Thermoreceptors Research Articles

Cool and warm ionotropic receptors control multiple thermotaxes in Drosophila larvae.

Animals are continuously confronted with different rates of temperature variation. The mechanism underlying how temperature-sensing systems detect and respond to fast and slow temperature changes is not fully understood in fly larvae. Here, we applied two-choice behavioral assays to mimic fast temperature variations and a gradient assay to model slow temperature changes. Previous research indicates that Rhodopsin 1 (Rh1) and its phospholipase C (PLC) cascade regulate fast and slow temperature responses. We focused on the ionotropic receptors (IRs) expressed in dorsal organ ganglions (DOG), in which dorsal organ cool-activated cells (DOCCs) and warm-activated cells (DOWCs) rely on IR-formed cool and warm receptors to respond to temperature changes. In two-choice assays, both cool and warm IRs are sufficient for selecting 18°C between 18°C and 25°C but neither function in cool preferences between 25°C and 32°C. The Rh1 pathway, on the other hand, contributes to choosing preferred temperatures in both assays. In a gradient assay, cool and warm IR receptors exert opposite effects to guide animals to ∼25°C. Cool IRs drive animals to avoid cool temperatures, whereas warm IRs guide them to leave warm regions. The Rh1 cascade and warm IRs may function in the same pathway to drive warm avoidance in gradient assays. Moreover, IR92a is not expressed in temperature-responsive neurons but regulates the activation of DOWCs and the deactivation of DOCCs. Together with previous studies, we conclude that multiple thermosensory systems, in various collaborative ways, help larvae to make their optimal choices in response to different rates of temperature change.

Activation of peripheral TRPM8 mitigates ischemic stroke by topically applied menthol

BackgroundNo reports exist as to neuroprotective effects associated with topical activation of transient receptor potential melastatin 8 (TRPM8), a noted cold receptor. In the present study, we identified whether activating peripheral TRPM8 can be an adjuvant therapy for ischemic stroke.MethodsMenthol, an agonist of TRPM8, was applied orally or topically to all paws or back of the mouse after middle cerebral artery occlusion (MCAO). We used Trpm8 gene knockout (Trpm8−/−) mice or TRPM8 antagonist and lidocaine to validate the roles of TRPM8 and peripheral nerve conduction in menthol against ischemic stroke.ResultsApplication of menthol 16% to paw derma attenuated infarct volumes and ameliorated sensorimotor deficits in stroke mice induced by MCAO. The benefits of topically applied menthol were associated with reductions in oxidative stress, neuroinflammation and infiltration of monocytes and macrophages in ischemic brains. Antagonizing TRPM8 or Trpm8 knockout dulls the neuroprotective effects of topically application of menthol against MCAO. Immunohistochemistry analyses revealed significantly higher TRPM8 expression in skin tissue samples obtained from the paws compared with skin from the backs, which was reflected by significantly smaller infarct lesion volumes and better sensorimotor function in mice treated with menthol on the paws compared with the back. Blocking conduction of peripheral nerve in the four paws reversed the neuroprotective effects of topical menthol administrated to paws. On the other hand, oral menthol dosing did not assist with recovery from MCAO in our study.ConclusionOur results suggested that activation of peripheral TRPM8 expressed in the derma tissue of limbs with sufficient concentration of menthol is beneficial to stroke recovery. Topical application of menthol on hands and feet could be a novel and simple-to-use therapeutic strategy for stroke patients.

Characterization and Modelling of Flexible VO2 Mott Memristor for the Artificial Spiking Warm Receptor

AbstractIn this work, high‐performance VO2 Mott memristors with the simple via‐hole structure of Pt/VO2/Pt are fabricated on flexible Kapton polymide (PI) substrate with high endurance (>104 sweep‐voltage cycles), good bending stability (>103), and low operating current (<130 µA). The electrical properties of flexible memristor are well modeled by using the 3D Poole–Frenkel emission and Newton's law of cooling considering the temperature dependence of electrical and thermal properties of VO2. As a result, a flexible artificial spiking warm receptor is achieved by using a single VO2 Mott memristor driven by a current source. And an oscillation circuit model is presented to thoroughly study the effects of the memristor electrical properties on the spiking frequency. With the stimulus temperature elevated from 20 to 40 °C, the spiking frequency of artificial spiking warm receptor first increases, then falls off rather quickly to zero at the higher temperature of 45 °C, resembling the response characteristics of biological warm receptors. Hence, the proposed flexible artificial spiking warm receptor is a promising candidate for the bio‐inspired electronic skin of spike‐based intelligence machines with neuromorphic computing.

