Cutaneous Heat Research Articles

Novel therapies for cancer-induced bone pain

Cancer pain is a growing problem, especially with the substantial increase in cancer survival. Reports indicate that bone metastasis, whose primary symptom is bone pain, occurs in 65–75% of patients with advanced breast or prostate cancer. We optimized a preclinical in vivo model of cancer-induced bone pain (CIBP) involving the injection of Lewis Lung Carcinoma cells into the intramedullary space of the femur of C57BL/6 mice or transgenic mice on a C57BL/6 background. Mice gradually reduce the use of the affected limb, leading to altered weight bearing. Symptoms of secondary cutaneous heat sensitivity also manifest themselves. Following optimization, three potential analgesic treatments were assessed; 1) single ion channel targets (targeting the voltage-gated sodium channels NaV1.7, NaV1.8, or acid-sensing ion channels), 2) silencing µ-opioid receptor-expressing neurons by modified botulinum compounds, and 3) targeting two inflammatory mediators simultaneously (nerve growth factor (NGF) and tumor necrosis factor (TNF)). Unlike global NaV1.8 knockout mice which do not show any reduction in CIBP-related behavior, embryonic conditional NaV1.7 knockout mice in sensory neurons exhibit a mild reduction in CIBP-linked behavior. Modified botulinum compounds also failed to cause a detectable analgesic effect. In contrast, inhibition of NGF and/or TNF resulted in a significant reduction in CIBP-driven weight-bearing alterations and prevented the development of secondary cutaneous heat hyperalgesia. Our results support the inhibition of these inflammatory mediators, and more strongly their dual inhibition to treat CIBP, given the superiority of combination therapies in extending the time needed to reach limb use score zero in our CIBP model.

Methylene blue dose-dependently induces cutaneous inflammation and heat hyperalgesia in a novel rat model.

Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1β and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1β, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.

Role of cholinergic agonists & hyperthermia on regional skin barriers: exposure science implications

Regional differences in skin barrier properties are common in mammals, as some exterior surfaces are fairly impermeable and others are leakier. Neural-induced changes in skin physiology and temperature have the potential to alter skin barrier properties, but the circumstances and mechanisms are unclear. We hypothesized that increasing methylcholine (MCh) or acetylcholine (ACh) concentration would decrease the transepithelial resistance (an index of the skin barrier) measured across mouse paw pad skin jacketed at neutral skin (32°C) or internal (37°C) temperature. Additionally, we hypothesized that paw pads would have lower transepithelial resistance compared to mouse tail skin, and subjecting samples to 40°C (local cutaneous heat stress) would lower transepithelial resistance compared to paw pad skin tested at 32°C. 30 C57BL/6 mouse rear paw pads (containing sweat glands) and 7 mouse tail skins (no sweat glands) were dissected and mounted into a vertical Ussing chamber filled with Kreb’s bicarbonate buffer, gassed with 95% O₂ & 5% CO₂, and encased in a temperature jacket. Transepithelial resistance utilized a current clamp and was measured with Ag-AgCl2 electrodes placed in both epidermal and hypodermal baths during hypodermal-side-only cholinergic dosing (5 min/dose). ACh (0, 0.0833, 0.1666, 0.2499, 0.4166, 0.58323, and 0.74989 M) significantly decreased transepithelial resistance in paw pads clamped at 37°C in a dose-dependent manner. Tail skin had significantly higher transepithelial resistance than paw pad skin. However, transepithelial resistance decreased significantly with MCh (same dosing as ACh) at both skin sites. Increasing jacket temperature to 40°C did not alter the magnitude of decrease in transepithelial resistance to MCh in paw pads compared to 32°C. Transepithelial resistance observations were similar when data were expressed as absolute or relative changes to baseline. Increased ion movement in murine skin (signifying a leakier epithelium) occurred with cholinergic stimulation but not with local hyperthermia, suggesting that neural influences can suffciently affect skin function to directly alter regional skin barriers. P30ES026529 with additional support from TL1TR001997 and R25ES027684. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Defect of the Endogenous Inhibitory Pain System in Idiopathic Restless Legs Syndrome: A Laser Evoked Potentials Study.

