cold-water immersion averaged 1250 ± 388 CVC %peak · min in non-smokers which was larger (p < .05) than smokers with or without nicotine (789 ± 542 and 862 ± 517 CVC %peak · min, respectively). Chronic smoking impaired the CIVD response to cold-water immersion of the hand; however, the impaired CIVD response in 16 h of abstinence from smoking was not influenced by application of a 21mg transdermal nicotine patch.

Genetic-fuzzy logic model for a non-invasive measurement of a stroke volume

BackgroundDespite the importance of stroke volume readings in understanding the work of the cardiovascular system in patients, its routine daily measurement outside of a hospital in the absence of special equipment presents a problem for a comprehensive assessment of the heart performance. ObjectiveThe purpose of this study was to develop a new non-invasive technique for measuring a stroke volume based on the relationship between time skin warming and a blood flow. Methods. Ninety two randomly selected volunteers (54 males, aged 30.1 ± 11.9 years old, and 38 females, aged 35.8 ± 12.4 years old) were recruited for this study. The time skin warming was determined by applying on the wrist above the arterial pulsation a thermoelectric cooler using the Peltier effect. During recording the participants were in the supine position. Blood pressure was measured by sphygmomanometer. Heart performance was assessed by Murata ballistocardiographic sensor, detecting displacement of the whole body during each cardiac ejection of blood. The data provided by this sensor included heart rate, respiratory rate, heart rate variability and a stroke volume. Linear, non-linear statistical regression models and fuzzy logic were used to analyse the degree of interrelation between BCG-measured stroke volume and the time skin warming. ResultsComparative analysis of results indicated that the generic-fuzzy logic model demonstrated a high level of dependency (R = 0.803) between input (participants’ time skin warming, pulse pressure and age) and output (ballistocardiographic stroke volume) parameters. ConclusionsThe method described in the paper offers a simple, portable, and low-cost solution that can even be used in a home setting to measure the stroke volume. The principle of the proposed method is based on the interrelation between time skin warming and blood flow. The latter, corrected by corresponding age and pulse pressure, expresses the participant's stroke volume. Adopting the genetic-fuzzy model significantly improved the accuracy of stroke volume's measurement and made the proposed method reliable for assessing of the cardiovascular system. This daily practice technique would help healthcare provider get an early diagnosis of cardiac dysfunctions and track heart changes during stress, e.g., in sport.

A Clinical and Biochemical Evaluation of a Temperature-Controlled Continuous Non-Invasive Radiofrequency Device for the Treatment of Melasma.

BackgroundMelasma shows characteristic histological features of photoaged skin.ObjectiveWe evaluated the effect of dermal rejuvenation using a temperature-controlled continuous non-invasive radiofrequency (RF) device on melasma.MethodsContinuous skin heating at the temperature of 43°C for 20 minutes was performed in ten subjects with melasma who underwent 3 tri-weekly RF sessions. Pigmentation was evaluated with Mexameter® and investigator’s global assessment (IGA). Immunohistochemical staining and image analysis was performed to evaluate biopsies from melasma skin before and after the treatment.ResultsThe lesional melanin index was decreased by 13.7% at week 9. IGA score was improved from 3.50 at baseline to 2.95 at week 9. No significant adverse event was reported. Histologic analysis revealed reduced melanin and increased collagen density and thickness. The expression of procollagen-1 and type IV collagen was increased after the treatment. The number of p16INK4A-positive senescent fibroblasts was reduced after the treatment, while the expression of heat shock protein 70 and 90 was increased. Stromal derived factor-1, a senescence-associated anti-melanogenic factor secreted from the fibroblasts, was up-regulated after the treatment, while the level of c-kit was not changed.ConclusionThermal skin stimulation by the temperature-controlled continuous RF device improved melasma through dermal rejuvenation.

Myths and methodologies: Reliability of forearm cutaneous vasodilatation measured using laser-Doppler flowmetry during whole-body passive heating.

