Cold Receptor Activity Research Articles

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

BackgroundMenthol 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.Methods1.5% 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.ResultsThe 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.ConclusionIt 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.

Correlation of Nasal Mucosal Temperature With Subjective Nasal Patency in Healthy Individuals.

Historically, otolaryngologists have focused on nasal resistance to airflow and minimum airspace cross-sectional area as objective measures of nasal obstruction using methods such as rhinomanometry and acoustic rhinometry. However, subjective sensation of nasal patency may be more associated with activation of cold receptors by inspired air than with respiratory effort. To investigate whether subjective nasal patency correlates with nasal mucosal temperature in healthy individuals. Healthy adult volunteers first completed the Nasal Obstruction Symptom Evaluation (NOSE) and a unilateral visual analog scale to quantify subjective nasal patency. A miniaturized thermocouple sensor was then used to record nasal mucosal temperature bilaterally in 2 locations along the nasal septum: at the vestibule and across from the inferior turbinate head. Nasal mucosal temperature and subjective patency scores in healthy individuals. The 22 healthy adult volunteers (12 [55%] male; mean [SD] age, 28.3 [7.0] years) had a mean (SD) NOSE score of 5.9 (8.4) (range, 0-30) and unilateral VAS score of 1.2 (1.4) (range, 0-5). The range of temperature oscillations during the breathing cycle, defined as the difference between end-expiratory and end-inspiratory temperatures, was greater during deep breaths (mean [SD] change in temperature, 6.2°C [2.6°C]) than during resting breathing (mean [SD] change in temperature, 4.2°C [2.3°C]) in both locations (P < .001). Mucosal temperature measured at the right vestibule had a statistically significant correlation with both right-side visual analog scale score (Pearson r = -0.55; 95% CI, -0.79 to -0.17; P = .008) and NOSE score (Pearson r = -0.47; 95% CI, -0.74 to -0.06; P = .03). No other statistically significant correlations were found between mucosal temperature and subjective nasal patency scores. Nasal mucosal temperature was lower (mean of 1.5°C lower) in the first cavity to be measured, which was the right cavity in all participants. The greater mucosal temperature oscillations during deep breathing are consistent with the common experience that airflow sensation is enhanced during deep breaths, thus supporting the hypothesis that mucosal cooling plays a central role in nasal airflow sensation. A possible correlation was found between subjective nasal patency scores and nasal mucosal temperature, but our results were inconsistent. The higher temperature in the left cavity suggests that the sensor irritated the nasal mucosa, affecting the correlation between patency scores and mucosal temperature. Future studies should consider noncontact temperature sensors to prevent mucosa irritation. NA.

Desensitization of menthol-activated cold receptors in lower extremities during local cooling in young women with a cold constitution.

To test the hypothesis that topical menthol-induced reactivity of cold sensation and cutaneous vasoconstriction to local cooling is augmented in individuals with a cold constitution, we examined thermal sensation and cutaneous vasoconstrictor responses at menthol-treated and untreated sites in the legs during local skin cooling in young women complaining of chilliness (C group) and young women with no complaint as a normal control group (N group). During local skin cooling, the sensitivity to cold sensation was greater in the C group than in the N group. The application of menthol enhanced the cold sensation at a low temperature in the N group, but not in the C group. Cutaneous vasoconstrictor responses to local skin cooling were not altered by menthol treatment in either of the two groups. These findings suggest the desensitization of menthol-activated cold receptors in the legs of C group subjects, and a minor role of cold receptor activity in cutaneous vasoconstrictor response to local cooling.