Restless legs syndrome (RLS) is a complex sensorimotor disorder. Symptoms worsen toward evening and at rest and are temporarily relieved by movement. Symptoms are perceived as painful in up to 45% of cases, and nociception system may be involved. To assess the descending diffuse noxious inhibitory control in RLS patients. Twenty-one RLS patients and twenty age and sex-matched healthy controls (HC) underwent a conditioned pain modulation protocol. Cutaneous heat stimuli were delivered via laser evoked potentials (LEPs) on the dorsum of the right hand (UL) and foot (LL). N2 and P2 latencies, N2/P2 amplitude and pain ratings (NRS) were recorded before (baseline), during, and after a heterotopic noxious conditioning stimulation (HNCS) application. The baseline/HNCS ratio was calculated for both UL and LL. N2 and P2 latencies did not vary between groups at each condition and limbs. Both groups showed a physiological N2/P2 amplitude and NRS reduction during the HNCS condition in UL and LL in comparison to baseline and post conditions (all, P < 0.003). Between-groups comparisons revealed a significant lower amplitude reduction in RLS at the N2/P2 amplitude during the HNCS condition only for LL (RLS, 13.6 μV; HC, 10.1 μV; P = 0.004). Such result was confirmed by the significant difference at the ratio (RLS, 69%, HC, 52.5%; P = 0.038). The lower physiological reduction during the HNCS condition at LL in RLS patients suggests a defect in the endogenous inhibitory pain system. Further studies should clarify the causal link of this finding, also investigating the circadian modulation of this paradigm. © 2023 International Parkinson and Movement Disorder Society.

Determinants of body core temperatures at fatigue in rats subjected to incremental-speed exercise: The prominent roles of ambient temperature, distance traveled, initial core temperature, and measurement site

Understanding the factors that underlie the physical exercise-induced increase in body core temperature (TCORE) is essential to developing strategies to counteract hyperthermic fatigue and reduce the risk of exertional heatstroke. This study analyzed the contribution of six factors to TCORE attained at fatigue in Wistar rats (n = 218) subjected to incremental-speed treadmill running: ambient temperature (TAMB), distance traveled, initial TCORE, body mass, measurement site, and heat loss index (HLI). First, we ran hierarchical multiple linear regression analyses with data from different studies conducted in our laboratory (n = 353 recordings). We observed that TAMB, distance traveled, initial TCORE, and measurement site were the variables with predictive power. Next, regression analyses were conducted with data for each of the following TCORE indices: abdominal (TABD), brain cortex (TBRAIN), or colonic (TCOL) temperature. Our findings indicated that TAMB, distance traveled (i.e., an exercise performance-related variable), initial TCORE, and HLI predicted the three TCORE indices at fatigue. Most intriguingly, HLI was inversely related to TABD and TBRAIN but positively associated with TCOL. Lastly, we compared the temperature values at fatigue among these TCORE indices, and the following descendent order was noticed - TCOL, TABD, and TBRAIN - irrespective of TAMB where experiments were conducted. In conclusion, TCORE in rats exercised to fatigue depends primarily on environmental conditions, performance, pre-exercise TCORE, and measurement site. Moreover, the influence of cutaneous heat loss on TCOL is qualitatively different from the influence on TABD and TBRAIN, and the temperature values at fatigue are not homogenous within the body core.

The peripheral vascular responses in non-freezing cold injury and matched controls.