Laser-Doppler flowmetry (LDF) is commonly used to assess cutaneous vasodilatation responses, but its reliability (i.e. consistency) during whole-body passive heating is unknown. We therefore assessed the reliability of LDF-derived indices of cutaneous vasodilatation during incremental whole-body heating. Fourteen young men (age: 24 (SD 5) years) completed three identical trials, each separated by 1week. During each trial, a water-perfused suit was used to raise and clamp oesophageal temperature at 0.6°C (low-heat strain; LHS) and 1.2°C (moderate-heat strain; MHS) above baseline. LDF-derived skin blood flow (SkBF) was measured at three dorsal mid-forearm sites, with local skin temperature clamped at 34°C. Data were expressed as absolute cutaneous vascular conductance (CVCabs ; SkBF/mean arterial pressure) and normalised to maximal conductance (%CVCmax ) achieved via simultaneous local skin heating to 44°C and increasing oesophageal temperature to 1.8°C above baseline. Between-day reliability was characterised as measurement consistency across trials, while within-day reliability was characterised as measurement consistency across adjacent skin sites during each trial. Between- and within-day absolute reliability (coefficient of variation) generally improved with increasing heat strain, changing from poor (>25%) at baseline, poor-to-moderate (15-34%) at LHS, and moderate (10-25%) at MHS. Generally, these estimates were more consistent when expressed as %CVCmax . Conversely, relative reliability was mostly acceptable (intraclass correlation coefficient ≥0.70) during LHS and when data were expressed as CVCabs . These findings indicate that the consistency of LDF-derived CVC estimates during heat stress depends on the level of heat strain and method of data expression, which should be considered when designing and interpreting experiments.

Periocular skin warming promotes body heat loss and sleep onset: a randomized placebo-controlled study

Periocular skin warming was reported to have favorable effects on subjective and objective sleep quality. We hypothesized that enhancing body heat loss by periocular skin warming would reduce sleep onset and improve sleep quality. Eighteen healthy volunteers were asked to maintain wakefulness with their eyes closed for 60 min after applying either a warming or sham eye mask, followed by a 60-min sleep period. Compared to the sham, periocular warming increased the distal skin temperature and distal–proximal skin temperature gradient only during the 30-min thermal manipulation period. In the subsequent sleep period, periocular warming facilitated sleep onset, increased stage 2 sleep and electroencephalographic delta activity during the first half of the sleep period relative to the sham. These results suggest that periocular skin warming may accelerate and deepen sleep by enhancing physiological heat loss via the distal skin, mimicking physiological conditions preceding habitual sleep.

KCa channels are major contributors to ATP-induced cutaneous vasodilation in healthy older adults

ObjectiveTo examine the contributions of calcium-activated K+ (KCa) channels and nitric oxide synthase (NOS) to adenosine triphosphate (ATP)-induced cutaneous vasodilation in healthy older adults. MethodsIn eleven older adults (69 ± 2 years, 5 females), cutaneous vascular conductance, normalized to maximum vasodilation (%CVCmax) was assessed at four dorsal forearm skin sites that were continuously perfused with either 1) lactated Ringer solution (Control), 2) 50 mM tetraethylammonium (TEA, KCa channel blocker), 3) 10 mM Nω-nitro-L-arginine (L-NNA, NOS inhibitor), or 4) combined 50 mM TEA +10 mM L-NNA, via microdialysis. Local skin temperature was fixed at 33 °C at all sites with local heaters throughout the protocol while the cutaneous vasodilator response was assessed during coadministration of ATP (0.03, 0.3, 3, 30, 300 mM; 20 min per dose), followed by 50 mM sodium nitroprusside and local skin heating to 43 °C to achieve maximum vasodilation (20–30 min). ResultsBlockade of KCa channels blunted %CVCmax relative to Control from 0.3 to 300 mM ATP (All P < 0.05). A similar response was observed for the combined KCa channel blockade and NOS inhibition site from 3 to 300 mM ATP (All P < 0.05). Conversely, NOS inhibition alone did not influence %CVCmax across all ATP doses (All P > 0.05). ConclusionIn healthy older adults, KCa channels play an important role in modulating ATP-induced cutaneous vasodilation, while the NOS contribution to this response is negligible.