The cold receptor TRPM8, a new target against the aggravating effects of metabolic syndrome in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) has nowadays become a major public health issue worldwide. HFpEF is usually associated with metabolic syndrome (MS) such as type II diabetes. A growing attention has been shed on Δ9-desaturase (SCD1), the bottleneck enzyme in the mono-desaturation of fatty acids. Indeed, SCD1 controls the balance between inflammation regulated by saturated lipids and weight gain regulated by unsaturated lipids. Targeting SCD1 looks an attractive strategy in limiting the deleterious effects of the MS and HFpEF. In our recent work, we found that isoforms of the cold receptor, TRPM8, control SCD1 expression in epithelial cells and we wonder if this mechanism could be used to prevent HFpEF. (1) To identify the mechanisms by which TRPM8 regulates SCD1 in cell models. (2) Study whether genetic or pharmacological inhibition of TRPM8 prevents MS and HFpEF. Epithelial cells were transfected by siRNA targeting TRPM8 then SCD1 expression was assessed by western blot. Golgi expansion was studied by immunofluorescence after transfection with SCD1-YFP. In vivo, we will finish the metabolic and cardiac phenotype of TRPM8-/- mice. Then we plan to feed wild type and TRPM8-/- mice with chow or high fat high sucrose diet for 16 weeks. Endurance test, blood chemistry, echocardiography will be done to assess development of HFpEF. Lipidomic analysis will assess changes in lipid profile between the 2 groups and inflammation will be assessed by ELISA and flow cytometry. In vitro studies: SCD1 expression has transiently increased upon TRPM8 knockdown in epithelial cells. This was associated with an increase in unsaturated lipids (MUFAs and PUFAs) that led to increase in the Golgi surface area and impairment of vesicles trafficking. Golgi expansion could be suppressed by SCD1 knockdown. In vivo studies, phenotyping the TRPM8-/- mouse line showed a lean phenotype, with modifications in lipid metabolism in liver characterized by a 50% decrease in SCD1 level and resistance to adipogenesis under a short-term high fat diet. Besides, TRPM8-/- mice were less fat and had a heavier heart. TRPM8 regulates the expression of SCD1, which is dysregulated in metabolic disorders. We aim to exploit this mechanism and study if TRPM8 inhibition can prevent MS and HFpEF.

The Cold Receptor TRPM8 Mediates the Antioxidant and Cytoprotective Effects of Mild Hypothermia in Cerebral Endothelial Cells During Inflammation

Cerebral vascular endothelium, the key component of the neurovascular unit, is most vulnerable to oxidative stress injury. Our previous reports in newborn pigs indicated that brain hypothermia prevents cerebral endothelial injury by oxidative stress caused by neonatal seizures and asphyxia. We used primary cerebral vascular endothelial cells (CVEC) from newborn pigs as an in vitro model of oxidative stress condition in the brain caused by inflammation. During normothermia (37˚C), CVEC respond to a pro‐inflammatory cytokine TNF‐alpha (30 ng/ml) by excessive formation of reactive oxygen species (ROS) leading to cell death by apoptosis (caspase‐3 activation, DNA fragmentation, loss of cell‐cell contacts). Remarkably, mild hypothermia (24.5°C) reduced ROS and prevented apoptosis in CVEC exposed to TNF‐alpha. We tested the hypothesis that the cold sensing menthol receptor TRPM8 mediates the cytoprotective effects of mild hypothermia in cerebral endothelium. TRPM8 (mRNA and protein) is expressed in CVEC. The TRPM8 agonist icilin (5 µM) reduced ROS and prevented apoptosis in CVEC exposed to TNF‐alpha at 37˚C, thus mimicking the cytoprotective effects of mild cooling. The TRPM8 antagonist AMTB (20 µM) reversed the icilin‐mediated cytoprotective effects during inflammation. The cell surface biotinylation technique suggested that mild hypothermia and icilin (at 37˚C) promote a time‐dependent TRPM8 translocation from an intracellular compartment to the plasma membrane concomitantly with the receptor activation. We used the in vitro model of the blood‐brain barrier (BBB) to test the functional consequences of TRPM8‐mediated cytoprotection. Confluent monolayers of CVEC cultured on transwell inserts with semipermeable membranes were exposed to TNF‐alpha during normothermia and mild hypothermia conditions. The BBB properties were detected by transendothelial electrical resistance (TEER) and the permeability to 3 kDa fluorescent Dextran. During a 2‐6 h exposure to TNF‐alpha at 37°C, TEER was time‐dependently reduced, and the Dextran permeability was elevated indicating the BBB opening. Mild hypothermia (24.5°C) and icilin (at 37˚C) largely preserved the BBB properties during inflammatory conditions. Overall, our findings demonstrate that mild hypothermia, via a TRPM8‐mediated mechanism, reduces oxidative stress, promotes cell survival, and prevents BBB damage during inflammation. The TRPM8 targeting approaches may provide a promising therapeutic strategy for cerebrovascular disease caused by brain inflammation.

