Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study.

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution. Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome. Results: Cold stimulated skin temperatures decreased less with LT3 vs. LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P<0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P<0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups. Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611.

Thermoregulatory effects of guava leaf extract-menthol toner application for post-exercise use.

CONTEXT: Psidium guajava L. (Myrtaceae) leaf contains a wide variety of bioactive compounds that contribute valuable effects on human well-being. OBJECTIVE: This study investigates the influence of guava leaf extract-menthol toner on thermoregulation, including perspiration, skin temperature, and recovery heart rate. MATERIALS AND METHODS: This randomised, placebo-controlled clinical trial assessed the effects of the guava leaf extract-menthol toner and placebo with a 1-week washout period. Sixty-four participants were enrolled. The participants exercised on a treadmill until a 75% heart rate reserve was achieved for 5 min, followed by a 5 min post-exercise rest period. The skin temperature and heart rate were then measured before 5 mL of the testing product was sprayed to specific areas of the body, left it for 30 sec before wiped off. Post-exercise perspiration and skin temperatures were collected by sweat patches and measured by the Skin-thermometer ST500, respectively. A 20 min heart rate monitoring period started 10 min after the exercise and measured every 2 min intervals. RESULTS: Use of the toner significantly reduced post-exercise perspiration to approximately half of the baseline and placebo use values (p < 0.05). Furthermore, relative heart rate changes showed no significant differences among the tests (p > 0.05). Skin temperature was also unaffected (p > 0.05). DISCUSSION AND CONCLUSION: Guava leaf extract-menthol toner reduced perspiration by astringent effects but did not influence heat dissipation and did not affect cardiovascular mechanism compared to the controls. Additional cleaning with guava leaf extract-menthol toner could offer better hygiene after a workout.

Associations between peripheral perfusion disorders, mean arterial pressure and dose of norepinephrine administrated in the early phase of septic shock.

The aim of the study was to explore the correlations between peripheral perfusion, mean arterial pressure and the dose-rate of norepinephrine (NE) infused for the treatment of septic shock. The study is retrospective analysis of data acquired prospectively on 57 patients during the first 24 hours after the occurrence of the shock. Clinical and haemodynamic characteristics, skin perfusion parameters (capillary refill time [CRT], mottling score and temperature gradients) and the dose rate of NE infusion were collected. Negative correlations between mean arterial pressure (MAP) and temperature gradients (core-to-toe: P = .03, core-to-index: P = .04) were found and abnormal CRT was associated with lower MAP (P = .02). The dose rate of NE was negatively correlated with temperature gradients (core-to-toe: P = .02, core-to-index: P = .01, forearm-to-index: P = .008) in the overall population. In patients receiving NE for at least 12 hours, the NE dose rate positively was correlated with the mottling score (P = .006), temperature gradients (core-to-toe: P = .04, forearm-to-index: P = .02, core-to-index: P = .005) and CRT (P = .001). The dose of NE administrated was associated with 14-days mortality (odds ration [OR] = 1.21 [1.06-1.38], P = .006) and with 28-days mortality (OR = 1.17 [1.01-1.36], P = 0.04). In conclusion, the study described the presence of correlations between peripheral perfusion and MAP and between peripheral perfusion and the dose rate of NE infusion.

Effects of neurokinin 3 receptor antagonist fezolinetant on hot flash-like symptoms in ovariectomized rats.

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1-10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause.

Effects of Norepinephrine Infusion on Cutaneous Surface Temperatures of the Distal Extremities.

OBJECTIVES: The etiology of vasopressor-induced digital necrosis is poorly understood, but the skin changes resemble those of frostbite, and it is known from experience that patients taking vasopressors have decreased digital temperatures. We aimed to examine the effects of norepinephrine use on surface temperatures of the distal extremities because there have been no studies examining this relation. METHODS: Surface temperatures of all digits, palms, and soles were measured using an infrared thermometer in patients receiving different rates of norepinephrine infusion in the intensive care unit and compared with those not receiving any vasopressors. RESULTS: A total of 101 measurements from 41 unique individuals were obtained. Temperature gradients between the core and the fingertips were consistently more pronounced in those receiving norepinephrine compared with those not receiving norepinephrine and increased with increasing rates of norepinephrine infusion, except with high-dose norepinephrine. Temperature gradients were more pronounced in the toes. CONCLUSIONS: Norepinephrine use was associated with greater core-to-fingertip temperature gradients and were more pronounced in the toes compared with the fingers.