Evidence for wall shear stress-dependent t-PA release in human conduit arteries: role of endothelial factors and impact of high blood pressure.

Tissue plasminogen activator (t-PA) converts plasminogen into the serine protease plasmin, which in turn degrades fibrin clots. This study assessed whether an increase in shear stress is associated in humans in vivo with the release of t-PA in peripheral conduit arteries, the impact of high blood pressure and the role of NO and CYP450-derived epoxyeicosatrienoic acids (EETs). Local t-PA levels were quantified at baseline and during a sustained increase in radial artery wall shear stress induced by hand skin heating (from 34 to 44 °C) in a total of 25 subjects, among whom 8 were newly diagnosed essential hypertensive patients. The impact of the brachial infusion of NO synthase (L-NMMA) and CYP450 inhibitors (fluconazole) on t-PA release was assessed. The increase in shear stress induced by heating was associated with an increase in local t-PA release (from 3.0 ± 0.5 to 19.2 ± 5.5 ng/min, n = 25, P < 0.01). The magnitude of t-PA release was positively correlated with the increase in shear stress (r = 0.64, P < 0.001) and negatively correlated with mean blood pressure (r = -0.443, P = 0.027). These associations persisted after multiple adjustments for confounding factors. Finally, t-PA release was reduced by L-NMMA and to a larger extent by the combination of L-NMMA and fluconazole without a change in shear stress. The increase in wall shear stress in the peripheral conduit arteries induces a release of t-PA by a mechanism involving NO and EETs. The alteration of this response by high blood pressure may contribute to reducing the fibrinolytic potential and enhancing the risk of arterial thrombosis during exercise.

Optical coherence tomography: a novel imaging approach to visualize and quantify cutaneous microvascular structure and function in patients with diabetes

IntroductionThe pathophysiology of microvascular disease is poorly understood, partly due to the lack of tools to directly image microvessels in vivo.Research design and methodsIn this study, we deployed a novel...

Near-infrared heating of skin to delineate non-melanoma skin cancer lesions: A pilot study.

Surgical excision is a mainstay of treatment for non-melanoma skin cancer (NMSC); improving margin delineation can reduce the need for further monitoring/treatment. The objective of this pilot study was to determine if near-infrared radiation (NIR) application to skin causes visible changes in normal and NMSC skin, to help delineate margins. Eleven biopsy-proven NMSC lesions were included. The skin was then heated under a 175W NIR heating bulb; margins were traced onto acetate film before and after heating. Lesions were then randomly assigned to excision based on pre- or post-heating margins. Composite images were generated by overlaying the heat and no-heat lesion contours. All specimens were sent for histopathology. The range of closest margins in the control group was 2.0-3.0mm with a median of 2.0mm; the range in the intervention group was 4.0-9.0mm with a median of 5.0mm. Composite images showed larger heat contours when the initial lesion was larger. There was a statistically significant difference between the two groups. Overall, NIR light caused visible hyperaemia to skin, and more intense erythema to malignant skin lesions. Near-infrared light may have use in an outpatient setting for skin cancer delineation, possibly reducing the rate of positive margins.

