Activation mechanism of the mouse cold-sensing TRPM8 channel by cooling agonist and PIP2.

The transient receptor potential melastatin 8 (TRPM8) channel is the primary molecular transducer responsible for the cool sensation elicited by menthol and cold in mammals. TRPM8 activation is controlled by cooling compounds together with the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Our knowledge of cold sensation and the therapeutic potential of TRPM8 for neuroinflammatory diseases and pain will be enhanced by understanding the structural basis of cooling agonist- and PIP2-dependent TRPM8 activation. We present cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gating pathway. Our results uncover two discrete agonist sites, state-dependent rearrangements in the gate positions, and a disordered-to-ordered transition of the gate-forming S6-elucidating the molecular basis of chemically induced cool sensation in mammals.

Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age = 22 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC = flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p > 0.05). After 30 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, p = 0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16 ± 0.04 vs. 0.29 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, p = 0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p > 0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.

The Effect of Isolated and Combined Application of Menthol and Carbohydrate Mouth Rinses on 40 km Time Trial Performance, Physiological and Perceptual Measures in the Heat.

The current study compared mouth swills containing carbohydrate (CHO), menthol (MEN) or a combination (BOTH) on 40 km cycling time trial (TT) performance in the heat (32 °C, 40% humidity, 1000 W radiant load) and investigates associated physiological (rectal temperature (Trec), heart rate (HR)) and subjective measures (thermal comfort (TC), thermal sensation (TS), thirst, oral cooling (OC) and RPE (legs and lungs)). Eight recreationally trained male cyclists (32 ± 9 y; height: 180.9 ± 7.0 cm; weight: 76.3 ± 10.4 kg) completed familiarisation and three experimental trials, swilling either MEN, CHO or BOTH at 10 km intervals (5, 15, 25, 35 km). The 40 km TT performance did not differ significantly between conditions (F2,14 = 0.343; p = 0.715; η2 = 0.047), yet post-hoc testing indicated small differences between MEN and CHO (d = 0.225) and MEN and BOTH (d = 0.275). Subjective measures (TC, TS, RPE) were significantly affected by distance but showed no significant differences between solutions. Within-subject analysis found significant interactions between solution and location upon OC intensity (F28,196 = 2.577; p < 0.001; η2 = 0.269). While solutions containing MEN resulted in a greater sensation of OC, solutions containing CHO experienced small improvements in TT performance. Stimulation of central CHO pathways during self-paced cycling TT in the heat may be of more importance to performance than perceptual cooling interventions. However, no detrimental effects are seen when interventions are combined.

Modality-Specific Modulation of Temperature Representations in the Spinal Cord after Injury.

Different types of tissue injury, such as inflammatory and neuropathic conditions, cause modality-specific alternations on temperature perception. There are profound changes in peripheral sensory neurons after injury, but how patterned neuronal activities in the CNS encode injury-induced sensitization to temperature stimuli is largely unknown. Using in vivo calcium imaging and mouse genetics, we show that formalin- and prostaglandin E2-induced inflammation dramatically increase spinal responses to heating and decrease responses to cooling in male and female mice. The reduction of cold response is largely eliminated on ablation of TRPV1-expressing primary sensory neurons, indicating a crossover inhibition of cold response from the hyperactive heat inputs in the spinal cord. Interestingly, chemotherapy medication oxaliplatin can rapidly increase spinal responses to cooling and suppress responses to heating. Together, our results suggest a push-pull mechanism in processing cold and heat inputs and reveal a synergic mechanism to shift thermosensation after injury.SIGNIFICANCE STATEMENT In this paper, we combine our novel in vivo spinal cord two-photon calcium imaging, mouse genetics, and persistent pain models to study how tissue injury alters the sensation of temperature. We discover modality-specific changes of spinal temperature responses in different models of injury. Chemotherapy medication oxaliplatin leads to cold hypersensitivity and heat hyposensitivity. By contrast, inflammation increases heat sensitivity and decreases cold sensitivity. This decrease in cold sensitivity results from the stronger crossover inhibition from the hyperactive heat inputs. Our work reveals the bidirectional change of thermosensitivity by injury and suggests that the crossover inhibitory circuit underlies the shifted thermosensation, providing a mechanism to the biased perception toward a unique thermal modality that was observed clinically in chronic pain patients.