Cold perception of the bladder during ice water test. Study on 120 patients

ObjectiveIf the pathophysiology of bladder cooling reflex (BCR) elicited during an ice water test (IWT) is well-known (triggered by activation of cold receptors within the bladder wall supplied by unmyelinated C fiber afferents) and is widely used for the diagnosis of upper motor neurological lesions, the significance of having a perception of cold in the bladder (PCB) during IWT has not been properly defined yet. Patient and methodsHundred and twenty patients undergoing IWT were analyzed and separated into four groups: group 1 (G1): patients with idiopathic overactive bladder syndrome (OAB); group 2 (G2): patients with functional dysuria (difficult urination due to bladder-neck obstruction, or congenital large bladder); group 3 (G3): patients with multiple sclerosis (MS) and group 4 (G4): patients with cauda equina syndrome (CES). All patients had a cystometry and IWT. After performing IWT, the patients were asked specific questions regarding the various sensations experienced during the cystometry and IWT, especially for detecting the presence or not of a cold sensation when their bladder was filling up. ResultsPatients with idiopathic OAB had more frequently a PCB than patients with MS (P<0.02). Patients with bladder-neck obstruction were more likely to retain a PCB than patients with CES (P<0.01). Lack of PCB is more frequent in patients with neurological diseases (P<0.001), with a sensitivity of 66% and specificity of 65%. ConclusionPatients without neurological disease have a heightened PCB during the IWT than patients with neurological diseases. The lack of PCB may reflect an alteration of the afferent pathways or spinal reflex pathways or central neural pathways.

ThermoTRP channels and cold sensing: what are they really up to?

Cooling is sensed by peripheral thermoreceptors, the main transduction mechanism of which is probably a cold- and menthol-activated ion channel, transient receptor potential (melastatin)-8 (TRPM8). Stronger cooling also activates another TRP channel, TRP (ankyrin-like)-1, (TRPA1), which has been suggested to underlie cold nociception. This review examines the roles of these two channels and other mechanisms in thermal transduction. TRPM8 is activated directly by gentle cooling and depolarises sensory neurones; its threshold temperature (normally approximately 26-31 degrees C in native neurones) is very flexible and it can adapt to long-term variations in baseline temperature to sensitively detect small temperature changes. This modulation is enabled by TRPM8's low intrinsic thermal sensitivity: it is sensitised to varying degrees by its cellular context. TRPM8 is not the only thermosensitive element in cold receptors and interacts with other ionic currents to shape cold receptor activity. Cold can also cause pain: the transduction mechanism is uncertain, possibly involving TRPM8 in some neurones, but another candidate is TRPA1 which is activated in expression systems by strong cooling. However, native neurones that appear to express TRPA1 respond very slowly to cold, and TRPA1 alone cannot account readily for cold nociceptor activity or cold pain in humans. Other, as yet unknown, mechanisms of cold nociception are likely.

Cooling of the urinary bladder activates neurons in the dorsal horn of the spinal cord.

Although visceral innocuous cold receptors have been documented, the central termination of their afferents is unknown. We used menthol solution (0.6 mM) to obtain selective activation of cold receptors in the urinary bladder of rats. Innocuous cold stimulation induced Fos expression in a population of neurons in the superficial dorsal horn of L6-S1 segments of the spinal cord. Neurons in other regions of the spinal cord, e.g. the lumbar parasympathetic nucleus or the dorsal commissure region, were activated to a similar degree by menthol and control infusions, indicating a response to bladder filling. Our results are consistent with the proposal that subsets of modality-specific dorsal horn neurons convey specific information regarding the exteroceptive and interoceptive state of the animal.

Discharge pattern analysis suggests existence of a low-threshold calcium channel in cold receptors

The regular periodic activity patterns of mammalian cold receptors have been quantitatively studied. Analysis of the timing of either single impulses or impulse groups demonstrated that the periodic receptor process is maintained independently of impulse generation and continues to operate under conditions when afferent impulses are not initiated. These results imply that the underlying conductances must be operational at threshold potentials related to impulse generation. In addition to temperature, the periodic process is considerably sensitive to calcium, which affects mainly the probability of impulse generation during each cycle. Reduction of external calcium and application of calcium entry blockers with relative selectivity for low-threshold calcium channels are similarly effective in modulating cold receptor activity. The data imply the existence of a low-threshold calcium conductance at the sensory terminal.

Modulation of periodic cold receptor activity by ouabain

The effect of ouabain on the periodic discharge pattern of feline cold receptors was studied in order to substantiate a possible contribution of Na/K pump activity to signal transduction. Afferent activity was recorded from the cold fibres of an isolated preparation of the tongue. The periodic pattern consisted of beating activity and of grouped discharges and was characterized by two parameters, the oscillation frequency and the number of impulses initiated per cycle. Ouabain (10(-7)-10(-6)M) induced in all receptors excitatory responses, consisting of a short vigorous increase of activity followed by inhibition. Thus the receptors never stabilized to or maintained a new static level of activity. The ouabain-induced responses occurred repeatedly in several receptors and were produced by remarkable stereotyped modifications of both the oscillation frequency and the number of impulses per cycle. The oscillation frequency attained peak values which increased monotonically with higher static temperatures and which were considerably greater than peak control values. The data indicate that an electrogenic Na/K pump contributes to the transducer process of cold receptors and that inhibition of this pump evidently gives rise to a depolarizing imbalance of the membrane potential, accelerating the oscillation frequency to a maximum value. Thus the oscillation frequency seems to be controlled by temperature and by membrane potential in cold receptors.