Effects of local forearm skin heating on skin properties

This study investigated impacts of local skin heating on skin properties and tested whether skin changes depended on heat-induced hyperaemia. It was reasoned that heat-induced vasodilation impacts accompanying interstitial fluid changes. Forearm skin was locally heated from a baseline of 35°C to 40-42°C in 30 young adults (15 females, 15 males, 24.9±2.1years) and non-heated in 10 others (5 females, 5 males, 25.2±1.3years. Skin blood flow (SBF) was continuously measured using a laser Doppler method and skin tissue dielectric constant (TDC), stratum corneum capacitance (SCC) and transepidermal water loss (TEWL) were measured before and after maintained heat for 12min. TDC values were determined to effective measurement depths of 1.5mm (TDC15) and 2.5mm (TDC25). Results showed a large heat-induced hyperaemia, with SBF increasing on average 8.8-fold from its baseline of 35°C. Heating also caused significant increases in TDC, SCC and TEWL that, compared to preheating, increased approximately 1.1-fold, 3.1-fold and 4.5-fold. None of these skin changes correlated with the magnitude of the SBF hyperaemic response. Absence of this correlation may indicate that in young healthy adults, increased capillary filtration due to heat-induced arteriolar vasodilation is rapidly accommodated by postcapillary reabsorption, enhanced lymphatic activity and TEWL processes. An alternate explanation is that heating caused increased red cell oscillations that were detected as part of the laser Doppler increase without representing increased capillary flux. The major determinant of the Increases in TDC, SCC and TEWL is likely a consequence of heat-induced eccrine gland activation. Studies of older persons or those with depressed function are warranted.

Impact of tetraplegia vs. paraplegia on venoarteriolar, myogenic and maximal cutaneous vasodilation responses of the microvasculature: Implications for cardiovascular disease

Objective: Cardiovascular disease (CVD) is a leading cause of mortality in persons with SCI. While macrovascular remodeling and function after SCI is well documented, changes in the microvascular structure and function are comparably understudied, but importantly predict CVD risk. Specifically, the integrity of venoarteriolar (VAR), myogenic (MYO) and maximal vasodilation responses are largely unknown after SCI, especially in persons with tetraplegia (TP) at highest risk of CVD. This is the first to examine the differences in VAR (cuff inflation), MYO (limb dependency) and maximal vasodilation responses of the microvasculature between able bodied (AB) versus those with TP and paraplegia (PP). Design: Observational. Setting: Laboratory. Participants: Eight AB, 6 TP, and 8 PP persons. Interventions: One forearm and calf were treated topically with lidocaine 2.5%/prilocaine 2.5% while contralateral limb served as a control. Laser doppler flowmeters were applied over treated and control sites during limb dependency, cuff inflation and local skin heating (Tloc) up to 42°C. Outcome measures: Skin vascular resistance (SkVR) change with cuff inflation and limb dependency and maximal cutaneous vascular conductance (CVC) during local heating. Results: Change in SkVR was not significantly different between groups or extremity (upper vs. lower) during cuff inflation or limb dependency. However, CVC at Tloc 42°C was significantly different in the lower extremity (LE) of TP and PP (P = 0.007, 0.35) compared to AB. Conclusion: Increases in SkVR during cuff inflation (VAR) and limb dependency (VAR and MYO) are unaltered after SCI, however maximal vasodilation in the LE post-SCI is higher than AB persons.

Assessment of endothelium-dependent vasodilation in the clinic: what endothelial factor are we studying?

Objective . To study the contribution of the main endothelial vasodilators using different functional tests. Design and methods . Blood flow in the microvessels of the forearm skin was assessed in 30 healthy volunteers (20-21 years) using high-frequency Doppler ultrasound. Three functional tests were performed: iontophoresis with acetylcholine, a test with reactive hyperemia and a temperature test with local heating of the forearm skin to 42 °C. To analyze the mechanisms of endothelium-dependent vasodilation we carried out iontophoresis of vasoactive substances: L-Nitro-Arginine Methyl Ester (L-NAME) — inhibitor of endothelial NO synthase (eNOS), tetraethylammonium (TEA) — inhibitor of endothelial hyperpolarizing factor (EDHF), diclofenac sodium — inhibitor of cyclooxygenase (COX). Results . During the test with acetylcholine was characterized by a rapid increase in the volume rate of blood flow for 2 minutes, from 4 minutes there was a slow decrease in the volume rate of blood flow. The blockade of nitric oxide and prostacyclin led to a slowdown in blood flow growth and the blockade of EDHF to accelerate the recovery of the reaction of microvessels to acetylcholine. In postocclusion test changes in blood flow occur only under blockade of nitric oxide, while the blockade of EDHF and prostacyclin showed no effect on reactive hyperemia. Similar results were obtained by local heating of the skin. Conclusions. Nitric oxide plays a leading role in all tests, including local heat test and flow-mediated dilation. Endothelial hyperpolarizing factor is significant only in the mechanism of acetylcholine-induced vasodilation.