Development of a "Cooling" Menthol Energy Gel for Endurance Athletes: Effect of Menthol Concentration on Acceptability and Preferences.

Menthol is effective at stimulating thermosensitive neurons that evoke pleasant cooling sensations. Internal application of menthol can be ergogenic for athletes, and hence, addition of menthol to sports nutrition products may be beneficial for athletes. The aim of this study was to develop a menthol energy gel for consumption during exercise and to determine acceptability and preferences for gels with different menthol concentrations. With a randomized, crossover, and double-blind placebo-controlled design, 40 endurance athletes (20 females) ingested an energy gel with a menthol additive at a high (0.5%; HIGH) or low concentration (0.1%; LOW), or a mint-flavored placebo (CON), on separate occasions during outdoor endurance training sessions. The athletes rated the gels for cooling sensation, mint flavor intensity, sweetness, and overall experience and provided feedback. Results are reported as median (interquartile range). Both menthol gels successfully delivered a cooling sensation, with a significantly greater response for HIGH (5.0 [4.0-5.0]) compared with LOW (3.5 [3.0-4.0]; p = .022) and CON (1.0 [1.0-2.0]; p < .0005), and LOW compared with CON (p < .0005). Ratings of mint flavor intensity followed the same trend as cooling sensation, while ratings of overall experience were significantly worse for HIGH (2.0 [1.0-3.0]) compared with LOW (4.0 [2.0-4.0]; p = .001) and CON (4.0 [3.0-4.0]; p < .0005). An energy gel with the addition of menthol at 0.1-0.5% provides a cooling sensation for athletes with a dose-response when ingested during exercise. The 0.1% concentration is recommended to maximize the overall experience of the gel.

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.

Differential genetic risk for methamphetamine intake confers differential sensitivity to the temperature-altering effects of other addictive drugs.

Mice selectively bred for high methamphetamine (MA) drinking (MAHDR), compared with mice bred for low MA drinking (MALDR), exhibit greater sensitivity to MA reward and insensitivity to aversive and hypothermic effects of MA. Previous work identified the trace amine-associated receptor 1 gene (Taar1) as a quantitative trait gene for MA intake that also impacts thermal response to MA. All MAHDR mice are homozygous for the mutant Taar1 m1J allele, whereas all MALDR mice possess at least one copy of the reference Taar1 + allele. To determine if their differential sensitivity to MA-induced hypothermia extends to drugs of similar and different classes, we examined sensitivity to the hypothermic effect of the stimulant cocaine, the amphetamine-like substance 3,4-methylenedioxymethamphetamine (MDMA), and the opioid morphine in these lines. The lines did not differ in thermal response to cocaine, only MALDR mice exhibited a hypothermic response to MDMA, and MAHDR mice were more sensitive to the hypothermic effect of morphine than MALDR mice. We speculated that the µ-opioid receptor gene (Oprm1) impacts morphine response, and genotyped the mice tested for morphine-induced hypothermia. We report genetic linkage between Taar1 and Oprm1; MAHDR mice more often inherit the Oprm1 D2 allele and MALDR mice more often inherit the Oprm1 B6 allele. Data from a family of recombinant inbred mouse strains support the influence of Oprm1 genotype, but not Taar1 genotype, on thermal response to morphine. These results nominate Oprm1 as a genetic risk factor for morphine-induced hypothermia, and provide additional evidence for a connection between drug preference and drug thermal response.

Effect of intravenous dexamethasone on the anaesthetic characteristics of peripheral nerve block: a double-blind, randomised controlled, dose-response volunteer study.