Nitrous oxide improves cardiovascular, respiratory, and thermal stability during prolonged isoflurane anesthesia in juvenile guinea pigs.

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N2 O (ISO+ N2 O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO2 ), and thermal (Tre and Tsk ) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N2 O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N2 O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N2 O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia.

Sustained release buprenorphine effectively attenuates postoperative hypersensitivity in an incisional pain model in neonatal rats (Rattus norvegicus).

Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.

The influence of menthol dose on human temperature regulation and perception.

INTRODUCTION: This study assessed the influence of High (H, 4.13%), Medium (M, 2.0%) and Low (L, 0.1%) doses of menthol on temperature perception and regulation, compared to a Placebo Condition (P). METHOD: Sixteen participants underwent the aforementioned conditions on four separate days. During each test participants rested supine (Environmental conditions: 30 °C, 50% rh) for 30-min before 40 mL of L, M, H or P gel was applied to the anterior upper body, then rested 30-min thereafter. Primary measures included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature (Tre), and skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, sternocleidomastoid). The area under the curve (AUC) from minute 30 to 60 was compared between conditions using relevant non/parametric tests (alpha level = 0.05). RESULTS: A cooling trend in Tre was observed following Placebo gel application, but this significantly (p < 0.05) reversed into a heat storage response in M and H. Both TS and TC significantly differed by condition (p < 0.001) in a dose-dependent manner, with L, M, and H doses eliciting significantly cooler sensations and more discomfort than P (p < 0.05). Irritation significantly differed by condition (p < 0.01) in a dose-dependent manner, with L and M eliciting significantly greater irritation than P (p < 0.01). No other differences were observed. CONCLUSIONS: Menthol exerts perceptual and thermoregulatory effects independent of skin temperature. A menthol dose-dependent perceptual cooling effect was evident with possible saturation at the moderate dose. A dose-dependent alteration in deep body temperature was also evident.

Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress.

NEW FINDINGS: What is the central question of this study? Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress? What is the main finding and its importance? A 7-day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post-supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat-stressed older individuals. ABSTRACT: This study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole-body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7-day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 µmol l-1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole-body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment-by-time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress.

Systemic acyl-ghrelin increases tail skin temperature in rats without affecting their thermoregulatory behavior in a cold environment.

Fasting increases ghrelin that is a peptide hormone with two circulating isoforms, acyl and des-acyl ghrelin. We reported that fasting or des-acyl ghrelin facilitates behavioral thermoregulation in the cold in rats assessed by tail-hiding behavior that was the indicator of rats' thermoregulatory behavior in the cold; however, the effect of acyl-ghrelin on the same process remains to be elucidated. We investigated the effect of acyl-ghrelin on thermoregulatory behavior in the cold in rats. The animals received an intraperitoneal saline or 24 µg acyl-ghrelin injection and were exposed to 27 °C or 15 °C for 2 h, while their body temperature, tail skin temperature, and tail-hiding behavior were constantly monitored. cFos immunoreactive (cFos-IR) cells in the median preoptic area, medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus were counted. Body temperature and the duration of thermoregulatory behavior did not show a significant difference between the acyl-ghrelin-treated and control groups at 15 °C; however, tail skin temperature in the acyl-ghrelin-treated group was higher than that in the control group. The number of cFos-IR cells in the PVN was greater in the control group than that in the acyl-ghrelin-treated group at 27 °C. These results indicate that acyl-ghrelin did not affect behavioral thermoregulation but might affect tail skin temperature in rats in the cold.

Effects of a Standardized Oligomerized-Polyphenol from Litchi chinensis Fruit Extract and Mixed Plant Extract Supplementation on Peripheral Circulation and Cold Sensitivity.