What is the central question of this study? Does non-freezing cold injury (NFCI) alter normal peripheral vascular function? What is the main finding and its importance? Individuals with NFCI were more cold sensitive (rewarmed more slowly and felt more discomfort) than controls. Vascular tests indicated that extremity endothelial function was preserved with NFCI and that sympathetic vasoconstrictor response might be reduced. The pathophysiology underpinning the cold sensitivity associated with NFCI thus remains to be identified. The impact of non-freezing cold injury (NFCI) on peripheral vascular function was investigated. Individuals with NFCI (NFCI group) and closely matched controls with either similar (COLD group) or limited (CON group) previous cold exposure were compared (n=16). Peripheral cutaneous vascular responses to deep inspiration (DI), occlusion (PORH), local cutaneous heating (LH) and iontophoresis of acetylcholine and sodium nitroprusside were investigated. The responses to a cold sensitivity test (CST) involving immersion of a foot in 15°C water for 2min followed by spontaneous rewarming, and a foot cooling protocol (footplate cooled from 34°C to 15°C), were also examined. The vasoconstrictor response to DI was lower in NFCI compared to CON (toe: 73 (28)% vs. 91 (17)%; P=0.003). The responses to PORH, LH and iontophoresis were not reduced compared to either COLD or CON. During the CST, toe skin temperature rewarmed more slowly in NFCI than COLD or CON (10min: 27.4 (2.3)°C vs. 30.7 (3.7)°C and 31.7 (3.9)°C, P<0.05, respectively); however, no differences were observed during the footplate cooling. NFCI were more cold-intolerant (P<0.0001) and reported colder and more uncomfortable feet during the CST and footplate cooling than COLD and CON (P<0.05). NFCI showed a decreased sensitivity to sympathetic vasoconstrictor activation than CON and greater cold sensitivity (CST) compared to COLD and CON. None of the other vascular function tests indicated endothelial dysfunction. However, NFCI perceived their extremities to be colder and more uncomfortable/painful than the controls.

Efficiency of cutaneous heat diffusion after local hyperthermia for the treatment of itch.

Today, itching is understood as an independent sensory perception, which is based on a complex etiology of a disturbed neuronal activity and leads to clinical symptoms. The primary afferents (pruriceptors) have functional overlaps with afferents of thermoregulation (thermoceptors). Thus, an antipruritic effect can be caused by antagonizing heat-sensitive receptors of the skin. The ion channel TRP-subfamily V member 1 (TRPV1) is of particular importance in this context. Repeated heat application can induce irreversible inactivation by unfolding of the protein, causing a persistent functional deficit and thus clinically and therapeutically reducing itch sensation. To demonstrate relevant heat diffusion after local application of heat (45°C to 52°C for 3 and 5 seconds) by a technical medical device, the temperature profile for the relevant skin layer was recorded synchronously on ex vivo human skin using an infrared microscope. The results showed that the necessary activation temperature for TRPV1 of (≥43°C) in the upper relevant skin layers was safely reached after 3 and 5 seconds of application time. There were no indications of undesirable thermal effects. The test results show that the objectified performance of the investigated medical device can be expected to provide the necessary temperature input for the activation of heat-sensitive receptors in the skin. Clinical studies are necessary to prove therapeutic efficacy in the indication pruritus.

Detailed organisation of the human midbrain periaqueductal grey revealed using ultra-high field magnetic resonance imaging

The midbrain periaqueductal grey (PAG) is a critical region for the mediation of pain-related behavioural responses. Neuronal tract tracing techniques in experimental animal studies have demonstrated that the lateral column of the PAG (lPAG) displays a crude somatotopy, which is thought to be critical for the selection of contextually appropriate behavioural responses, without the need for higher brain input. In addition to the different behavioural responses to cutaneous and muscle pain – active withdrawal versus passive coping – there is evidence that cutaneous pain is processed in the region of the lPAG and muscle pain in the adjacent ventrolateral PAG (vlPAG). Given the fundamental nature of these behavioural responses to cutaneous and muscle pain, these PAG circuits are assumed to have been preserved, though yet to be definitively documented in humans. Using ultra-high field (7-Tesla) functional magnetic resonance imaging we determined the locations of signal intensity changes in the PAG during noxious cutaneous heat stimuli and muscle pain in healthy control participants. Images were processed and blood oxygen level dependant (BOLD) signal changes within the PAG determined. It was observed that noxious cutaneous stimulation of the lip, cheek, and ear evoked maximal increases in BOLD activation in the rostral contralateral PAG, whereas noxious cutaneous stimulation of the thumb and toe evoked increases in the caudal contralateral PAG. Analysis of individual participants demonstrated that these activations were located in the lPAG. Furthermore, we found that deep muscular pain evoked the greatest increases in signal intensity in the vlPAG. These data suggest that the crude somatotopic organization of the PAG may be phyletically preserved between experimental animals and humans, with a body-face delineation capable of producing an appropriate behavioural response based on the location and tissue origin of a noxious stimulus.