Obstacle induced spiral waves in a multilayered Huber-Braun (HB) neuron model.

Various dynamical properties of four-dimensional mammalian cold receptor model have been discussed widely in the literature considering noise and temperature as important parameters of discussion. Though various spiking and bursting behaviors of the neuron under various noise and temperature conditions studied for a single neuron, no much discussions have been done on the collective behavior. We investigate the collective behavior of these temperature dependent stochastic neurons and unlike the neuron models when forced by periodic external force there is no wave reentry or spiral waves in the network. Hence, we introduce obstacle in the network and depending on the orientation and size of the introduced obstacle, we could show their effects on the wave reentry in the network. Various significant discussions are produced in this paper to confirm that obstacles placed parallel to the wave entry affects the excitability of the tissues significantly compared to those obstacles place perpendicular. We could also show that those obstacles which are lesser in dimensions doesn't affect the excitabilities and hence doesn't contribute for wave reentry. We introduce a new technique to identify wave reentry and spiral waves using the period of individual nodes is proposed. This technique could help us identify even the lowest of excitability change which cannot be seen when using spatiotemporal snapshots.

Profile of David Julius and Ardem Patapoutian: 2021 Nobel Laureates in Physiology or Medicine

Three apparently unrelated findings led to the discovery of the temperature receptors: a better understanding of pain-sensing, the molecular nature of the channels in charge of touch and proprioception, and the 2021 Nobel Prize in Physiology or Medicine bestowed to David Julius and Ardem Patapoutian. In 1953, state-of-the-art research in temperature sensing concluded that temperature afferent fibers came in two flavors, “cold” and “warm,” characterized by discharging by a lowering in temperature and an increase in temperature, respectively (1). Hensel and Zotterman had previously described the sensitizing effect of menthol upon cold receptors (2). It is also an old observation that acute application of capsaicin, the active component of chili peppers, causes intense pain, and that its repeated administration renders animals insensitive to the action of this vanilloid compound (3). The fact that capsaicin induces a depolarization of ventral root neurons from the isolated rat spinal cord suggested to Theriault et al. (4) that capsaicin’s acute and chronic effects on nociception could be explained by a direct action on primary sensory neurons. On the other hand, McCarter et al. (5) demonstrated the existence of mechanosensitive currents in rat dorsal root ganglion (DRG) cells, clearly pointing to the existence of mechanosensitive ion channels as being responsible for the sense of touch. David Julius. Image credit: University of California, San Francisco. Since temperature is an “intensive” thermodynamic parameter (i.e., one that does not depend on the size of the system), it was difficult to think of specialized temperature receptors. However, the seminal 1997 Nature paper from Julius’ laboratory demonstrated that living beings have evolved to transduce all stimuli coming from the external world using ion channels, including temperature (6). Caterina et al. (6) used an expression cloning strategy to search for the capsaicin receptor and found a single clone in which capsaicin induced a significant … [↵][1]1To whom correspondence may be addressed. Email: ramon.latorre{at}uv.cl. [1]: #xref-corresp-1-1

Effects of menthol on esophageal motility in humans: Studies using high-resolution manometry.

