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The role of the hypothalamic cold-sensitive ion channels - transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) in homeostatic systems of thermoregulation and water-salt balance - is not clear. The interaction of homeostatic systems of thermoregulation and water-salt balance without additional temperature load did not receive due attention, too. On the models of water-balance disturbance, we tried to elucidate some aspect of these problems. Body temperature (T body ), O 2 consumption, CO 2 excretion, electrical muscle activity (EMA), temperature of tail skin (T tail ), plasma osmolality, as well as gene expression of hypothalamic TRPM8 and TRPA1 have been registered in rats of 3 groups: control; water-deprived (3 days under dry-eating); and hyperhydrated (6 days without dry food, drinking liquid 4 % sucrose). No relationship was observed between plasma osmolality and gene expression of Trpm8 and Trpa1. In water-deprived rats, the constriction of skin vessels, increased fat metabolism by 10 % and increased EMA by 48 % allowed the animals to maintain T body unchanged. The hyperhydrated rats did not develop sufficient mechanisms, and their T body decreased by 0.8 °C. The development of reactions was correlated with the expression of genes of thermosensitive ion channels in the anterior hypothalamus. T tail had a direct correlation with the expression of the Trpm8 gene, whereas EMA directly correlated with the expression of the Trpa1 gene in water-deprived group. The obtained data attract attention from the point of view of management and correction of physiological functions by modulating the ion channel gene expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Analysis of the role of genomic regulation of systolic BP (SBP) in normal and hypertensive rats showed the presence of an inverse relationship between the level of Trpa1 gene expression in the anterior hypothalamus and SBP. Losartan, an antagonist of angiotensin II type 1 receptors, shifts it to the region of lower SBP and greater expression of the Trpa1 gene, which can attest to interaction of the TRPA1 ion channel in the anterior hypothalamus with angiotensin II type 1 receptors. No association was found between the expression of the Trpv1 gene in the hypothalamus and SBP. We have previously shown that activation of the peripheral ion channel TRPA1 in the skin also contributes to SBP decrease in hypertensive animals. Hence, activation of the TRPA1 ion channel both in the brain and at the periphery has similar effects on SBP and leads to its decrease., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature.)

The present study is aimed to elucidate the possible involvement of the thermosensitive TRPM2 ion channel in changing of the temperature sensitivity of the hypothalamus after different cold exposures-long-term adaptation to cold and short-term cooling. Quantitative RT-PCR was used to study the expression of the gene of thermosensitive TRPM2 ion channel in the hypothalamus in the groups of control (kept for 5 weeks at +20 to +22 °C) and cold-adapted (5 weeks at +4 to +6 °C) rats, as well as in the groups of animals which were subjected to acute cooling (rapid or slow) with subsequent restoration of body temperature to the initial level. It has been shown that after long-term adaptation to cold, the decrease in the Trpm2 gene expression was observed in the hypothalamus, while a short-term cooling does not affect the expression of the gene of this ion channel. Thus, long-term adaptation to cold results in the decrease in the activity not only of the TRPV3 ion channel gene, as shown earlier, but also of the Trpm2 gene in the hypothalamus. The overlapping temperature ranges of the functioning of these ion channels and their unidirectional changes during the adaptation of the homoeothermic organism to cold suggest their functional interaction. The decrease in the Trpm2 gene expression may indicate the participation of this ion channel in adaptive changes in hypothalamic thermosensitivity, but only as a result of long-term cold exposure and not of a short-term cooling. These processes occurring at the genomic level are one of the molecular mechanisms of the adaptive changes.