BACKGROUND: Intravenous dexamethasone is thought to prolong the duration of peripheral nerve block, but the dose-response relationship remains unclear. The aim of this volunteer study was to evaluate the dose-response effect of i.v. dexamethasone on the prolongation of median nerve block. METHODS: In a double-blind, randomised controlled study, 18 volunteer subjects received two median nerve blocks separated by a washout period. One block was conducted alongside an infusion of saline and the other alongside i.v. dexamethasone 2, 4, or 8 mg. The primary outcome was time to return of normal pinprick sensation. Secondary outcomes included thermal quantitative sensory testing (QST) for the time to return of cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), area under QST curves, grip strength, and the incidence of adverse effects. RESULTS: The primary outcome, time to recovery of pinprick sensation, was similar between volunteers receiving saline or i.v. dexamethasone, regardless of dose (P=0.99). The time to recovery of QST milestones was similar between groups, although area under QST curves indicated prolongation of CDT (0 vs 8 mg, P=0.002) and WDT (0 vs 2 mg, P=0.008; 0 vs 4 mg, P=0.001; 0 vs 8 mg, P<0.001). There was no difference in motor recovery or adverse effects. CONCLUSIONS: Intravenous dexamethasone failed to significantly prolong the duration of pinprick anaesthesia regardless of dose. However, area under QST curve analysis indicated a dose-independent prolongation of CDT and WDT, the clinical significance of which is unclear. CLINICAL TRIAL REGISTRATION: NCT02864602 (clinicaltrials.gov).

Ranirestat Improved Nerve Conduction Velocities, Sensory Perception, and Intraepidermal Nerve Fiber Density in Rats with Overt Diabetic Polyneuropathy.

Distal sensory-motor polyneuropathy is one of the most frequent diabetic complications. However, few therapies address the etiology of neurodegeneration in the peripheral nervous systems of diabetic patients. Several metabolic mechanisms have been proposed as etiologies of this polyneuropathy. In this study, we revisited one of those mechanisms, the polyol pathway, and investigated the curative effects of a novel strong aldose reductase inhibitor, ranirestat, in streptozotocin-induced diabetic rats with preexisting polyneuropathy. Twelve weeks after the onset of diabetes, rats which had an established polyneuropathy were treated once daily with a placebo, ranirestat, or epalrestat, over 6 weeks. Before and after the treatment, nerve conduction velocities and thermal perception threshold of hindlimbs were examined. After the treatment, intraepidermal fiber density was evaluated. As an ex vivo assay, murine dorsal root ganglion cells were dispersed and cultured with or without 1 µmol/l ranirestat for 48 hours. After the culture, neurite outgrowth was quantified using immunological staining. Sensory nerve conduction velocity increased in diabetic rats treated with ranirestat (43.3 ± 3.6 m/s) compared with rats treated with placebo (39.8 ± 2.3). Motor nerve conduction velocity also increased in the ranirestat group (45.6 ± 3.9) compared with the placebo group (38.9 ± 3.5). The foot withdrawal latency to noxious heating was improved in the ranirestat group (17.7 ± 0.6 seconds) compared with the placebo group (20.6 ± 0.6). The decrease in the intraepidermal fiber density was significant in the diabetic placebo group (21.6 ± 1.7/mm) but not significant in the diabetic ranirestat group (26.2 ± 1.2) compared with the nondiabetic placebo group (30.3 ± 1.5). Neurite outgrowth was promoted in the neurons supplemented with ranirestat (control 1446 ± 147 µm/neuron, ranirestat 2175 ± 149). Ranirestat improved the peripheral nervous dysfunctions in rats with advanced diabetic polyneuropathy. Ranirestat could have potential for regeneration in the peripheral nervous system of diabetic rats.

The effect of intradermal microdosing of a transient receptor potential cation channel subfamily V member 1 antagonist on heat evoked pain and thermal thresholds in normal and ultraviolet-C exposed skin in healthy volunteers.