Certain individuals tend to suffer from a cold sensation-particularly in the lower extremities-despite most people not suffering from the same sensation. In Japan, this phenomenon is called "hie-sho" and reduces quality of life for several people, particularly women. A previous study has shown that a standardized oligomerized-polyphenol from Litchi chinensis fruit extract (OPLFE) reportedly causes a significant increase in body surface temperature. The present study aimed to investigate whether supplementation with OPLFE affected peripheral circulation and cold sensitivity. This randomized, double-blind, placebo-controlled trial was performed including 25 participants (age, 45.0±10.4 y; 3 males and 22 females) who were assigned to consume OPLFE, mixed plant extract with OPLFE, or placebo capsules for 14 d. Participants were instructed to relax for 60 min in a temperature-controlled room prior to obtaining measurements. Changes in skin temperature and peripheral blood flow of the middle finger were assessed immediately before and 1, 5, 10, 20, and 30 min after immersion in cold water (10ºC). Participants' height, weight, skin temperature, and blood flow in peripheral tissue were measured; furthermore, their "hie-sho" was measured using the Visual Analog Scale (VAS). Skin temperature and blood flow in peripheral tissue increased in the OPLFE and mixed plant extract with OPLFE groups on day 14 compared with those on day 1. In addition, cold sensitivity in these two groups significantly improved between day 1 and day 14. These findings suggest that OPLFE improves "hie-sho" by increasing peripheral blood flow and skin temperature.

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.

Polydeoxyribonucleotide Exerts Therapeutic Effect by Increasing VEGF and Inhibiting Inflammatory Cytokines in Ischemic Colitis Rats.

Ischemic colitis is resulted from an inadequate blood supply to a segment or entire colon. Polydeoxyribonucleotide (PDRN), extracted from salmon sperm, has been reported to exert anti-inflammatory and anti-ischemic effects through the adenosine A2A receptor (A2AR). We investigated whether PDRN possesses therapeutic effectiveness on ischemic colitis rats. Ischemic colitis was induced by selective devascularization. The skin temperature on the ischemic colitis-induced region was determined. To assess the colonic damage score and collagen deposition, colonic tissue sections were stained with hematoxylin and eosin (H&E), and Masson trichrome staining was performed. Western blot analysis for A2AR, vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6, Bax, Bcl-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) was performed. Skin temperature was increased and mucosal damage and collagen deposition were observed in the affected colonic tissues in the ischemic colitis rats. Expressions of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and inflammatory mediator (COX-2) were upregulated in the ischemic colitis rats. Apoptosis was increased by decreasing the ratio of Bcl-2 to Bax and by suppressing the phosphorylated form of ERK1/2 expression in the ischemic colitis rats. Treatment with PDRN alleviated mucosal damage reduced the expressions of inflammatory cytokines and COX-2 and inhibited apoptosis in the ischemic colitis rats. PDRN treatment more enhanced the expressions of A2AR and VEGF in the ischemic colitis rats. PDRN showed therapeutic effectiveness on ischemic colitis by increasing VEGF expression and inhibiting inflammatory cytokines and COX-2 through enhancing A2AR expression.

Efficacy and safety of ucha-shinki-hwan on korean patients with cold hypersensitivity in the hands and feet: Study protocol clinical trial (SPIRIT Compliant).

BACKGROUND: Cold hypersensitivity in the hands and feet (CHHF) is a common complaint in Asian female population especially in Korea. Due to the symptoms of CHHF the quality of individual's daily life can be degraded. Ucha-Shinki-Hwan (UCHA) is widely used in the treatment of various diseases including CHHF by harmonizing Yin and Yang, and improving the vitality of whole body. However, the efficacy of UCHA as a treatment option of CHHF has not been assessed in trials. Thus, we aimed to investigate the efficacy and safety of UCHA in Korean women with CHHF through this trial. METHODS: This study will be an exploratory, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Korean women aged 19 to 59 years who complaint with CHHF will be enrolled from 5 university affiliated Korean medicine hospitals. A total of 164 subjects will be randomly assigned to a treatment group (UCHA) or a placebo group at a 1:1 ratio. The subjects will receive 2.5 g of either UCHA or placebo three times a day for 8 weeks. The primary outcome will be evaluated with the visual analog scale score of CHHF. The secondary outcome measures will be changes in skin temperature in extremities as measured by using a thermometer and the Korean version of the World Health Organization Quality of Life Scale Abbreviated Version. DISCUSSION: This study will be the first trial to explore the efficacy and safety of UCHA for CHHF patient. This will provide meaningful clinical information on herbal medicine treatment of CHHF and a clinical evidence for planning a full randomized clinical trial. DISCLOSURES AND ACKNOWLEDGMENTS: The authors report no competing interests. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, ID: NCT03790033. Registered on (31 December 2018) PROTOCOL VERSION:: The final approved version of the trial protocol is V1.3. (25 January 2019).

Treprostinil Hydrogel Iontophoresis in Systemic Sclerosis-Related Digital Skin Ulcers: A Safety Study.