Cutaneous heat and light-induced pain thresholds in post-traumatic headache attributed to mild traumatic brain injury.

The purpose of this study was to characterize cutaneous heat and light-induced pain thresholds in people with post-traumatic headache (PTH) compared with healthy controls (HCs). Photophobia and allodynia are common in PTH, and there is emerging evidence to support multimodal sensory dysfunction. In this age- and sex-matched cohort study, individuals with PTH (n=20) and HCs (n=20), aged 18-65 years, were recruited from an institutional database of research volunteers, from the concussion clinic, and via the use of approved flyers posted on the Mayo Clinic Campus in Scottsdale, Arizona. Participants were assessed using the Allodynia Symptom Checklist (ASC-12), Photosensitivity Assessment Questionnaire (PAQ), State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI). Quantitative sensory testing quantified heat pain thresholds. A light stimulation device quantified light-induced pain thresholds. Subsequently, heat pain thresholds were obtained immediately, 10, and 40min after a bright light stressor. The mean photophobia symptom severity score, based on the PAQ, was higher in participants with PTH compared with HCs, mean 0.62 (SD=0.25) versus mean 0.24 (SD=0.24), p<0.001. Light-induced pain thresholds were lower in participants with PTH (median=90.5lux and quartiles=17.8 to 378.5) compared with HCs (median=863.5lux and quartiles=519.9 to 4906.5) and were independent from BDI and STAI (p<0.001). Allodynia scores did not differ between participants with PTH and HCs after adjusting for BDI and STAI scores. Baseline forehead heat pain thresholds were not different, participants with PTH mean 41.9°C (SD=0.89) versus HCs mean 44.3°C (SD=0.89), p=0.061; however, forearm heat pain thresholds were lower in participants with PTH compared with HCs, mean 40.8°C (SD=0.80) versus mean 44.4°C (SD=0.80), p=0.002. The forehead heat pain threshold change from baseline post bright light stressor in participants with PTH versus HCs was different immediately (mean -1.2 (SD=0.53), p=0.025), 10min (mean -1.8 (SD=0.74), p=0.015), and 40min (mean -1.8 (SD=0.88), p=0.047). The forearm heat pain threshold change immediately post bright light stressor in participants with PTH versus HCs was different, mean -1.9°C (SD=0.58), p=0.001, however, not different at 10 and 40min. Photophobia is higher and light-induced pain thresholds are lower in participants with PTH. Exposure to a light stressor reduced heat pain thresholds in participants with PTH immediately post bright light stressor, but not in HCs. This study provides evidence for multimodal sensory dysfunction in people with PTH.

Cutaneous Microvascular Responses to Local Heating on Ventral and Dorsal Aspects of the Forearm