Analysis of facial cold receptor activity in the rat

Afferent activity of single facial cold receptors was extracellularly recorded from infraorbital nerve fibers in the rat, and the response properties of 28 receptors to thermal stimulation were quantitatively studied. Generally, on repeated stimulation, the afferent activity was highly reproducible and was not dependent on previous adapting temperatures. At constant temperatures, a periodic pattern was apparent in the discharges of 24 receptors; in the remaining 4 receptors periodic elements could not reliably be detected. The temperature dependence of the cyclic pattern corresponded to that observed in other mammalian cold receptor populations: we observed regular impulse groups (bursts) at lower and beating activity at higher adapting temperatures. Rapid changes of temperature induced transient alterations of activity. The dynamic response to cooling was biphasic, indicating a complex sequence of receptor events. A transient acceleration of impulse frequency was followed by a dynamic burst discharge which was characterized by longer pauses and a greater number of impulses per burst compared with the steady-state activity at the same temperature. This indicates a deceleration of the periodic receptor events during the adaptation process following dynamic responses, which is accompanied by a concomitant shift of these processes to a more pronounced suprathreshold condition. In an additional series of experiments, parameters of the periodic activity in the rat were compared with corresponding data of facial and lingual cold receptors in the cat. Whereas the number of impulses per cycle was similar in the 3 receptor populations, the frequency of the periodic pattern proved to be considerably higher in the rat than in the cat.

Static and dynamic activity of cutaneous cold receptors induced by noradrenaline infusion

Experiments on rats showed that cutaneous cold receptors are sensitive to altered blood level of noradrenaline (NA). Both rise in and re-establishing of NA at a new, higher level exert an effect on firing activity in cutaneous cold receptors. When sustained at the raised level, NA alters both static and dynamic activity of cold receptors. The pattern of change (whether excitatory or inhibitory) depends on initial type of receptor activity.

Analysis of cold and warm receptor activity in vampire bats and mice.

The response characteristics of facial thermoreceptors of the common vampire bat and of the mouse have been quantitatively studied. Cold receptors were identified in bat and mouse; warm receptors were only established in the bat. Cold and warm receptor populations of the two species share most of their properties with facial thermoreceptor populations of various mammalian species investigated so far. The temporal pattern of activity of cold receptors of the mouse corresponded to that observed in cats, dogs and monkeys: impulse groups at lower, and beating activity at higher temperatures. At maintained temperature, no impulse groups were initiated in cold receptors of the bat. However, cooling steps from various initial temperatures induced a transient grouped discharge in both cold receptor populations. A discharge in regular groups of impulses was occasionally generated in warm receptors of the bat at maintained temperatures and following warming steps. The data indicate that the temperature dependence of periodic activity in warm receptors is not as uniform as it is in cold receptors. It is concluded that cyclic processes are involved in sensory transduction of both warm and cold receptors, and that this cyclic behavior seems to be a general property of thermoreceptors of presumably all vertebrate species.

A quantitative study of the dependence of feline cold receptor activity on the calcium concentration

An isolated preparation of the cat tongue was developed to study quantitatively the relation between single cold receptor activity and calcium concentration. The activity recorded from lingual cold fibres of the isolated preparation was identical to that observed by previous authors in lingual cold receptors of whole animals. A perfusing solution containing excess calcium (5 mmol/l) suppressed discharge at constant temperatures as well as the dynamic response to rapid cooling. Reduced calcium levels (0.5 mmol/l) enhanced cold fibre activity at adapting temperatures above 15 degrees C. Cold receptor activity was linearly inversely related to the logarithm of calcium concentration at adapting temperatures above 20 degrees C. The linear relation was valid for both the discharge at constant temperatures and the dynamic peak frequency during cooling steps. From this relation it was calculated that at 25 degrees C an elevation of 0.1 mmol/l external calcium above the control value (1.53 mmol/l) reduces static firing rate by 0.35 impulses per second. It is concluded that neither the in vitro conditions nor the application of various external calcium concentrations impair cold receptor function. The data are consistent with the hypothesis of a calcium-stimulated outward current controlling the static and dynamic response characteristics of cold receptors.