Regional Cutaneous Vasodilator Responses to Rapid Local Heating in Young Women and Men

The cutaneous vasodilator response to rapid, non‐painful, local skin heating is commonly used to test microvascular reactivity in health and disease states. The response is characterized by a transient initial vasodilatory peak that is primarily mediated by cutaneous sensory nerves, followed by a sustained plateau phase that is mainly nitric oxide dependent. While this test is most often performed on the forearm due to ease of administration, examining how local neurovascular (initial peak) and endothelium‐dependent (sustained plateau) vasodilator function varies across the body may provide important knowledge underlying regional differences in cutaneous perfusion. Thus, the purpose of this study was to characterize regional cutaneous vasodilator responses to rapid local skin heating in young adults and to determine if sex modulates these responses. In twenty‐nine (14 women) young adults, cutaneous red blood cell flux (AU, arbitrary units) was measured via laser‐Doppler flowmetry on the anterior calf, anterior thigh, abdomen, dorsal forearm, arm, and chest. Participants rested in the supine position for 30 min with skin sites in all regions controlled at 33°C. Following a 10 min baseline period all sites were rapidly heated to 42°C (1°C×20−s) with local heaters and maintained until a stable plateau was achieved (20–30 min). Sites were then heated to 44°C (20–30 min) to achieve maximum vasodilation. Blood pressure was measured manually every 10 min throughout. Cutaneous vasodilator responses were presented as cutaneous vascular conductance (CVC, AU×mmHg−1), normalized to maximum local heating (%CVCmax). Statistical significance was set at P&lt;0.05 and all comparisons are presented as mean differences (95%CI) relative to the forearm. Baseline, initial peak, and plateau responses represent the combined group (n=29) since there were no sex differences across body regions (all P&gt;0.05). At baseline, only responses at the chest (+5.0[2.2,7.8]%CVCmax), thigh (+4.8[1.9,7.6]%CVCmax), and calf (+4.8[1.4,8.2]%CVCmax) differed from the forearm (all P&lt;0.05). For the initial peak, only the arm (+6.5[0.5,12.5]%CVCmax) and abdomen (−10.0[−17.2,−2.8]%CVCmax) differed from the forearm (both P&lt;0.05). During the sustained plateau phase only the abdomen (−13.7[−19.4,−7.9]%CVCmax) and thigh (−6.0[−9.5,−2.4]CVCmax) differed from the forearm (both P&lt;0.05). During maximum local heating, there was a significant sex by region interaction for absolute CVC (P&lt;0.05). No regional differences in maximum responses were found for women, while for men maximum responses were greater at the thigh (−1.3[−2.1,−0.4] AU×mmHg−1) and calf (−1.3[−2.1,−0.5] AU×mmHg−1) relative to the forearm (both P&lt;0.05). Our findings demonstrate that neurovascular (initial peak) and endothelium‐dependent (sustained plateau) cutaneous vasodilator responses to rapid local heating across the body are similar to the forearm, except for the abdomen, which was attenuated. Further, sex does not modulate these responses in young adults.Support or Funding InformationFunding support: Natural Sciences and Engineering Research Council of Canada (held by Dr. Kenny).

