Central and peripheral thermoreceptors. Comparative analysis of effects of the long-term adaptation to cold and noradrenaline

The data obtained in our experiments concerning the effect of long-tern adaptation to cold and noradrenaline on impulse activity of the central hypothalamic and peripheral skin thermoreceptors, are reviewed. The problems of sympathetic system participator in cold adaptive modifications and importance of thermoreceptors in formation of cold-defense responses, as well as the role of different types of thermoreceptors in thermal sensation, are discussed.     

The hypothalamus neurons response to the signals from surface and deep skin thermoreceptors

1. 1.197 neurons have been studied in the anterior and posterior hypothalamus of 30 rabbits; 28 of them responded to the thermal skin stimulation. The response latencies were different and varied from 2–5 to 50–80 s; the response latencies of the same neuron were constant under repeated stimulation.

2. 2.These differences were concluded to be accounted for by some neurons being connected to the surface skin layers thermoreceptors, and others to the deeper ones. These facts support the hypotheses that the thermoregulatory system measures the intensity of the heat flow through the skin.

Effect of menthol on human temperature sensitivity

Application of 1% methol, which, along with cold, activates specific thermosensitive ionic channels, changes the number of functioning cold receptors on the skin of the forearm similarly to the cold exposure test; however, it does not affect the number of heat receptors and does not significantly change the threshold of cold sensation. Group variants of responses to menthol that indicate individual differences in the sensitivity of skin receptors to the effects of methol and cold have been found. The results obtained give grounds to suggest that, from the variant of response to menthol (a decrease, increase, or absence of changes in the number of functioning cold receptors 5 min after menthol application), it is possible to predict specific features of response to cold.     

Subjects with Knee Osteoarthritis Exhibit Widespread Hyperalgesia to Pressure and Cold

Hyperalgesia to mechanical and thermal stimuli are characteristics of a range of disorders such as tennis elbow, whiplash and fibromyalgia. This study evaluated the presence of local and widespread mechanical and thermal hyperalgesia in individuals with knee osteoarthritis, compared to healthy control subjects. Twenty-three subjects with knee osteoarthritis and 23 healthy controls, matched for age, gender and body mass index, were recruited for the study. Volunteers with any additional chronic pain conditions were excluded. Pain thresholds to pressure, cold and heat were tested at the knee, ipsilateral heel and ipsilateral elbow, in randomized order, using standardised methodology. Significant between-groups differences for pressure pain and cold pain thresholds were found with osteoarthritic subjects demonstrating significantly increased sensitivity to both pressure (p = .018) and cold (p = .003) stimuli, compared with controls. A similar pattern of results extended to the pain-free ipsilateral ankle and elbow indicating widespread pressure and cold hyperalgesia. No significant differences were found between groups for heat pain threshold, although correlations showed that subjects with greater sensitivity to pressure pain were also likely to be more sensitive to both cold pain and heat pain. This study found widespread elevated pain thresholds in subjects with painful knee osteoarthritis, suggesting that altered nociceptive system processing may play a role in ongoing arthritic pain for some patients.     

Cutaneous sensory afferents recorded from the nervus intramandibularis ofGallus gallus vardomesticus

Summary The responses of single sensory afferent nerve fibres were recorded from small nerve bundles of the intramandibular nerve of the chicken following thermal and mechanical stimulation of the beak. Thermoreceptors, nociceptors and mechanoreceptors were identified and their responses characterized.Of the thermoreceptors identified 11 units were classified as cold receptors, which responded to cooling the receptive field by increasing the discharge rate and had conduction velocities in the range 0.83 to 4.4 m/s. Only one warm unit was identified.Two classes of nociceptors were identified: mechano-thermal (polymodal) nociceptors and high threshold mechanical nociceptors. The discharge characteristics and stimulus-response curves of both types were described. While the mechanothermal nociceptors were exclusively C-fibres (c.v. 0.4 to 1.86 m/s), the high threshold mechanoreceptors contained both C and A delta fibres (c.v. 1 to 5.5 m/s). Thermal response thresholds for the mechano-thermal units ranged from 41 to 50 °C with mechanical thresholds of 2 to over 50 g. Mechanical thresholds for the high threshold units ranged from 5 to over 50 g.The mechanoreceptors were either slowly or rapidly adapting. The pattern of response together with stimulus-response curves were presented for the slowly adapting units. Conduction velocities of the slowly adapting units varied from 0.7 to 20 m/s and mechanical threshold from 0.1 to 2 g. On the basis of their response to a vibrating, and a ramp-and-hold mechanical stimulus, the rapidly adapting units were divided into Herbst and Grandry units with only the Herbst units responding accurately to the vibrating stimulus. Both units had fibres conducting in the 50 m/s range with thresholds in the 0.1 to 10 g range.The results are discussed in relation to the receptors found in other avian species and mammalian peripheral sensory afferents.Abbreviations c.v. conduction velocity - RA rapidly adapting (receptors) - SA slowly adapting (receptors)     