Effect of menthol on cold receptor activity. Analysis of receptor processes.

The effect of menthol on the discharge pattern of feline nasal and lingual cold receptors was analyzed in order to elucidate the underlying sensory transducer mechanism. A repetitive beating activity and burst (grouped) discharges were observed in both cold receptor populations at constant temperatures and after rapid cooling. An analysis of the impulse activity revealed a cyclic pattern of impulse generation, which suggested the existence of an underlying receptor potential oscillation that initiates impulses in the afferent nerve when it exceeds a threshold value. The frequency and amplitude of the periodic impulse-inducing receptor processes were characterized by the burst frequency, which increased with warming, and by the average number of impulses generated during each cycle, which increased with cooling. Menthol at micromolar concentrations induced an acceleration of the burst frequency at higher temperatures, but reduced the burst frequency in the midtemperature range. At temperatures above 25 degrees C, menthol increased the number of impulses elicited during each cycle and induced bursting in previously repetitively discharging fibers. At low temperatures, menthol suppressed bursting and finally inhibited all cold receptor activity. The impulse pattern at constant temperatures and during the dynamic response to rapid cooling was comparably affected by menthol. Calcium application completely abolished the stimulating menthol effect. Since, in equal concentrations, menthol specifically impairs neuronal calcium currents, the results are consistent with the conjecture that in cold receptors, menthol reduces the activation of a calcium-stimulated outward current by an impeding effect on a calcium conductance, thereby inducing depolarization and a modification of bursting behavior. The data confirm the hypothesis of a calcium-controlled outward conductance being involved in the generation of cyclic afferent activity in cold receptors.

Projection of a cutaneous nerve to the spinal cord of the pigeon. II. Responses of dorsal horn neurons.

The responses of dorsal horn neurons to both electrical stimulation of a cutaneous nerve and natural stimulation of skin receptors have been studied in an avian species, the pigeon. Neurons located in either lamina I or lamina IV were recorded. Most lamina IV neurons had short-latency responses to electrical stimulation of a cutaneous nerve and were activated by stimulation of sensitive mechanoreceptors. This points to an input from mechanoreceptors innervated by large afferent fibers. Lamina I neurons which were usually located near the entrance zone of small fibers had longer latency responses and had often an input from several groups of afferent fibers including C-fibers. Many lamina I neurons were activated specifically by noxious stimulation. Some had an input from sensitive mechanoreceptors but possibly through an additional synapse. A few lamina I neurons responded specifically to activation of cold receptors. Some dorsal horn neurons showed segmental inhibition. Altogether, the characteristics of dorsal horn neurons in the pigeon studied so far were similar to those in mammalian species.

Static an dynamic activity of cold receptors in cats after long-term exposure to various temperatures.

Ten cats were adapted for 4.7 years in a climatic chamber to an ambient temperature of 5 degree C an 8 cats to 30 degree C under artificial illumination and food ad libitum., Cats living at 5 degree C had 15.2 +/- 0.5 mean nasal and 38.0 +/- 0.3 degree C mean rectal temperature; the corresponding values for cats living at 30 degree C were 31.0 +/- 0.4 degree an 38.3 +/- 0.1 degree C. Static and dynamic activities of single specific cold fibers from the nose were recorded when applying static temperature of 40, 35, 30, 25, 20, 15 and 10 degree C and dynamic cooling steps of 5 degree C starting from static temperature between 40 and 15 degree C. In each group, a population of 100 cold fibers was examined. The average static frequencies between 35 and 20 degree C slightly but not significantly lower in the cold adapted group, the respective values for both groups at 30 degree C being 5.6 and 5.6s-1. The average dynamic maxima were considerably lower in the cold adapted group throughout the whole temperature range, the values at 30 degree C being 44 and 61s-1, respectively. The difference between the dynamic frequency-temperature curves of both fiber populations was highly significant (P less than 0.001). The distribution of static maxima of individual cold fibers as well as the distribution of fibers with static bursts was nearly identical for both groups, whereas the distribution of dynamic maxima and dynamic bursts was significantly shifted lower temperatures in the could adapted group. Seven sub-groups of cold fibers were formed according to their static maximum at temperatures between 40 and 10 degree C. The most pronounced adaptive modification was a significantly lower dynamic peak frequency of the sub-groups with static maxima at 15, 20, 25, 35 and 40 degree C in the cold adapted animals.