Local Heating Mediated Vasodilation Increased 48 Hours After Remote Ischemic Preconditioning

IntroductionRemote ischemic preconditioning (RIPC), induced by brief periods of blood flow occlusion to a limb followed by reperfusion, protects distant tissues from ischemia‐reperfusion (IR) injury. A single bout of RIPC confers a delayed window of protection that begins 24 hrs after RIPC and last for 2–3 days; however, whether this timeline also applies to the microvasculature is unclear. We hypothesize that the hyperemic response to local heating will increase after a single bout of RIPC.MethodsSixteen healthy, young adults (7M, 9F) underwent a single session of RIPC, which consisted of four periods of inflating an arm cuff to 200mmHg for five min interspersed with five min of reperfusion. Laser speckle contrast imaging (LSCI) was used to measure the hyperemia response to local skin heating (Tsk = 42°C) at five time points; before treatment, and 24, 48, 72, and 168 hrs post‐RIPC. LSCI data are expressed as cutaneous vascular conductance (CVC = LSCI flux/mean arterial pressure).ResultsCompared to pre‐RIPC (1.58 ± 0.09 flux · mmHg−1), the vasodilation response to local heating was increased only at the 48‐hr post‐RIPC time point (24 hrs: 1.59 ± 0.10, 48 hrs: 1.69 ± 0.10, 72 hrs: 1.54 ± 0.13, 160 hrs: 1.53 ± 0.11 flux · mmHg−1).ConclusionThese results indicate that the modest increase in local‐mediation dilation exhibited a delayed response that peaked 48 hrs following a single RIPC bout. This suggests that a single bout of RIPC may have a protective effect on the microvasculature.Support or Funding InformationNASA – Iowa Space Consortium Grant

Cutaneous microvessel circulation and vasomotion responses to local skin heating in women with HIV.

BackgroundPatients infected with the human immunodeficiency virus (HIV) who are well treated by ART still suffer from many complications of microvascular dysfunction. Our previous ex vivo study reported that subcutaneous microvessels from women living with HIV had severe endothelial dysfunction. However, it is unknown whether the microvascular defect is more widespread. We tested the hypothesis that microvascular endothelial, neural and myogenic functions are impaired in women living with HIV compared to control women (control).MethodsWomen with HIV (n = 35) were compared to matched controls (n = 24). HIV infection was virally suppressed on antiretroviral therapy and both groups were enrolled in the DC Women’s Interagency HIV Study (DC – WIHS). Cutaneous blood flow (CBF) was measured by laser Doppler flowmetry (LDF) during an increase of local skin temperature from 33°C to 42°C. Vasomotion responses were analyzed using a wavelet transform to calculate the power of the frequency intervals associated with endothelial (0.0095 ‐0.012Hz), neural (0.021‐0.05Hz) and myogenic (0.051 ‐0.15Hz) activities of the Laser‐Doppler signal. Data are present as mean ± SEM.ResultCBF was increased in both groups with LH at 42°C, but the increases of CBF to heat was lower in HIV infected women than controls (13.9 ± 1.1 vs 15.6 ± 1.2 fold, p&lt;0.05). Vasomotion activities were similar between groups at baseline (33°C) and increased in both groups with LH at 42°C, but the increase was less in HIV compared to controls (13.9 ± 1.1 vs 15.6 ± 1.2 fold change, P &lt;0.05). Moreover, compared to the control group, HIV had lower wavelet amplitude during LH in endothelial (100±3.8 vs 149± 15 PU/Hz/min, P&lt;0.05), neural (92 ± 5 vs 132 ±15 PU/Hz/min, P&lt;0.05) and myogenic (46±3 vs 60 ±7 PU/Hz/min, P=NS) frequency intervals.ConclusionWomen living with HIV have impaired microvascular dysfunction with a complex derangement of microvascular circulatory regulation involving the endothelial, neural and myogenic components. Thus, fully preventing microvascular disease in HIV will require correction of widespread microvascular defects.Support or Funding InformationNational Heart, Lung, and Blood Institute (NHLBI), R01 HL134511