The cutaneous microvasculature is considered a representative vascular bed and is regularly used to interrogate the mechanisms of microvascular function in healthy and diseased humans. For instance, cutaneous dilation in response to local heating can provide an index of nitric oxide (NO) bioavailability. While the skin of the forearm is typically used for local heating studies, some studies have used the ventral forearm while others have used the dorsal forearm skin for this assessment. Since the dorsal aspect of the forearm typically has more hair and receives greater sun exposure than the ventral side, there is speculation that cutaneous dilation may differ from one side of the forearm to the other, in magnitude and/or mechanism. As such, studies utilizing different sides of the forearm may not be comparable. Therefore, we aimed to test the hypothesis that cutaneous local heating responses differ between the ventral and dorsal aspects of the forearm in response to the two most common temperature stimuli, 39°C and 42°C.MethodsTen young, normotensive individuals (6 men/4 women, age: 26 ± 2 years) were studied on two separate occasions separated by 2‐7 days. At each visit, 4 intradermal microdialysis fibers were placed in either the ventral or dorsal forearm, in a random order. Two fibers were perfused with Ringer’s solution to serve as control sites and the other 2 fibers were perfused with 10 mM N(G)‐Nitro‐L‐arginine methyl ester (L‐NAME) to inhibit NO synthase. Red blood cell flux (RBCF) was assessed at all sites via laser Doppler flowmetry. Each pair of sites (control and L‐NAME) was heated to either 39°C or 42°C for ~40‐45 min until RBCF plateaued. All sites were then infused with 28 mM sodium nitroprusside and heated to 43°C to establish maximal RBCF. Cutaneous vascular conductance (CVC) was calculated as RBCF / mean arterial pressure measured during the plateau and maximal phases. Plateau results are reported as a percentage of maximal CVC at each respective site. The relative NO contribution is reported as: [(control plateau – L‐NAME plateau)/control plateau] x 100.ResultsNo differences were observed at the control site between ventral and dorsal aspects of the forearm when heated to 39°C (62 ± 13 vs. 62 ± 16 % CVCmax, P=0.99). Likewise, the heating response to 42°C was similar across the forearm (ventral: 90 ± 9 vs. dorsal: 86 ± 12% CVCmax, P=0.21). The relative contribution of NO to the plateau was comparable across the forearm at 39°C (ventral: 70 ± 20 vs. dorsal: 66 ± 21%, P=0.71) and 42°C (ventral: 63 ± 16 vs. dorsal: 69 ± 11%, P=0.11).DiscussionThese preliminary findings suggest that cutaneous vasodilation elicited by local heating is similar on both sides of the forearm at both 39°C and 42 °C. Additionally, it appears that the relative contribution of NO to local heating‐induced microvascular vasodilation is not different across the forearm.

Perioperative Prewarming: Heat Transfer and Physiology.

To appreciate the strategy of prewarming, perioperative personnel should have a basic understanding of the physics of heat transfer and the thermoregulatory pathophysiology of anesthesia. The dominant cause of postinduction hypothermia is anesthesia-related redistribution of heat within the body; the role of cutaneous heat loss is minimal. Physiologic thermoregulatory system changes that occur in response to anesthesia make it almost impossible to reverse intraoperative hypothermia. However, prewarming is an effective strategy to prevent postinduction hypothermia from redistribution because it creates a temporary excess of heat in the body's peripheral thermal compartment. Perioperative nurses should implement active and passive prewarming strategies in accordance with the warming devices at their facility and available time. This article focuses on two major topics necessary to understand prewarming: the effect of anesthesia on postinduction thermoregulation and thermodynamic conditions that successful treatment strategies must exploit to produce desired outcomes.

Metabolic trade-offs favor regulated hypothermia and inhibit fever in immune-challenged chicks.

The febrile response to resist a pathogen is energetically expensive, while regulated hypothermia seems to preserve energy for vital functions. We hypothesized here that immune-challenged birds facing metabolic trade-offs (reduced energy supply/increased energy demand) favor a regulated hypothermic response at the expense of fever. To test this hypothesis, we compared 5day old broiler chicks exposed to fasting, cold (25°C), and fasting combined with cold with a control group fed under thermoneutral conditions (30°C). The chicks were injected with saline or with a high dose of endotoxin known to induce a biphasic thermal response composed of a drop in body temperature (Tb) followed by fever. Then Tb, oxygen consumption (metabolic rate), peripheral vasomotion (cutaneous heat exchange), breathing frequency (respiratory heat exchange) and huddling behavior (heat conservation indicator) were analyzed. Irrespective of metabolic trade-offs, chicks presented a transient regulated hypothermia in the first hour, which relied on a suppressed metabolic rate for all groups, increased breathing frequency for chicks fed/fasted at 30°C, and peripheral vasodilation in chicks fed/fasted at 25°C. Fever was observed only in chicks kept at thermoneutrality and was supported by peripheral vasoconstriction and huddling behavior. Fed and fasted chicks at 25°C completely eliminated fever despite the ability to increase metabolic rate for thermogenesis in the phase correspondent to fever when it was pharmacologically induced by 2,4-dinitrophenol. Our data suggest that increased competing demands affect chicks' response to an immune challenge, favoring regulated hypothermia to preserve energy while the high costs of fever to resist a pathogen are avoided.