Generation and processing of peripheral temperature signals in mammals.

Temperature transduction in peripheral cold receptors and processing of peripheral temperature signals in the spinal cord were studied in cats and rats. The temperature dependence of the generator potential is attributed to different temperature coefficients of an electrogenic Na-efflux and the passive Na-influx. Cold receptor activity and particularly its bursting pattern is considerably modulated by the local Ca-concentration, but the effect of elevated Ca-concentration is abolished by the ATPase blocker ouabain. — The peripheral temperature signals from the scrotal skin of rats are transformed in dorsal horn neurones (DHN) into temperature reactions, which occur only above (warm reaction) or below (cold reaction) a certain temperature threshold and are limited to an operational range of 1–4°C. Convergency of different temperature inputs were observed in one and the same DHN. Supraspinal control of temperature reactive DHN appears to be complex but predominantly excitatory.

Some Response Properties of Cold Fibers to Cooling

Publisher Summary This chapter discusses the methods of systems analysis that are used to describe the responses of feline facial cold receptors to ramp-shaped cool stimuli that varied in rate, intensity, and the temperature to which the skin is preadapted. Two processes, such as an excitatory and an inhibitory process, interact to produce a change in the frequency of cold receptor activity upon cool stimulation. Linear and non-linear components of the responses to 5°C cool stimuli are investigated. The linear components, which occurred at the 40°C and 45°C adapting temperatures, are described as exponential functions with rate constants that increased by about 25 % as the adapting temperatures decreased from 45°C to 20°C. Non-linearity of the responses to 5°C cool stimuli increased as the adapting temperature decreased from 35°C to 20°C. This nonlinearity is described as an exponential function whose rate constant is a function of the adapting temperature. This component of the system equation might be because of the depletion of the ionic reservoir responsible for restoring the receptor membrane polarization or action potential generation. The second major outcome of the system analysis indicated that the steady state and dynamic responses of cold receptors arose from different processes, although they may be loosely coupled.

Functional and Structural Basis of Thermoreception

This chapter illustrates the functional and structural basis of thermoreception. Cutaneous warm and cold receptors have been investigated in various homoiotherms and poikilotherms. In biophysical terms, warm (cold) receptors are defined by an overshoot (transient inhibition) on dynamic warming and a transient inhibition (overshoot) on dynamic cooling. At constant temperatures, thermoreceptors show a static discharge with a bell-shaped temperature frequency curve. The static discharge does not allow an unequivocal discrimination between warm and cold receptors. Specific thermoreceptors are insensitive to mechanical stimulation. The dynamic overshoot is up to 30 times higher than the static discharge. For a given temperature change, the dynamic response is relatively small for warm receptors in the rat's scrotum, medium for the cold receptors in the cat's nose and large for warm receptors in the cat's nose and in the labial region of Boa constrictor . In certain single fibers from the ampullae of Lorenzini in the dogfish, a spontaneous inversion from cold to warm sensitivity of unknown origin has been observed. Ionized calcium inhibits cold receptor activity but enhances the activity of warm receptors. Direct comparisons have been made, between peripheral and central neural events following thermal stimulation of the rat scrotum.

Effect of leukocytic pyrogen on thermosensitive neurons in the anterior hypothalamus

Unit activity in the medial preoptic and septal regions of the brain was studied in rabbits in response to changes in the local temperature and to systemic injection of leukocytic and bacterial pyrogens. A decrease in the discharge frequency of warmth receptors and activation of cold receptors were found under the influence of the pyrogens. Leukocytic pyrogen induced a faster decrease than bacterial pyrogens in the activity of warmth receptors. Temperature-neutral neurons did not respond significantly to pyrogens of either type.

Diurnal rhythm of cold receptor activity in man

Diurnal rhythm of cold receptor activity in man