Location of heat sensitive region in human skin

Heat sensitive points on the body skin were investigated in the course of psychophysiological research using thermal and mechanical stimulation on 98 volunteers residing under conditions of pronounced continental climate, in the town of Alma-Ata, with an age range of 20 to 46. Heat sensitive and cold sensitive points were divided into four and two classes respectively on the basis of minimum arousal threshold and nature of the sensation. Receptors of each class were located in the skin at the areas of greatest concentration. Comparison of the thermal range of activity and numbers of active points at different cutaneous sites in humans revealed their differing capacity for perception of different temperature levels.Institute of Physiology, Kazakhstan Academy of Sciences, Alma-Ata. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 591–598, September–October, 1992.     

Effect of central axotomy of sensory neurones on the mechanoreception recovery in initial regeneration of the injured sciatic nerve in rats

No apparent effect of lumbar dorsal rhizotomy performed simultaneously with the peripheral nerve injury, has been revealed on the triggering of regeneration of sensitive nerve fibers. Re-innervation of the foot skin by either decentralized regeneration of nerve fibers or those sustaining their connections with the central nervous system (CNS), has been shown to start 30 days after surgery. Using the recording of impulse activity of a single nerve fibre, the mechanical thresholds of decentralized regenerating receptors were found to be significantly higher as compared to the thresholds of the regenerating receptors sustaining their connections with the CNS. The findings suggest that afferent nerve fibers and mechanical receptors formed on the periphery, continue functioning after decentralization and sustain their regenerative capacity after injury. However, in marked contrast, the decrease in sensitivity of regenerating receptors is more pronounced.     

How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation

Recognition of temperature is a critical element of sensory perception and allows us to evaluate both our external and internal environments. In vertebrates, the somatosensory system can discriminate discrete changes in ambient temperature, which activate nerve endings of primary afferent fibers. These thermosensitive nerves can be further segregated into those that detect either innocuous or noxious (painful) temperatures; the latter neurons being nociceptors. We now know that thermosensitive afferents express ion channels of the transient receptor potential (TRP) family that respond at distinct temperature thresholds, thus establishing the molecular basis for thermosensation. Much is known of those channels mediating the perception of noxious heat; however, those proposed to be involved in cool to noxious cold sensation, TRPM8 and TRPA1, have only recently been described. The former channel is a receptor for menthol, and links the sensations provided by this and other cooling compounds to temperature perception. While TRPM8 almost certainly performs a critical role in cold signaling, its part in nociception is still at issue. The latter channel, TRPA1, is activated by the pungent ingredients in mustard and cinnamon, but has also been postulated to mediate our perception of noxious cold temperatures. However, a number of conflicting reports have suggested that the role of this channel in cold sensation needs to be confirmed. Thus, the molecular logic for the perception of cold-evoked pain remains enigmatic. This review is intended to summarize our current understanding of these cold thermoreceptors, as well as address the current controversy regarding TRPA1 and cold signaling.     

Corneal Sensitivity and Dry Eye Symptoms in Patients with Keratoconus

Purpose

To investigate corneal sensitivity to selective mechanical, chemical, and thermal stimulation and to evaluate their relation to dry eye symptoms in patients with keratoconus.

Methods

Corneal sensitivity to mechanical, chemical, and thermal thresholds were determined using a gas esthesiometer in 19 patients with keratoconus (KC group) and in 20 age-matched healthy subjects (control group). Tear film dynamics was assessed by Schirmer I test and by the non-invasive tear film breakup time (NI-BUT). All eyes were examined with a rotating Scheimpflug camera to assess keratoconus severity.