The cold receptor, transient receptor potential melastatin 8 (TRPM8), has been reported to be expressed in esophageal vagal afferents. Esophageal infusion of menthol modulates esophageal perception in reflux patients via TRPM8, but the effects of menthol on esophageal motility are not well investigated. This study aimed to test the hypothesis whether the infusion of menthol into the esophagus could affect esophageal peristaltic characteristics. Eighteen healthy adults (men 13, mean age 27) underwent high-resolution manometry (HRM) using a catheter with the injection port located in mid-esophagus. Primary peristalsis was performed with ten wet swallows, while secondary peristalsis was generated by 10 rapid air injections. Two different sessions were randomly performed including acute administration of menthol (3mM) and the placebo. Menthol significantly decreased upper esophageal (UES) pressure of primary peristalsis than the placebo (p=0.019). There was no difference in distal contractile integral (p=0.33), distal latency (p=0.86), basal lower esophageal sphincter pressure (p=0.19), or 4-second integrated relaxation pressure (p=0.75) between menthol and placebo. Menthol significantly decreased the frequency of secondary peristalsis subsequent to the administration of menthol during rapid injections with 20mL air (p=0.04). Intraluminal infusion of menthol reduces UES basal pressure and inhibits peristaltic frequency of secondary peristalsis. The data suggest that the triggering of secondary peristalsis is probably modulated by TRPM8-sensitive mechanoreceptors; however, the activation of TRPM8 from menthol does not alter esophageal motility following deglutition or distension-induced secondary peristalsis.

Clustering and Differentiation of glr-3 Gene Function and Its Homologous Proteins

In order to adapt to the low temperature environment, organisms transmitexcitement to the central system through the thermal sensing system, whichis a classic reflex reaction. The cold receptor GLR-3 perceives cold and produces cold avoidance behavior through peripheral sensory neurons ASER.In order to further understand the gene encoding of the cold sensing glr-3gene and the evolution of its homologous gene group function and proteinfunction, the nucleotide sequence and amino acid sequence of the glr-3gene and its homologous gene in 24 species were obtained and compared.By clustering with the GRIK2 gene sequence of Rana chensinensis, the bioinformatics method was used to predict and sequence analyze the change ofgene, evolution rate, physical and chemical properties of protein, glycosylation sites, phosphorylation sites, secondary structure and tertiary structureof protein. The analysis results show that the glr-3 gene and its homologousgene have obvious positive selection effect. The protein prediction analysisshowed that the glr-3 gene and its homologous genes encoded proteinsin these 25 species were hydrophilic proteins, and the proportion of sidechains of aliphatic amino acids was high. The transmembrane helix waswidespread and there were more N-glycosylation sites and O-glycosylationsites. The protein phosphorylation sites encoded were serine, threonine andtyrosine phosphorylation sites. Secondary structure prediction showed thatthe secondary structure units of the encoded protein were α-helix, β-turn,random coil and extended chain, and the proportion of α-helix was the largest. This study provides useful information on the evolution and function ofthe cold sensing gene glr-3 and its homologous genes.

The cold receptor TRPM8 activation leads to attenuation of endothelium-dependent cerebral vascular functions during head cooling

Using the cranial window technique, we investigated acute effects of head cooling on cerebral vascular functions in newborn pigs. Head cooling lowered the rectal and extradural brain temperatures to 34.3 ± 0.6°C and 26.1 ± 0.6°C, respectively. During the 3-h hypothermia period, responses of pial arterioles to endothelium-dependent dilators bradykinin and glutamate were reduced, whereas the responses to hypercapnia and an endothelium-independent dilator sodium nitroprusside (SNP) remained intact. All vasodilator responses were restored after rewarming, suggesting that head cooling did not produce endothelial injury. We tested the hypothesis that the cold-sensitive TRPM8 channel is involved in attenuation of cerebrovascular functions. TRPM8 is immunodetected in cerebral vessels and in the brain parenchyma. During normothermia, the TRPM8 agonist icilin produced constriction of pial arterioles that was antagonized by the channel blocker AMTB. Icilin reduced dilation of pial arterioles to bradykinin and glutamate but not to hypercapnia and SNP, thus mimicking the effects of head cooling on vascular functions. AMTB counteracted the impairment of endothelium-dependent vasodilation caused by hypothermia or icilin. Overall, mild hypothermia produced by head cooling leads to acute reversible reduction of selected endothelium-dependent cerebral vasodilator functions via TRPM8 activation, whereas cerebral arteriolar smooth muscle functions are largely preserved.