ISIAH (inherited stress-induced arterial hypertension) rats are characterized by high blood pressure and decreased Trpm8 gene expression in the anterior hypothalamus. Thermosensitive ion channel TRPM8 plays a critical role in the transduction of moderately cold stimuli that give rise to cool sensations. In normotensive animals, the activation of skin TRPM8 is known to induce changes in gene expression in the hypothalamus and induce alterations of thermoregulatory responses. In this work, in hypertensive rats, we studied the effects of activation of the peripheral TRPM8 by cooling and by application of a 1% menthol suspension on (1) the maintenance of body temperature balance and (2) mRNA expression of thermosensitive TRP ion channels in the hypothalamus. In these hypertensive animals, (1) pharmacological activation of peripheral TRPM8 did not affect the thermoregulatory parameters either under thermoneutral conditions or during cold exposure; (2) the expression of Trpm8 in the anterior hypothalamus approximately doubled (to the level of normotensive animals) under the influence of (a) slow cooling and (b) at pharmacological activation of the peripheral TRPM8 ion channel. The latter fact seems the quite important because it allows the proposal of a tool for correcting at least some parameters that distinguish a hypertensive state from the normotensive one.

The present review summarizes the data concerning the influence of serotonin (5-HT) receptors on body temperature in warm-blooded animals and on processes associated with its maintenance. This review includes the most important part of investigations from the first studies to the latest ones. The established results on the pharmacological activation of 5-HT 1A , 5-HT 3, 5-HT 7 and 5-HT 2 receptor types are discussed. Such activation of the first 3 type of receptors causes a decrease in body temperature, whereas the 5-HT 2 activation causes its increase. Physiological mechanisms leading to changes in body temperature as a result of 5-HT receptors' activation are discussed. In case of 5-HT 1A receptor, they include an inhibition of shivering and non-shivering thermogenesis, as well simultaneous increase of peripheral blood flow, i.e., the processes of heat production and heat loss. The physiological processes mediated by 5-HT 2 receptor are opposite to those of the 5-HT 1A receptor. Mechanisms of 5-HT 3 and 5-HT 7 receptor participation in these processes are yet to be studied in more detail. Some facts indicating that in natural conditions, without pharmacological impact, these 5-HT receptors are important links in the system of temperature homeostasis, are also discussed.

The effect of TRPA1-ion channel on thermoregulatory responses depending on the level of its activity was studied in Wistar rats. To activate the TRPA1 ion channel localized in the skin, its agonist allyl isothiocyanate (AITC) was used in different concentrations (0.04, 0.4, 1, and 2.5%). Low concentration of AITC (0.04%) enhanced and high concentrations (1 and 2.5%), on the contrary, inhibited cold-defense responses (decreased their magnitude and led to their later initiation due to an increase in temperature thresholds). With an increase in TRPA1 activation, the increase in temperature thresholds (afferent link) was ahead of the decrease in the magnitude of responses (efferent link), which can attest to different sensitivity of these processes to TRPA1 activation.

Experiments on rats showed that activation of the peripheral ion channel TRPM8 with menthol and rapid cooling (decrease in core temperature by 3°C) led to 1.5-fold activation of the expression of TRPV3 ion channel gene in the posterior hypothalamus, but had no effect on the expression of this gene in the anterior hypothalamus. Neither stimulation of peripheral TRPМ8, nor acute cooling affected the expression of genes for other thermosensitive ion channels (TRPV1, TRPV2, TRPV4, TRPA1, and TRPМ8) in the hypothalamus. Enhanced expression of Trpv3 gene can indicate increased sensitivity of hypothalamic neurons in the range of TRPV3 ion channel functioning (31-39oC). The relationship between the changes in Trpv3 gene expression and the shift of thermoregulatory reaction thresholds is discussed. Our findings attest to the presence of a functional relationship between TRP ion channels of the peripheral nervous system and TRP channels in the central structures of the brain.