Results

KC patients had significatly decreased tear secretion and significantly higher ocular surface disease index (OSDI) scores compared to controls (5.3±2.2 vs. 13.2±2.0 mm and 26.8±15.8 vs. 8.1±2.3; p<0.001). There was no significant difference in NI-BUT between the two groups (KC: 9.8±4.8 vs. control: 10.7±3.8; p>0.05). The mean threshold for selective mechanical (KC: 139.2±25.8 vs. control: 109.1±24.0 ml/min), chemical (KC: 39.4±3.9 vs. control: 35.2±1.9%CO₂), heat (KC: 0.91±0.32 vs. control: 0.54±0.26 Δ°C) and cold (KC: 1.28±0.27 vs. control: 0.98±0.25 Δ°C) stimulation in the KC patients were significantly higher than in the control subjects (p<0.001, for all parameters). No correlation was found between age and mechanical, chemical, heat or cold thresholds in the patients with KC (p>0.05), whereas in the control subjects both mechanical (r = 0.52, p = 0.02), chemical (r = 0.47, p = 0.04), heat (r = 0.26, p = 0.04) and cold threshold (r = 0.40, p = 0.03) increased with age. In the KC group, neither corneal thickness nor tear flow, NI-BUT or OSDI correlated significantly with mechanical, chemical, heat or cold thresholds (p>0.05 for all variables).

Conclusions

Corneal sensitivity to different types of stimuli is decreased in patients with keratoconus independently of age and disease severity. The reduction of the sensory input from corneal nerves may contribute to the onset of unpleasant sensations in these patients and might lead to the impaired tear film dynamics.     

Hypothalamic mechanisms in thermoregulation

Certain preoptic and rostral hypothalamic neurons are sensitive to changes in local preoptic temperature (Tpo). These neurons also receive much afferent input from peripheral thermoreceptors and control a variety of thermoregulatory responses. In thermode-implanted animals, preoptic warming increases the firing rate in warm-sensitive neurons and elicits heat loss responses such as panting and sweating. Preoptic cooling increases the firing rate in cold-sensitive neurons and elicits, first, heat retention responses (e.g., cutaneous vasoconstriction and thermoregulatory behavior), then heat production responses (e.g., shivering and nonshivering thermogenesis). It is likely that the preoptic thermosensitive neurons control these thermoregulatory responses because both respond similarly to changes in Tpo and skin temperature. Specifically, skin warming not only increases panting, skin blood flow, and the firing rate of warm-sensitive neurons, but also decreases the sensitivity of all these responses to Tpo changes. Skin cooling not only increases metabolic heat production, heat retention behavior, and the firing rate of cold-sensitive neurons, but also increases the hypothalamic thermosensitivity of all these responses. Low-firing warm-sensitive neurons receive little afferent input and are most sensitive to high Tpo. Many of these low-firing neurons probably serve in controlling heat loss responses. High-firing warm-sensitive neurons receive much excitatory afferent input and are usually sensitive only to low Tpo. These neurons probably exert their greatest influence on heat production responses, possibly by inhibiting and, thus, determining the thermosensitive characteristics of nearby cold-sensitive neurons.     

The enigma of deep-body thermosensory specificity

Information provided by the analysis of peripheral cold and warm receptors may be considered a useful guide for assessing the specificity of thermal information originating in deep-body tissues. A wealth of data concerning the location of deep-body thermosensors and their neuronal correlates and modes of transduction permits the following theses to be proposed. 1. Unlike the peripheral warm and cold receptors, deep-body thermosensors are only in part represented by afferent fibers, mostly warm sensitive ones that are not character- ized in detail, as the source of thermal information outside the central nervous system (CNS). The more important thermal information generated in the CNS originates mainly from warm-sensitive neurons but contributions of cold-sensitive neurons are not definitely excluded. 2. Unlike the peripheral thermoreceptors, monomodality with respect to natural physical stimuli does not seem to be an essential property of deep-body thermosensors. By contrast, multimodality may underlie at least some of the multitude of interactions between thermoregulatory and other homeostatic control systems. 3. Temperature transduction seems to utilize molecular mechanisms that are also found in neurons that lack any thermosensory functions, and so the transduction mechanisms identified in warm-sensitive CNS neurons do not seem to be specific per se. 4. The observation of a multitude of temperature/response characteristics for thermosensitive CNS neurons has been helpful for categorizing these neurons, but there is no clear information that any one might be particularly relevant. 5. Originating from the peripheral cold and warm receptors two separate but interacting cold- and warm-signal pathways ascend multisynaptically to the hypothalamus as the highest level of thermoregulatory control, and to some extent go further to the sensory cortex. The signal contributed by a deep-body thermosensitive neuron, irrespective of its location, attains specificity by being fed properly into one of the two ascending thermosensory pathways. Received: 25 January 2000 / Accepted: 10 April 2000     