Effect of Cold Plasma on the Levels Mineral Blood Components <i>In Vivo</i>

This study illustrates effect of cold plasma CAP on the mineral blood components in vivo. the mineral blood component (Ca, Na, Cl, K and Fe) are used. Floating Electrode-Dielectric Barrier Discharge (FE-DBD) system of probe diameter 4cm is used for this purpose, and variable voltage (0-20) kV and variable frequency (0-30) kHz, the output power was ranged from (10 - 70) W. the effect of cold atmospheric plasma on mineral blood is studied with different exposure durations (30,45,60) sec. As the plasma exposure duration increases, the calcium, potassium and iron components in the blood increased, while The sodium and chlorine elements decreased. These results give an indication of the cold plasma receptor to be used to treat many diseases related to mineral blood components.

Recent, Bioelectricity-Related Articles Selected by Ann M. Rajnicek, Media Editor of Bioelectricity.

Recent, Bioelectricity-Related Articles Selected by Ann M. Rajnicek, Media Editor of Bioelectricity.

Comparative Transcriptome Profiling of Cold Exposure and β3-AR Agonist CL316,243-Induced Browning of White Fat.

Beige adipocytes are newly identified thermogenic-poised adipocytes that could be activated by cold or β3-adrenergic receptor (β3-AR) signaling and offer therapeutic potential for treating obesity and metabolic diseases. Here we applied RNA-sequencing analysis in the beige fat of mice under cold exposure or β3-AR agonist CL316,243 (CL) treatment to provide a comparative and comprehensive analysis for the similarity and heterogeneity of these two stimulants. Importantly, via KEGG analysis, we found that cold and CL commonly induced oxidative phosphorylation. Meanwhile, cold increased glycerolipid and amino acids metabolism while CL treatment triggered a broader spectrum of metabolic responses including carbohydrate metabolism. Besides, cold or CL treatment featured greater heterogeneity in downregulated gene programs. Of note, the top changed genes in each category were confirmed by qPCR analysis. Overall, our analysis provided a better understanding of the heterogeneity of differential models for beige adipocytes activation and a possible clue for optimizing β3-AR agonists in the future.

UCP1 and TRPM8 Expression in the Brown Fat Did Not Affect the Restriction of Menthol-Induced Hyperthermia by Estradiol in Ovariectomized Rats.

Estradiol (E2) modulates the central and peripheral thermoregulatory responses to cold. Menthol is an agonist of transient receptor potential melastatin type 8 (TRPM8), which is a peripheral cold receptor. E2 suppresses menthol-induced elevation of body temperature (Tb) in ovariectomized rats, but the mechanism is unknown. The aim of the present study is to investigate the effect of E2 on uncoupling protein 1 (UCP1), a thermogenic gene, and TRPM8 mRNA levels in ovariectomized rats applied menthol. A silastic tube was implanted in ovariectomized rats with and without E2 underneath the dorsal skin (E2(+) and E2(-) groups), and data loggers for Tb measurement into peritoneal cavity. After application of 10% L-menthol or vehicle to the skin of the whole trunk of rats, Tb was measured for 2 h. The interscapular brown adipose tissue (BAT) and spinal ganglia of cervical, thoracic, and lumbar parts were obtained for RT-qPCR assay. In the menthol application, Tb in the E2(+) group was lower than that in the E2(-) group. The UCP1 mRNA in the BAT, TRPM8 mRNA in the BAT and spinal ganglia in all areas did not differ between the E2(+) and E2(-) groups. In conclusion, the UCP1 and TRPM8 expression in the brown fat did not affect the restriction of the menthol-induced hyperthermia by estradiol in ovariectomized rats.

The Behavioral Response to Heat in the Common Bed Bug, Cimex lectularius (Hemiptera: Cimicidae).

The bed bug, Cimex lectularius L., is a common ectoparasite found to live among its vertebrate hosts. Antennal segments in bugs are critical for sensing multiple cues in the environment for survival. To determine whether the thermo receptors of bed bugs are located on their antennae; innovative bioassays were created to observe the choice between heated and unheated stimuli and to characterize the response of bugs to a heat source. Additionally, the effect of complete antenectomized segments on heat detection were evaluated. Heat, carbon dioxide, and moisture are cues that are found to activate bed bug behavior; a temperature at 38°C was used to assess the direction/degree at which the insect reacts to the change in distance from said stimulus. Using a lightweight spherical ball suspended by air through a vacuum tube, bed bugs and other insects are able to move in 360° while on a stationary point. Noldus EthoVision XT was used to capture video images and to track the bed bugs during 5-min bioassays. A bioassay was created using four Petri dish arenas to observe bed bug attraction to heat based on antennae segments at 40°C. The purpose of this study was to evaluate the effects of heat on complete antenectomized segments of the antennae. The results in this experiment suggest that bed bugs detect and are attracted to heat modulated by nutritional status. Learning the involvement of antennae segments in heat detection will help identify the location and role of thermoreceptors for bed bug host interaction.

Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

Sensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

Epigenetic Regulators of White Adipocyte Browning.

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

The Effect of Cold on the Trigeminal Reflexes

Objective: Effects of muscle cooling on the spinal stretch and monosynaptic reflexes have been studied to describe the properties of Group I and II afferents of muscle spindles. Masseter muscle differs from extremity muscles in structural and numerical features of the muscle spindles. The aim of this study was to examine the muscle spindle afferent features of masseter muscle by applying cold to understand the role of Group I and II afferents in reflexes of masseter. Patients and Methods: We included 12 healthy subjects (7 females and 5 males) in the study. Masseter inhibitory reflex (MIR), jaw tendon reflex (JTR), trigeminal motor evoked potential (MEP), and trigeminal somatosensory evoked potential (SEP) were studied before and after cold application. Left masseter muscle was cooled down to 18°C. We compared the data obtained before and after cold application. Results: After cold application, the mean total duration of MIR was shortened and it was absent in four subjects. The mean amplitude of JTR was higher after cold application (P = 0.018) without any significant change in latency. The mean latency of MEP was delayed without any change in amplitude (P = 0.003). There was no significant difference in SEPs. Conclusions: Changes observed in MIR, JTR, and MEP could not be ascribed to any specific type of muscle spindle afferents. Delayed mean reflex latencies were attributed to the effect of cold on nerve conduction. Summation of peripheral cold and pain receptor features, spindle afferents, and cortical mechanisms might have caused cold-associated changes.

Menthol from Mentha piperita Suppresses the Milk Production of Lactating Mammary Epithelial Cells In Vivo and In Vitro.

Peppermint is traditionally used as an antigalactagogue in breastfeeding women. However, the suppressive mechanism remains unclear. The authors investigate whether and how peppermint influences milk production at the cellular and molecular levels. A lactating mammary epithelial cell (MEC) culture model that produces major milk components is prepared. Peppermint oil (PMO) suppresses β-casein production in conjunction with the induced enlargement of cytoplasmic lipid droplets (CLDs). PMO also significantly inactivates STAT5 and mTOR in the lactogenic signaling pathway. Menthol treatment, which is a primary PMO component, leads to decreases in β-casein production, enlarged CLDs, the inactivated STAT5 and mTOR. Eucalyptol and menthyl acetate, other components of peppermint, does not show suppressive effects on lactating MECs. The inactivation of STAT5 and mTOR upon menthol administration is also evident in alveolar MECs of lactating mice. Furthermore, lactating MECs expresses TRPM8 and TRPA1, which are menthol receptors known as cold receptors. Agonists of TRPM8 and TRPA1 suppresses β-casein production and inactivation of STAT5 and mTOR in the lactating MECs. These findings indicate that peppermint has potential as an antigalactagogue. Menthol is suggested to be an active compound in peppermint. TRPM8 and TRPA1 may function as receptors for menthol.

OSM-9 and OCR-2 TRPV channels are accessorial warm receptors in Caenorhabditis elegans temperature acclimatisation

Caenorhabditis elegans (C. elegans) exhibits cold tolerance and temperature acclimatisation regulated by a small number of head sensory neurons, such as the ADL temperature-sensing neurons that express three transient receptor potential vanilloid (TRPV) channel subunits, OSM-9, OCR-2, and OCR-1. Here, we show that an OSM-9/OCR-2 regulates temperature acclimatisation and acts as an accessorial warmth-sensing receptor in ADL neurons. Caenorhabditis elegans TRPV channel mutants showed abnormal temperature acclimatisation. Ectopic expression of OSM-9 and OCR-2 in non-warming-responsive gustatory neurons in C. elegans and Xenopus oocytes revealed that OSM-9 and OCR-2 cooperatively responded to warming; however, neither TRPV subunit alone was responsive to warming. A warming-induced OSM-9/OCR-2-mediated current was detectable in Xenopus oocytes, yet ADL in osm-9 ocr-2 double mutant responds to warming; therefore, an OSM-9/OCR-2 TRPV channel and as yet unidentified temperature receptor might coordinate transmission of temperature signalling in ADL temperature-sensing neurons. This study demonstrates direct sensation of warming by TRPV channels in C. elegans.