BACKGROUND: Three TRPV1 (Transient Receptor Potential Vanilloid Receptor 1) antagonists were developed for testing in situ in human skin (Sjögren et al., 2016; Sjögren et al., 2018; Sjögren et al., 2018). The first human study using these compounds and capsaicin, was performed to determine the required local antagonist concentrations needed for target engagement (Proof of Mechanism, PoM) (Sjögren et al., 2018). In this paper, the aim was to address a TRPV1 antagonist's ability to inhibit a more complex pain signal and to define translational endpoints that could be used in further drug development, when progressing orally bioavailable TRPV1 antagonists as novel analgesic medications. METHOD: This was a single centre, placebo-controlled, clinical proof of principle (PoP) study in 25 healthy volunteers. The subjects were exposed to UV irradiation, causing a local tissue inflammation. Three different doses of AZ12048189 were administered to assess pain perception through quantitative sensory testing (QST) and erythema using Laser Doppler scanning. RESULTS: AZ12048189 increased the warmth detection threshold (WDT) and the heat pain threshold (HPT) and decreased the intensity of supra threshold heat pain (STHP). AZ12048189 did not, however, have any significant effects as assessed using mechanical stimulation or Laser Doppler. CONCLUSIONS: This study validated translational tools to confirm target engagement for TRPV1 antagonists; WDT, HPT and STHP have utility in this respect, after oral administration of a TRPV1 antagonist. This study also proved that TRPV1 antagonists can inhibit a more complex, non-capsaicin dependent thermally induced pain signal.

Naltrexone alters responses to social and physical warmth: implications for social bonding.

Socially warm experiences, when one feels connected to others, have been linked with physical warmth. Opioids, hypothesized to support social bonding with close others and, separately, physical warmth, may underlie both experiences. In order to test this hypothesis, 80 participants were randomly assigned to the opioid antagonist, naltrexone or placebo before neural and emotional responses to social and physical warmth were collected. Social and physical warmth led to similar increases in ventral striatum (VS) and middle-insula (MI) activity. Further, feelings of social connection were positively related to neural activity to social warmth. However, naltrexone (vs placebo) disrupted these effects by (i) reducing VS and MI activity to social and physical warmth, (ii) erasing the subjective experience-brain association to social warmth and (iii) disrupting the neural overlap between social and physical warmth. Results provide additional support for the theory that social and physical warmth share neurobiological, opioid receptor-dependent mechanisms and suggest multiple routes by which social connections may be maintained.

The infusion of menthol into the esophagus evokes cold sensations in healthy subjects but induces heartburn in patients with gastroesophageal reflux disease (GERD).

Recent studies in animal models have reported that some afferent fibers innervating the esophagus express the cold receptor TRPM8. In the somatosensory system the stimulation of TRPM8 leads to cold sensations and in certain circumstances alleviates pain. It is therefore hypothesized in this paper that the esophageal infusion of the TRPM8 activator menthol evokes cold sensations from the esophagus and alleviates heartburn in humans. The esophageal infusion of menthol (3 mM, 20 min) evoked cold sensations in 11 of 12 healthy subjects. In striking contrast, the esophageal infusion of menthol evoked heartburn in 10 of 10 patients with gastroesophageal reflux disease (GERD). In healthy subjects the cold sensation evoked by menthol was perceived only as a minor discomfort as evaluated by the visual analog scale (VAS score 1.9 ± 0.3 on the scale 1-10). However, in patients with GERD the menthol-induced heartburn was perceived as painful (VAS score 5.6 ± 0.6, P < 0.01 compared to healthy subjects). It is concluded that the sensations evoked by esophageal infusion of menthol change from relatively nonpainful cold sensations in healthy subjects to painful heartburn sensations in patients with GERD. These qualitative and quantitative changes indicate substantial alterations in afferent signaling mediating sensations from the esophagus in patients with GERD.

Adductor canal block with a suture-method catheter - A parallel or perpendicular approach?