Characteristics of the formation of temperature information in afferent units

The impulse activity of single afferent fibers of the dorsal roots of the cat spinal cord is studied for local mechanical, heat, and cold influences on the skin receptor fields. A probability analysis of the impulse flux suggests that a change occurs in the distributions of the intervals between impulses in accordance with the stimuli presented, regardless of the variations in the mean frequency of impulsation. It is hypothesized that the afferent fibers acquire polyfunctional properties on account of their multichannel information.Institute of Physiology, Kazakhstan, Academy of Sciences, Alma-Ata. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 582–591, September–October, 1992.     

Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea

Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.     

Modulating effect of calcium on the cold defense response formation in normotensive and hypertensive rats

The effect of iontophoretic administration of calcium ions to skin in the area of cold stimulus application on the thermal thresholds and the magnitude of cold defense responses in normotensive Wistar and hypertensive inherited stress-induced arterial hypertensive rats was studied.In thermoneutral conditions, administration of calcium ions was without effect on the measured thermoregulatory parameters.Under the effect of calcium, the thresholds of all the thermoregulatory responses to rapid cooling (such as heat loss, oxygen consumption, shivering) are lowered and the values of heat loss and shivering thermogenesis are considerably increased. All changes are more expressive in hypertensive rats.The increased sensitivity of hypertensives to calcium suggests that change in their calcium metabolism may be a cause of the observed shifts in the thermoregulatory response to cold.     

Structure of spike activity of cold thermoreceptors at its various levels

In acute experiments on anesthetized rabbits we investigated the spike activity of cold fibers of the infraorbital nerve during a steady decrease in skin temperature from 39 to 7°C at a rate of 0.8 ± 0.05°/min. Analysis of interspike intervals (ISI) in the firing of receptors demonstrated that in the investigated range of skin temperatures the ISI histograms changed significantly several times, reflecting a shift in the pattern of firing. In addition, the reactions of each cold thermoreceptor had individual aspects, which lays the foundation for discussion of the perception of various characteristics of the temperature stimulus of the set of thermoreceptors.I. P. Pavlov Physiology Institute, Russian Academy of Sciences, Saint Petersburg. Translated from Neirofiziologiya, Vol. 24, No. 5, pp. 559–566, September–October, 1992.     

TREK-1 is a heat-activated background K(+) channel

Peripheral and central thermoreceptors are involved in sensing ambient and body temperature, respectively. Specialized cold and warm receptors are present in dorsal root ganglion sensory fibres as well as in the anterior/preoptic hypothalamus. The two-pore domain mechano-gated K(+) channel TREK-1 is highly expressed within these areas. Moreover, TREK-1 is opened gradually and reversibly by heat. A 10 degrees C rise enhances TREK-1 current amplitude by approximately 7-fold. Prostaglandin E2 and cAMP, which are strong sensitizers of peripheral and central thermoreceptors, reverse the thermal opening of TREK-1 via protein kinase A-mediated phosphorylation of Ser333. Expression of TREK-1 in peripheral sensory neurons as well as in central hypothalamic neurons makes this K(+) channel an ideal candidate as a physiological thermoreceptor.     

Effect of rapid and slow cooling on thermoregulatory responses in hypertensive and normotensive rats after calcium administration

The effect of iontophoretic administration of calcium ions to skin in the area of cold stimulus application on the thermal thresholds and the magnitude of cold defense responses in normotensive Wistar and hypertensive ISIAH rats was studied. In thermoneutral conditions, administration of calciumions wos without effect on the measured thermoregulatory parameters. Under the effect of calcium, the thresholds of all the thermoregulatory responses to cooling (such as heat loss, oxygen consumption, shivering) are lowered and the values of heat loss and shivering thermogenesis are considerably increased. The effects of calcium on thermoregulatory responses depend on the rate of cooling. All changes are more expressive in hypertensive rats. The increased sensitivity of hypertensives to calcium suggests that change in their calcium metabolism may be a cause of the observed shifts in the thermoregulatory response to cold.     