The role of peripheral transient receptor potential vanilloid 1 channels in stress-induced hyperthermia in rats subjected to an anxiogenic environment

Anxiety resulting from psychogenic stimuli elicit stress-induced hyperthermia in rats, often called “psychogenic fever”, which is part of a coordinated response to situations seen as novel or distressing. Brain transient receptor potential vanilloid 1 (TRPV1) channels modulate both thermoregulation and animal behavior; however, the role of peripheral TRPV1 channels in regulating these responses during exposure to an anxiogenic environment has not been determined. Thus, the present study aimed to investigate the involvement of abdominal TRPV1 channels in stress-induced hyperthermia and behavior in rats subjected to an unconditioned anxiety test. Desensitized rats (peripheral desensitization of TRPV1 channels with resiniferatoxin; RTX) and their respective controls were subjected to a 15-min open field (OF) test. The core body temperature (Tcore), tail skin temperature (Tskin), and rats’ movements inside the arena were recorded. The OF test induced a similar increase in Tcore in both groups throughout the exposure time; however, at the recovery period, the RTX-treated rats had a slower reduction in Tcore due to lower tail skin heat loss. Tskin decreased significantly in both groups during exposure to OF but, during recovery, the RTX-treated rats showed impaired skin vasodilation. Also, RTX-treated rats entered fewer times and spent less time in the OF center square, suggesting an anxiety-related behavior. Our findings indicate that, under stressful conditions, peripheral TRPV1 channels modulate thermoregulatory and behavioral responses. The TRPV1 desensitization induces a more prolonged hyperthermic response due to lower cutaneous heat dissipation, alongside a more evident anxiety-like behavior in rats subjected to the OF apparatus.

The passive leg movement technique for assessing vascular function: the impact of baseline blood flow.

What is the central question of this study? The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA): what is the impact of baseline CFA blood flow on the PLM response? What is the main finding and its importance? Although an attenuated PLM response is not an obligatory consequence of increased baseline CFA blood flow, increased blood flow through the deep femoral artery will diminish the response. Care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performing a PLM vascular function assessment. The passive leg movement (PLM) assessment of vascular function utilizes the blood flow response in the common femoral artery (CFA). This response is primarily driven by vasodilation of the microvasculature downstream from the deep (DFA) and, to a lesser extent, the superficial (SFA) femoral artery, which facilitate blood flow to the upper and lower leg, respectively. However, the impact of baseline CFA blood flow on the PLM response is unknown. Therefore, to manipulate baseline CFA blood flow, PLM was performed with and without upper and lower leg cutaneous heating in 10 healthy subjects, with blood flow (ultrasound Doppler) and blood pressure (finometer) assessed. Baseline blood flow was significantly increased in the CFA (∼97%), DFA (∼109%) and SFA (∼78%) by upper leg heating. This increase in baseline CFA blood flow significantly attenuated the PLM-induced total blood flow in the DFA (∼62%), which was reflected by a significant fall in blood flow in the CFA (∼49%), but not in the SFA. Conversely, lower leg heating increased blood flow in the CFA (∼68%) and SFA (∼160%), but not in the DFA. Interestingly, this increase in baseline CFA blood flow only significantly attenuated the PLM-induced total blood flow in the SFA (∼60%), and not in the CFA or DFA. Thus, although an attenuated PLM response is not an obligatory consequence of an increase in baseline CFA blood flow, an increase in baseline blood flow through the DFA will diminish the PLM response. Therefore, care should be taken to ensure that a genuine baseline leg blood flow is obtained prior to performance of a PLM vascular function assessment.