BACKGROUND: We performed a randomised blinded pilot study in 16 healthy volunteers to assess whether placing a suture-method catheter in the adductor canal is feasible with two different insertion techniques. METHODS: Each volunteer had a suture-method catheter placed approximately halfway between the superior anterior iliac spine and base of the patella in both legs. Catheters were placed using a parallel technique in one leg and a perpendicular technique in the other leg, according to randomisation. 15 mL lidocaine 1% was injected in each catheter. Successful placement was defined as loss of cold sensation in the saphenous area 30 min after injection. Volunteers were sent home and returned the following day and another dose of lidocaine (15 mL, 1%) was injected through the catheters. Catheter displacement distance was assessed by ultrasound and cold sensation was assessed. In case of preserved cold sensation, we attempted to reposition the catheter with a subsequent injection of lidocaine and reassessment of cold sensation. RESULTS: All primary placements were successful using the perpendicular approach (100%; 95% CI 81%-100%) whereas one placement failed using the parallel approach (94%; 95% CI 72%-99%). Three catheters placed using the perpendicular approach were displaced on day 2, compared to one catheter placed with the parallel approach. Displacement distance was highly variable. All catheters, except one, could be repositioned. Three volunteers reported transient sensory deficits lasting approximately 6-8 weeks. CONCLUSION: The suture-method catheter can be placed in the adductor canal with high success rates for initial placement with both techniques.

Intermittent sprint performance in the heat is not altered by augmenting thermal perception via L-menthol or capsaicin mouth rinses.

PURPOSE: Cooling sensations elicited by mouth rinsing with L-menthol have been reported as ergogenic. Presently, responses to L-menthol mouth rinsing during intermittent sprint performance (ISP) in the heat are unknown and the impact of increased thermal perception on ISP via capsaicin has also not been quantified. This experiment aimed to identify whether eliciting cooling/warming sensations via L-menthol/capsaicin would alter ISP in the heat. METHOD: Fourteen participants (mass = 72 ± 9 kg, [Formula: see text] = 3.30 ± 0.90 L min-1), undertook four experimental trials, involving 40 min of ISP in hot conditions (40.2 ± 0.6 °C, 42 ± 2% R.H.) with mouth rinsing (25 mL, 6 s) at the protocol onset, and every 10 min thereafter. Cooling (0.01% L-menthol; MEN), warming (0.2% capsaicin; CAP), placebo (0.3 sham-CHO; PLA), and control (water; CON) mouth rinses were utilized. Performance was quantified via power (PP) and work done (WD) during sprints. Heart rate (HR), core (Trec) and skin (Tskin) temperature, perceived exertion (RPE), thermal sensation (Tsens), and comfort (Tcom) were measured at 10 min intervals. Sweat rate (whole-body sweat rate) was calculated from ∆mass. RESULT: PP reduced over time (P < 0.05); however, no change was observed between trials for PP or WD (P > 0.05). Tcom increased over time and was lower in MEN (2.7 ± 1.1; P < 0.05) with no difference between CAP (3.1 ± 1.2), PLA (3.2 ± 1.3) and CON (3.1 ± 1.3). RPE, Tsens HR, Trec, and Tskin increased over time (P < 0.05) with no between trial differences (P > 0.05). CONCLUSION: Despite improved thermal comfort via L-menthol, ISP did not improve. Capsaicin did not alter thermal perception or ISP. The reduction in ISP over time in hot conditions is not influenced by thermal perception.

The time course of brief and prolonged topical 8% capsaicin-induced desensitization in healthy volunteers evaluated by quantitative sensory testing and vasomotor imaging.