A Physiological Validation of Spectral Analysis for Skin Flowmotion

In a series of studies, our laboratory has utilized microneurography coupled with laser Doppler flowmetry to examine sympathetic neural control of the cutaneous microvasculature during thermoregulatory stimuli. However, these techniques have limited clinical utility. Spectral analysis of the low frequency periodic oscillations in laser Doppler flowmetry‐derived red blood cell flux (i.e., skin flowmotion) is a noninvasive technique that has been used to quantify cutaneous microvascular control mechanisms (e.g., endothelial, neurogenic, myogenic). To date, conclusions regarding the mechanistic regulation of cutaneous microvascular function derived from spectral analysis have been primarily limited to basal conditions. Thus, the aim here was to examine the validity of spectral analysis to quantify sympathetic neural control of skin blood flow during a dynamic physiological stimulus (local skin heating to 42°C). We hypothesized that pharmacological blockade of sensory nerves would reduce the spectral power of the neurogenic frequency band during local heating. Eleven young healthy adults (7 women; 22±3 yrs, 25±2 kg/m2) participated. Laser Doppler flux was measured continuously during baseline (33°C) and a standardized local heating protocol (42°C) at a non‐treated control site (con) and a site treated with topical lidocaine (lido; 2.5% prilocaine+2.5% lidocaine) to pharmacologically block sensory nerves. Topical lido was applied for a minimum of 45 minutes prior to testing. Cutaneous vascular conductance was calculated and expressed as a percentage of maximum (local heat of 43°C). A raw Fourier transform was used to calculate spectral power around the 0.0095–0.02 Hz, 0.02–0.05 Hz, and 0.05–0.15 Hz frequency intervals, considered to correspond to endothelial, neurogenic, and myogenic activity, respectively. The initial peak of the local heating response was reduced by lido, (con: 62±2% vs. lido: 25±5%, p&lt;0.01), validating adequate sensory nerve blockade. However, there was no difference between sites during baseline (con: 12±1% vs. lido: 9±2%, p=0.07) or the local heating‐induced plateau (con: 95±3% vs. lido: 87±7%, p=0.20). There was no effect of lido on spectral power of any of the frequency intervals at baseline or during local heating. Total spectral power (i.e., the sum of the spectral power for all frequency bands) was significantly related to conductance in both sites at baseline (con: R2=0.69, p&lt;0.01; lido: R2=0.72, p&lt;0.01) and during local heating (con: R2=0.22, p&lt;0.02; lido: R2=0.71, p&lt;0.01). In conclusion, the physiological increase in cutaneous vascular conductance during local heating was mirrored by an increase in total spectral power. Although blockade of sensory nerves reduced the increase in conductance during the initial peak of the local heating response, it did not affect the neurogenic frequency interval derived from spectral analysis. These preliminary data suggest that skin flowmotion may not be a valid approach to evaluate neural control of cutaneous microvascular function during dynamic conditions.Support or Funding InformationAmerican Heart Association Grant #18UFEL33900164; College of Health and Human Development Summer 2019 Undergraduate Research Award; Noll Endowment for Undergraduate Research

The Sensory Coding of Warm Perception

SummaryHumans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3−/− triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates.

Cutaneous warmth, but not touch, increases muscle sympathetic nerve activity during a muscle fatigue hand-grip task

In homeostasis, somatosensory C fibre afferents are hypothesised to mediate input to the brain about interactions with external stimuli and sympathetic efference provides the output that regulates bodily functions. We aimed to test this hypothesis and whether different types of innocuous somatosensory input have differential effects. Healthy volunteers performed a muscle fatigue (hand-grip) task to exhaustion, which produces increased muscle sympathetic nerve activity (MSNA), as measured through microneurography. Participants completed the muscle fatigue task without concurrent cutaneous sensory stimulation (control) or we applied skin warming (heat pack) as a C fibre stimulation, slow brush stroking as C and Aβ fibre stimulation, or vibration as Aβ fibre stimulation, to the participant’s forearm. We also measured heart rate, the duration of the hand-grip task, and ratings of pain at the end of the task. Concurrent skin warming showed increased MSNA compared to the other conditions. Tactile stimuli (brushing, vibration) were not significantly different to the control (no intervention) condition. Warming increased the pain from the muscle contraction, whereas the tactile stimuli did not. We interpret the effect of warming on MSNA as providing relevant afferent information during muscle contraction, which needed to be counteracted via vasoconstriction to maintain homeostasis. Brushing and vibration were less homeostatically relevant stimuli for the muscle contraction and hence had no significant effect. The findings add sensory specificity to our current understanding of homeostatic regulation through somatosensory afferent and sympathetic efferent pathways.