Estimation of heat exchanges in Boer crossbred goats maintained in a climate chamber.

Exposure of goats to high air temperatures can induce physiological and behavioral adjustments, increasing the dissipation of excess body heat in the latent form, and intensification of the use of these thermoregulatory tools can result in physiological and productive damage to animals. With this, the objective of the research was to quantify the levels of thermal stress and the sensible and latent heat losses of Boer crossbred goats submitted to different air temperatures, in a climatic chamber. Six male crossbred goats of the Boer breed, with an average weight of 25.06±4.43kg and mean age of six months, were grouped using a completely randomized design, with three treatments (air temperatures of the 26, 30 and 34°C, respectively) and six replicates (animals) with 68% relative humidity. The temperature and relative humidity of the air were collected to calculate the temperature and humidity index (THI) and heat exchanges. Were collected the physiological responses rectal temperature (RT) and surface (ST) and respiratory rate (RF), with these data were estimated the heat exchanges by radiation (L), convection (Cr), total sensitive (Gs), latent of the respiratory tract (Er), cutaneous (Ec), total latent (Et) and total heat exchange (Wt). It was found that the THI values were classified as thermal comfort, moderate stress and very stressful, respectively, in the three conditions evaluated. With the increase in AT, the animals significantly increased (P<0.05) the RT, ST and RF, and consequently reduced sensitive heat exchanges, from 38 to 8%, and increased latent heat exchanges, from 62 to 92%, when compared air temperatures of 26 and 34°C, respectively. Physiological responses showed a significant negative (P<0.05) correlation with sensitive heat exchanges and a positive correlation with latent heat exchanges. In very stressful thermal conditions, the animals lost almost all of the excess metabolic heat by latent means (skin and respiratory tract).

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Independent effects of rapid eye movement sleep deprivation and exposure to environmental heat stress on aerobic performance and thermoregulatory responses in exercising rats

ABSTRACT Evidence indicates that aerobic performance is degraded either by environmental heat stress or sleep deprivation. However, whether these conditions interact to produce more significant performance impairment deserves further investigation. Therefore, this study investigated the effects of experimental sleep deprivation (24 h or 96 h) on aerobic performance and thermoregulatory responses in rats exercised on a treadmill at different environmental conditions. Adult male Wistar rats were subjected to rapid eye movement sleep deprivation (RSD) using the modified multiple platform method and were then subjected to an incremental-speed exercise until they were fatigued. Treadmill running was performed in a temperate (24°C) or warm (31°C) environment, and the colonic temperature (an index of core body temperature; TCORE) and the tail-skin temperature (TSKIN; an index of cutaneous heat loss) were recorded. 24-h and 96-h RSD produced small magnitude reductions in aerobic performance (Cohen’s d = 0.47–0.58) and minor changes in thermoregulation. Relative to control rats, sleep-deprived rats showed a higher TCORE at the exercise initiation and a higher threshold for activating cutaneous heat loss, but unchanged TCORE and TSKIN at fatigue. Exercise at 31°C induced large reductions in performance (d = 0.82–1.29) and marked changes in thermoregulation, as evidenced by higher TCORE and TSKIN at fatigue, compared to exercise at 24°C. Interestingly, none of the effects induced by RSD were exacerbated by environmental heat stress and vice-versa, indicating that both conditions did not interact. We conclude that RSD and heat stress modulate aerobic performance and thermoregulatory responses by acting independently.

Impaired thermoregulation in spontaneously hypertensive rats during physical exercise is related to reduced hypothalamic neuronal activation.