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer.

Oral L-Tyrosine Supplementation Improves Core Temperature Maintenance in Older Adults.

INTRODUCTION: During cold exposure, an increase in sympathetic nerve activity evokes vasoconstriction (VC) of cutaneous vessels to minimize heat loss. In older adults, this reflex VC response is impaired thereby increasing their susceptibility to excess heat loss and hypothermia. Because L-tyrosine, the amino acid substrate necessary for catecholamine production, has been shown to augment reflex VC in age skin, we hypothesize that oral ingestion of L-tyrosine will attenuate the decline in core temperature (Tc) during whole-body cooling in older adults. METHODS: In a randomized, double-blind design, nine young (25 ± 3 yr) and nine older (72 ± 8 yr) participants ingested either 150 mg·kg of L-tyrosine or placebo before commencing 90 min of whole-body cooling to decrease skin temperature to approximately 29.5°C. Esophageal temperature and forearm laser Doppler flux (LDF) were measured continuously throughout the protocol to provide an index of Tc and skin blood flow, respectively. The change in esophageal temperature (ΔTES) was the difference in temperature at the end of cooling subtracted from baseline. Cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVCBASELINE). RESULTS: Oral tyrosine ingestion augmented the cutaneous VC response to cooling in older adults (placebo, 14.4 ± 2.0; tyrosine, 32.7% ± 1.7% ΔCVCBASELINE; P < 0.05). Additionally, tyrosine improved Tc maintenance throughout cooling in older adults (placebo, -0.29 ± 0.07; tyrosine, -0.07 ± 0.07 ΔTES; P < 0.05). Both the cutaneous VC and Tc during cooling were similar between young and older adults supplemented with tyrosine (P > 0.05). CONCLUSIONS: These results indicate that L-tyrosine supplementation improves Tc maintenance in response to acute cold exposure in an older population.

Effect of the menstrual cycle phase on foot skin temperature during menthol application in young women.

According to the literature, the arteriovenous anastomoses in the peripheral parts (ex. hands and feet) respond thermal stimulation susceptibly. Thus, the feet are sensitive to cold stimulation. The aim of the present study was to investigate the effect of menstrual cycle on skin temperature (Tsk) of the foot during menthol application in young women. Tsk and partial cutaneous blood flow in the foot, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness during the preovulatory (P), luteal (L), and menstrual (M) phases during menthol application in young women using thermography, laser Doppler flowmetry, a digital blood pressure monitor, and VAS scale were examined at 25 °C. After application of the 0.5% menthol solution to the right foot, the measurements were continued for 20 min. The Tsk of the second and third right toes in the P phase were lower than that in the L phase. The Tsk of the little right toe in the P phase was lower than that in the L and M phases. No significant differences were observed in the Tsk of the dorsum of right foot, cutaneous Laser-Doppler flow in the right great toe, tympanic temperature, blood pressure, heart rate, thermal sensation and pleasantness among the phases. The menstrual cycle phase did not affect Tsk in the dorsum of the foot, but it affected Tsk in some toes during menthol application.

Thermal antinociceptive, sedative and cardiovascular effects of Governing Vessel 1 dexmedetomidine pharmacopuncture in healthy cats.

OBJECTIVE: To compare the antinociceptive, sedative and cardiovascular effects of dexmedetomidine pharmacopuncture at Governing Vessel 1 (GV 1) with dexmedetomidine intramuscular (IM) administration. STUDY DESIGN: Randomized, masked crossover design. ANIMALS: A group of eight healthy female cats. METHODS: Cats were randomly administered either dexmedetomidine (0.005 mg kg-1; Dex-IM) IM or at acupuncture point GV 1 (Dex-P) separated by 1 week. Prior to and up to 120 minutes posttreatment, skin temperature (ST), thermal threshold (TT), heart rate (HR), respiratory rate (fR), sedation, muscle relaxation and auditory response scores were recorded. Parametric data were analyzed using a two-way repeated measures anova followed by Tukey's test for multiple comparisons. Nonparametric data were analyzed using a Friedman test followed by Dunn's multiple comparisons test, and Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons. Significance was set at p ≤ 0.05. RESULTS: There were no differences within or between treatments for ST, fR and auditory response. TT was significantly higher at 30-90 minutes in Dex-P (p ≤ 0.0285) than baseline. TT was significantly higher at 60-90 minutes for Dex-P than for Dex-IM (p ≤ 0.0252). HR was significantly lower at 10-75 minutes in Dex-P (p ≤ 0.0378) and at 5-75 minutes in Dex-IM (p ≤ 0.0132) than baseline. Compared with baseline, sedation scores were higher at 25 minutes (p = 0.0327) and 30 minutes (p = 0.0327), and muscle relaxation scores were higher at 25 minutes (p = 0.0151) and 35 minutes (p = 0.0151) in Dex-P. There were no differences in HR, sedation and muscle relaxation scores between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Dex-P increased thermal antinociception compared with Dex-IM at the same dose of dexmedetomidine in cats. This antinociceptive effect must be evaluated under clinical situations.