Evolution of Analgesic Tolerance and Opioid-Induced Hyperalgesia Over 6 Months: Double-Blind Randomized Trial Incorporating Experimental Pain Models

Contributors to the ongoing epidemic of prescription opioid abuse, addiction, and death include opioid tolerance, withdrawal symptoms, and possibly opioid-induced hyperalgesia (OIH). Thirty stable chronic nonmalignant pain patients entered a 6-month long, randomized, double-blind, dose-response, 2-center trial of the potent opioid levorphanol, conducted over a decade ago during an era of permissive opioid prescribing. Eleven were taking no opioids at study entry and eleven were taking between 35 and 122 morphine equivalents. Five weeks titration preceded twenty weeks stable dosing. Tolerance and OIH were inferred individually based on chronic pain ratings, brief pain inventory scores, and results of the brief thermal sensitization model at 5 opioid dosing sessions.Seventeen patients completed. The average final daily opioid dose was 132; range 14 to 300; average addition 105 morphine equivalents. After observed dosing, the brief thermal sensitization area of hyperalgesia changed minimally but the painfulness of skin heating was reduced. Weekly 0 to 100 visual analog scale pain ratings (average 64 at study entry, 48 at end titration, 45 at end stable dosing) decreased a median 19%, but 8 completed with higher visual analog scale ratings. Three completers had evidence of both tolerance and hyperalgesia. A fully-powered trial similar to this feasibility study is ethically questionable. A large-scale pragmatic trial is more realistic. Trial RegistrationNCT00275249 Evolution of Analgesic Tolerance With Opioids PerspectiveA double-blind, 6-month, high-dose opioid feasibility trial, completed years ago, provides critically important data for clinically defining analgesic tolerance and OIH. Overall benefit was small, and 18% of patients had evidence of both tolerance and OIH. Future work requires a different approach than a classic randomized controlled trial design.

NO-mediated activation of KATP channels contributes to cutaneous thermal hyperemia in young adults

Local skin heating to 42°C causes cutaneous thermal hyperemia largely via nitric oxide (NO) synthase (NOS)-related mechanisms. We assessed the hypothesis that ATP-sensitive K+ (KATP) channels interact with NOS to mediate cutaneous thermal hyperemia. In 13 young adults (6 women, 7 men), cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with 1) lactated Ringer solution (control), 2) 5 mM glibenclamide (KATP channel blocker), 3) 20 mM NG-nitro-l-arginine methyl ester (NOS inhibitor), or 4) a combination of KATP channel blocker and NOS inhibitor. Local skin heating to 42°C was administered at all four treatment sites to elicit cutaneous thermal hyperemia. Thirty minutes after the local heating, 1.25 mM pinacidil (KATP channel opener) and subsequently 25 mM sodium nitroprusside (NO donor) were administered to three of the four sites (each 25-30 min). The local heating-induced prolonged elevation in CVC was attenuated by glibenclamide (19%), but the transient initial peak was not. However, glibenclamide had no effect on the prolonged elevation in CVC in the presence of NOS inhibition. Pinacidil caused an elevation in CVC, but this response was abolished at the glibenclamide-treated skin site, demonstrating its effectiveness as a KATP channel blocker. The pinacidil-induced increase in CVC was unaffected by NOS inhibition, whereas the increase in CVC elicited by sodium nitroprusside was partly (15%) inhibited by glibenclamide. In summary, we showed an interactive effect of KATP channels and NOS for the plateau of cutaneous thermal hyperemia. This interplay may reflect a vascular smooth muscle cell KATP channel activation by NO.