This study aimed to evaluate the physical exercise-induced neuronal activation in brain nuclei controlling thermoregulatory responses in hypertensive and normotensive rats. Sixteen-week-old male normotensive Wistar rats (NWRs) and spontaneously hypertensive rats (SHRs) were implanted with an abdominal temperature sensor. After recovery, the animals were subjected to a constant-speed treadmill running (at 60% of the maximum aerobic speed) for 30min at 25°C. Core (Tcore) and tail-skin (Tskin) temperatures were measured every minute during exercise. Ninety minutes after the exercise, the rats were euthanized, and their brains were collected to determine the c-Fos protein expression in the following areas that modulate thermoregulatory responses: medial preoptic area (mPOA), paraventricular hypothalamic nucleus (PVN), and supraoptic nucleus (SON). During treadmill running, the SHR group exhibited a greater increase in Tcore and an augmented threshold for cutaneous heat loss relative to the NWR group. In addition, the SHRs showed reduced neuronal activation in the mPOA (< 49.7%) and PVN (< 44.2%), but not in the SON. The lower exercise-induced activation in the mPOA and PVN in hypertensive rats was strongly related to the delayed onset of cutaneous heat loss. We conclude that the enhanced exercise-induced hyperthermia in hypertensive rats can be partially explained by a delayed cutaneous heat loss, which is, in turn, associated with reduced activation of brain areas modulating thermoregulatory responses.

Painful Cutaneous Electrical Stimulation vs. Heat Pain as Test Stimuli in Conditioned Pain Modulation.

Different paradigms can assess the effect of conditioned pain modulation (CPM). The aim of the present study was to compare heat pain, as an often used test stimulus (TS), to painful cutaneous electrical stimulation (PCES), having the advantage of the additional recording of PCES-related evoked potentials. In 28 healthy subjects we applied heat and PCES at the dominant hand as test stimulus (TS) to compare the CPM-effect elicited by hand immersion into cold water (10 °C) as conditioning stimulus (CS). Subjects rated the pain intensity of TS at baseline, during and 5 min after CS application and additionally of CS, on a numerical rating scale (NRS) (0–100). The ‘early’ (during CS–before CS) and ‘late’ (after CS–before CS) CPM-effects were analyzed. Parallel to the PCES, the related evoked potentials were recorded via Cz to evaluate any changes in PCES-amplitudes. CS reduced significantly the pain intensity of both PCES and heat pain as TS. On a group level, the CPM-effect did not differ significantly between both paradigms. Both early and late CPM-effect based on PCES correlated significantly with the CS pain intensity (r = −0.630 and −0.503, respectively), whereas using heat pain the correlation was not significant. We found a significant reduction of PCES-amplitudes during CS, but this did not correlate with the PCES-induced pain intensity. Correlation with the CS painfulness (r = −0.464) did not achieve the significance level after Bonferroni correction. The extent of the CPM effects was similar in both testing paradigms at group level, despite intraindividual differences. Future studies should further elicit the exact mechanisms explaining the modality of these specific differences.

Global warming, heat-related illnesses, and the dermatologist.

Global warming, provoked by the greenhouse effect of high levels of atmospheric gases (most notably carbon dioxide and methane), directly threatens human health and survival. Individuals vary in their capacity to tolerate episodes of extreme heat. Because skin is the organ tasked with heat dissipation, it is important for dermatologists to be versed in the physiology of cutaneous heat dissipation and cognizant of clinical settings in which the skin’s thermoregulatory responses may be impaired. When the external temperature is lower than that of the skin, the skin releases internal heat through direct thermal exchange with the environment, a process that is aided by an expansion of cutaneous blood flow and eccrine sweating. Cooling through the evaporation of sweat is effective even when the external temperature exceeds that of skin. Many factors, including environmental and physiological (e.g., age and sex), and pathological (e.g., preexisting illnesses, disorders of eccrine function, and medications) considerations, affect the skin’s capacity to thermoregulate. Identification of individuals at increased risk for heat-related morbidity and mortality will become increasingly important in the care of patients.