Interactions of benzodiazepines with heroin: Respiratory depression, temperature effects, and behavior.

Benzodiazepines are important therapeutic drugs, but they are often abused and co-abused with opioids. Clinical evidence suggests that benzodiazepines can inhibit respiration, and when combined with the respiratory-depressive effects of opioids, may increase likelihood of death. In this study we used oxygen sensors coupled with high-speed amperometry and multi-site thermorecording to examine how intravenous (iv) midazolam, a potent benzodiazepine, modulates the brain hypoxic and temperature effects of iv heroin in freely-moving rats. Oxygen levels and brain temperature were assessed with high temporal resolution in the nucleus accumbens (NAc), an important structure in the motivational-reinforcement circuit. When administered alone, midazolam (2 mg/kg) modestly decreased NAc temperature but had no evident effects on oxygen levels in this structure. In contrast, heroin (0.4 mg/kg) induced a strong decrease in NAc oxygen that was followed by a weaker, rebound-like oxygen increase. Midazolam pretreatment did not affect heroin-induced brain hypoxia but potentiated the initial hypothermia induced by heroin. However, co-administration of these drugs potentiated the heroin-induced oxygen decrease and enhanced heroin-induced brain hypothermia. Co-administration of heroin and midazolam also resulted in enhanced locomotor inhibition and loss of motor control. This effect caused some rats to collapse, resulting in nose and mouth occlusion, which caused a secondary hypoxic phase. These results could have important implications for human drug users, as the combined use of benzodiazepines with potent opioids not only results in sustained brain hypoxia but creates conditions of loss of motor control which could result in asphyxia and death. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.

The antinociceptive effects of intravenous administration of three doses of butorphanol tartrate or naloxone hydrochloride following hydromorphone hydrochloride to healthy conscious cats.

OBJECTIVE: To evaluate thermal antinociception from intravenous (IV) administration of hydromorphone alone or followed by butorphanol or naloxone in cats. STUDY DESIGN: Randomized, controlled, masked, crossover design. ANIMALS: A group of eight adult female cats. METHODS: Cats were administered six treatments of two IV injections 30 minutes apart: treatments S-S, two 0.9% saline; H-S, hydromorphone (0.1 mg kg-1) and saline; H-LB, hydromorphone and butorphanol (0.02 mg kg-1); H-MB, hydromorphone and butorphanol (0.1 mg kg-1); H-HB, hydromorphone and butorphanol (0.2 mg kg-1); H-N, hydromorphone and naloxone (0.04 mg kg-1). Skin temperature (ST), thermal threshold (TT) and sedation score (SS) were recorded before (baseline) and for 8 hours after the first injection. Percentage maximum possible effect (%MPE), thermal excursion (TE), TT, SS and ST were compared using two-way repeated measures anova or Friedman test followed by Tukey's or Dunn's multiple comparisons test when appropriate. Significance was set at p ≤ 0.05. RESULTS: Data from seven cats were analyzed. There were no significant differences among treatments in baseline values, SS and within S-S over time. Compared with respective 0.5 hour values following hydromorphone administration, %MPE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 4-8 hours for H-MB; at 6-8 hours for H-HB and at 1-8 hours for H-N. Compared with respective 0.5 hour values, TE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 2 and 4-8 hours for H-MB; at 6 and 8 hours for H-HB and at 1-8 hours for H-N. CONCLUSIONS AND CLINICAL RELEVANCE: Butorphanol and naloxone reduced hydromorphone-induced thermal antinociception. Butorphanol preserved hydromorphone antinociceptive properties better than naloxone. Butorphanol is recommended during non-life-threatening scenarios as a partial reversal agent for hydromorphone in cats.