Topically applied high-concentration capsaicin induces reversible dermo-epidermal denervation and depletion of capsaicin-sensitive nociceptors. This causes desensitization of distinct sensory modalities and is used to treat peripheral neuropathic pain and itch. For high-concentration capsaicin, the selectivity of loss of function and functional recovery rates of various afferent fibers subpopulations are unknown. This study used comprehensive quantitative sensory testing and vasomotor imaging to assess effectiveness, duration and sensory selectivity of high-concentration 8% capsaicin-ablation. Skin areas in 14 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 1 and 24 h and underwent comprehensive sensory and vasomotor testing at 1, 7 and 21 days postpatch removal. Tests consisted of thermal detection and pain thresholds, tactile and vibration detection thresholds, mechanical pain threshold and mechanical pain sensitivity as well as micro-vascular and itch reactivity to histamine provocations. The 24 h capsaicin drastically inhibited warmth detection (P < 0.001), heat pain (P < 0.001) as well as histamine-induced itch (P < 0.05) and neurogenic flare (P < 0.001), but had no impact on tactile sensitivity, cold detection and cold pain. A marginal decrease in mechanical pain sensitivity was observed (P < 0.05). Capsaicin for 1 h had limited and transient sensory effects only affecting warmth and heat sensations. Time-dependent functional recovery was almost complete 21 days after the 24 h capsaicin exposure, while recovery of neurogenic inflammatory responsiveness remained partial. The psychophysically assessed sensory deficiencies induced by the used 8% capsaicin-ablation correspond well with a predominant effect on TRPV1+-cutaneous fibers. The method is easy to apply, well tolerated, and utilizable for studies on, e.g., interactions between skin barrier, inflammation and capsaicin-sensitive afferents.

L-Menthol attenuates the magnitude of cold-induced vasodilation on the extremities of young females.

BACKGROUND: Menthol chemically triggers cold-sensitive receptors in the skin without conductive skin cooling. We investigated the effects of menthol-induced activation of cutaneous cold receptors on the cold-induced vasodilation (CIVD) of the finger. We hypothesized that the menthol application would attenuate typical CIVD responses. METHODS: 1.5% L-menthol was fully applied over the left hand and forearm, and then, the middle finger of the left hand was immersed into 4 °C water for 30 min. A trial consisted of 10-min rest followed by 30-min immersion and 20-min recovery in 28 °C air temperature with 20% relative humidity. Another trial without the menthol application was carried out as a control. Seventeen females (24.2 ± 2.6 years in age, 160.5 ± 5.1 cm in height, and 51.2 ± 5.7 kg in body weight) participated in the two trials. RESULTS: The results showed that the maximum and average temperatures of the finger during the water immersion were lower in the menthol application when compared to control (P < 0.05), whereas no significant differences appeared in the onset time of CIVD, the frequency of CIVD, and minimum finger temperature. These results imply that stronger stimulation of cold receptors without additional conductive skin cooling did not attenuate the triggering of CIVD responses but intensified vasoconstriction after the first occurrence of CIVD. CONCLUSION: It is suggested that substantial and conductive heat loss through the skin along with activation of cold receptors may be required to retain rewarming at a certain level.

Menthol Use for Performance in Hot Environments.

Menthol is a compound of plant origin and has recently been used to aid exercise performance in hot, humid environments. Menthol creates a sensation of coolness when applied to the skin or mucosal surfaces stimulating the cold receptors. In these environments, fatigue is known to be accelerated and feelings of being hot are one of the main contributors to the early onset of fatigue. However, current research indicates that nonthermal perceptual cooling interventions could alter behavior in the heat by reducing thermal perception. This would allow the athlete to feel cooler when exercising at the same work rate in the heat. Menthol has been investigated as an internal and external intervention. Greater benefits have currently been found for internal interventions than external methods. Future research should focus on the mechanisms, dosage, and timing of both internal and external interventions, and the role menthol could play within speed or strength.

Total Spinal Anesthesia Failure: Have You Assessed the Sensory Anesthesia in Sacral Dermatomes?

Intrathecal local anesthetic maldistribution is a well-known cause of spinal anesthesia failure (SAF). This could potentially result in sensory blockade restricted to the sacral dermatomes. We sought to determine the overall incidence of SAF and the role of sacral dermatomes in differentiating between total and partial failures. Of the 3111 spinals prospectively examined, 194 (6.2%) were classified as failures. Of the 72 presumed total failures based on the initial assessment, evaluation of the sacral dermatomes revealed sensory blockade in 32 (44%; 95% confidence interval, 32.7%-56.6%). Sacral dermatome assessment after SAF may be important in safely guiding subsequent anesthetic management.