The role of thermosensitive TRP ion channels in physiological processes in the whole organism is far from being clear. In present work we tried to understand the possible participation of the cold-sensitive ion channel TRPM8 in regulation of the pro-inflammatory cytokine level in blood, and to see if hypertension (widely spread disease) changes this relationship. Experiments were carried out on normotensive Wistar rats and rats with inherited stress-induced arterial hypertension. The effects of deep rapid and slow cooling with decrease in rectal temperature by 3°C, and activation of the skin TRPM8 ion channel by its agonist menthol (application of 1% L-menthol) on the concentration of pro-inflammatory cytokines (IL-6, IL-1β and TNFα) in blood have been studied. The data have shown that the TRPM8 ion channel participates in regulation of pro-inflammatory cytokine in the whole organism, as well as exposure to cold. In normotensive animals the activation of the cold-sensitive TRPM8 ion channel in skin by its agonist menthol without any temperature shifts causes an increase (about two fold) of pro-inflammatory cytokines IL-6 and IL-1 β in blood without any changes in the level of TNFα. The effect of cooling (slow or rapid) on IL-6 and IL-1β is comparable with the effect of the TRPM8 activation. The changes in TNFα concentration were observed only at slow cooling. In hypertensive rats there were no changes in the level of pro-inflammatory cytokines under the effect of cooling or activation of the TRPM8 ion channel. This evidences for the decrease in TRPM8 activity under arterial hypertension. One of possible mechanisms of profound changes at arterial hypertension may be the alteration in activity of some ion channels, and TRPM8 is one of them., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The gene expression of thermosensitive TRP (transient receptor potential) ion channels was studied by the method of quantitative reverse transcription-polymerase-chain-reaction (RT-PCR) in hypothalamus of control (normal) rats (5 weeks at the room temperature 20 +/- 22 degrees C) and rats adapted to cold (5 weeks at the room temperature 4 +/- 6 degrees C). For the first time in this brain region the expression of Trpv3 and Trpm8 genes was found, that was the evidence of the presence of TRPV3 and TRPM8 ion channels in the hypothalamus; it was made a comparison of the gene expression of the 6 thermosensitive ion channels (TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, TRPM8) and found that there was rather high expression of the genes of thermosensitive ion channels activated at temperatures above 30 degrees C, while, the gene expression level of cold sensitive TRPM8 and TRPA1 proved to be much lower; it was found that long-term cold adaptation modified the gene expression of TRPV3 ion channel. The findings support the assumption that thermosensitive TRP ion channels of hypothalamus may be involved in the mechanisms of thermal adaptation at the level of gene expression.

Mechanisms of maintenance of temperature homeostasis in warm and under effect of cold were studied in mice of AKR strain and of its coherent strain AKR.CBA-D13Mit76 with the changed gene i16st encoding the gp 130 receptor, via which IL-6 performs its action. Under thermoneutral conditions and under action of cold, there were recorded temperature parameters, total oxygen consumption, carbon dioxide release, respiratory coefficient, and electrical muscle activity. Animals of the studied strains demonstrated different reactions to equal cold effect. At cooling, all mice of the AKR strain entered the state of hypothermia by decreasing metabolism. Mice of the AKR.CBA-D13Mit76 line showed 2 different types of reaction: 39 % of the animals of this strain reacted like mice of the AKR strain, but the majority (61 %) resisted actively to the cold action, which was manifested as a marked increase of metabolism. Taking into account the gene penetrance, this can indicate effect of the gene i16st on choice of the active ("regulated") or passive ("dependent") way of the organism reacting to temperature actions.

Activation of central 5-HT(3) receptors by the selective agonist m-CPBG (1-(3-chlorophenyl)biguanide hydrochloride, 40 nM i.c.v.) produced stronger hypothermic effect in mice than activation of 5-HT(1A) receptors by their agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propilamino)tetralin) injected by the same route at an equimolar dose. The hypothermic effect of m-CPBG was realized by influence on both the heat production and the heat loss: oxygen consumption and CO(2) expiration were decreased; heat dissipation determined by the tail skin temperature was increased. The heat loss effect of 5-HT(3) receptors was significantly shorter than the decrease in metabolism indicating the prevalent role of heat production decrease in 5-HT(3) receptor-induced deep and long-lasing hypothermia. In addition, the decrease in the respiratory exchange ratio (RER) was shown suggesting that the activation of the 5-HT(3) receptors switched metabolism to prevalent use of lipids as the main energetic substrate. 5-HT(1A) receptor agonist 8-OH-DPAT (40 nM i.c.v.) produced less depressing effect on general metabolism: a decrease in oxygen consumption and CO(2) excretion began later and was not so deep as after m-CPBG administration. Heat-loss effect of 5-HT(1A) receptors activation was not observed. In contrast to m-CPBG effect, RER after 5-HT(1A) receptors activation raised immediately after injection and then gradually decreased to the values observed in m-CPBG-treated mice. Obtained results show that activation of central 5-HT(3) receptors are more effective in hypothermia induction due to marked decrease in thermogenesis and increase in heat loss., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The mRNA expression of serotonin receptors 5-HT1A and 5-HT2A was investigated by the quantitative method RT-PCR in rats adapted to cold (5 weeks at +4 -(+6) degrees C) and in control (5 weeks at +20-22 degrees C). Four brain regions were examined: frontal cortex, hypothalamus, hippocampus, and midbrain. The influence of cold adaptation on the mRNA expression of 5-HT15 receptor was not found to be absent. The mRNA expression of 5-HT2A receptor changed under long-term cold exposure. These changes in different brain regions were various: in hypothalamus, there was an increase of the 5-HT2A receptor mRNA expression; in the cortex, a decrease; in the hippocampus and midbrain, significant changes of the mRNA expression were absent. The findings appear bo te adaptive and, according to their localization in the central nervous system, regulatory. They also suggest involvement of brain serotoninergic system in mechanism of adaptive reorganization of temperature regulation.