Significant Determinants of Mouse Pain Behaviour

Transgenic mouse behavioural analysis has furthered our understanding of the molecular and cellular mechanisms underlying damage sensing and pain. However, it is not unusual for conflicting data on the pain phenotypes of knockout mice to be generated by reputable groups. Here we focus on some technical aspects of measuring mouse pain behaviour that are often overlooked, which may help explain discrepancies in the pain literature. We examined touch perception using von Frey hairs and mechanical pain thresholds using the Randall-Selitto test. Thermal pain thresholds were measured using the Hargreaves apparatus and a thermal place preference test. Sodium channel Nav1.7 knockout mice show a mechanical deficit in the hairy skin, but not the paw, whilst shaving the abdominal hair abolished this phenotype. Nav1.7, Nav1.8 and Nav1.9 knockout mice show deficits in noxious mechanosensation in the tail, but not the paw. TRPA1 knockout mice, however, have a loss of noxious mechanosensation in the paw but not the tail. Studies of heat and cold sensitivity also show variability depending on the intensity of the stimulus. Deleting Nav1.7, Nav1.8 or Nav1.9 in Nav1.8-positive sensory neurons attenuates responses to slow noxious heat ramps, whilst responses to fast noxious heat ramps are only reduced when Nav1.7 is lost in large diameter sensory neurons. Deleting Nav1.7 from all sensory neurons attenuates responses to noxious cooling but not extreme cold. Finally, circadian rhythms dramatically influence behavioural outcome measures such as von Frey responses, which change by 80% over the day. These observations demonstrate that fully characterising the phenotype of a transgenic mouse strain requires a range of behavioural pain models. Failure to conduct behavioural tests at different anatomical locations, stimulus intensities, and at different points in the circadian cycle may lead to a pain behavioural phenotype being misinterpreted, or missed altogether.     

Whole-body vibration mediates mechanical hypersensitivity through Aβ-fiber and C-fiber thermal sensation in a chronic pain model

Whole-body vibration (WBV), which is widely used as a type of exercise, involves the use of vibratory stimuli and it is used for rehabilitation and sports performance programmes. This study aimed to investigate the effect of WBV treatment in a chronic pain model after 10 WBV sessions. An animal model (chronic pain) was applied in 60 male Wistar rats (±180 g, 12 weeks old) and the animals were treated with low intensity exercise (treadmill), WBV (vibrating platform), and a combined treatment involving both. The controls on the platform were set to a frequency of 42 Hz with 2 mm peak-to-peak displacement, g ≈ 7, in a spiral mode. Before and after the vibration exposure, sensitivity was determined. Aβ-fibers-mediated mechanical sensitivity thresholds (touch-pressure) were measured using a pressure meter. C-fibers-mediated thermal perception thresholds (hot pain) were measured with a hot plate. After each session, WBV influenced the discharge of skin touch-pressure receptors, reducing mechanical sensitivity in the WBV groups (P < 0.05). Comparing the conditions “before vs. after”, thermal perception thresholds (hot pain) started to decrease significantly after the third WBV session (P < 0.05). WBV decreases mechanical hyperalgesia after all sessions and thermal sensitivity after the third session with the use of WBV.     

Body Site Variation of Heat Pain Sensitivity

Thirty-two healthy human subjects provided thresholds for the perception of slight and moderate heat pain. Four body sites were tested bilaterally: thenar eminence of the hand, plantar surface of the foot, dorsolateral forearm, and lateral calf. Thresholds for the glabrous skin of the hand and foot were significantly greater than thresholds for the hairy skin of the arm and leg, the average difference being 1.3°c. Laterality was not a statistically significant factor. Thresholds increased progressively over 2–4 weeks of repeated testing, resulting in values averaging 0.6°c higher in the later sessions. The difference between moderate and slight pain thresholds averaged 1.1°c, and was consistent across body sites and with repeated testing.

The threshold values were normally distributed across subjects. Considerable intersubject variability was observed for both slight and moderate pain thresholds, more so on glabrous than on hairy skin sites. In comparison, the distribution of right-left difference values was narrower, demonstrating less intrasubject versus intersubject variability.

The highly significant difference in thresholds between glabrous and hairy skin sites demonstrates the importance of skin type for heat pain sensitivity. In contrast, there was no significant difference in heat pain sensitivity between comparable sites on the upper versus lower extremities, or between left and right sides.