Brain serotonin 5-HT(1A) and 5-HT(2A) receptors have been implicated in both normal and pathological behavior, and in the action of anxiolytic and antidepressant drugs. In this study, detailed description and verification of a new RT-PCR technique to quantify the number of copies of 5-HT(1A) and 5-HT(2A) receptor mRNAs in the brain is presented. The number of copies of beta-actin and 5-HT(1A) or 5-HT(2A) receptor mRNAs in rat brain samples was evaluated with respect to the genomic DNA solution as the external exogenous standard. The expression of 5-HT receptors was calculated as the number of receptor mRNA copies per 100 copies of corresponding beta-actin mRNA. This presented technique is reliable, simple and can be easily set up in any neurobiological laboratory.

Laser doppler flowmetry was used for the intraoperative study of myocardial blood flow before and after revascularization in 116 patients with 2-3 vessel coronary artery disease and class II-IV angina. In patients without myocardial infarction, with microfocal myocardial infarction, or operated early after myocardial infarction revascularization caused no significant increase of myocardial blood flow. In patients with macrofocal infarction surgery was associated with significant increase of myocardial blood flow. Efficacy of revascularization could be assessed by lowering of flow gradients between various regions of the myocardium.

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, was determined in the brain stem in active awake frogs, and frogs in three sleep-like states: with plastic muscle tone (SLS-1), with rigid muscle tone (SLS-2), and with relaxed muscle tone (SLS-3). Significant decrease in the enzyme activity has been found in frogs in SLS-1 and SLS-2 compared to awake animals. The development in frogs a cataleptic-like immobility after treating the animals with rhythmic lighting was accompanied with a decrease in the brain tryptophan hydroxylase activity. These results provide strong evidence for the involvement of the brain serotonin in frogs in the control of evolutionary ancient sleep-like states, probably by the regulation of muscle tone.

Marked changes were revealed in the activity of the key enzyme in serotonin biosynthesis, tryptophan hydroxylase (TPH), during entry into hibernation, hibernation, and arousal in ground squirrels (Citellus erythrogenys). An increase in TPH activity was found in the midbrain, hippocampus, and striatum during the prehibernation period in euthermic ground squirrels. A further increase in TPH activity was observed during the entry into hibernation. Significant elevation was found not only in potential TPH activity measured at the incubation temperature of 37 degrees C but also at incubation temperature of 7 degrees C, approximating the body temperature in hibernation. Vmax in the midbrain of hibernating animals was about 50% higher than in active ones without significant changes in Km. Thus, brain TPH maintains functionality during torpidity and is activated before the entry into hibernation. The results support the idea that brain serotonin is crucially involved in the transition to and the maintenance of the hibernation state.

An assay of tryptophane hydroxylase activity in brain was based on fluorometric measurement of serotonin after condensation with o-phthalic aldehyde in 10 N HCl. The method proved to be more sensitive and simple as compared with the previously reported technique and enabled to measure the enzyme activity in brain samples as little as 10 mg. The method is recommended for laboratory routine use.