Synthetic heat at mild temperatures

"Synthetic heat", also known as the heat grill illusion, occurs when contact with spatially adjacent warm and cold stimuli produce a sensation of "heat". This phenomenon has been explained as a painful perception that occurs when warm stimulation inhibits cold-sensitive neurons in the spinothalamic tract (STT), which in turn unmasks activity in the pain pathway caused by stimulation of C-polymodal nociceptors (CPNs). The "unmasking model" was tested in experiment 1 by combining warm (35-40°C) and cool ( &#83 27°C) stimuli that were too mild to stimulate CPNs. After discovering that these temperatures produced nonpainful heat, experiment 2 was designed to determine whether heat could be induced when near-threshold cooling was paired with mild warmth, and whether lowering the base temperature for cooling would increase the noxious (burning, stinging) components of heat for fixed cooling steps of 1-3°C. Cooling by just 1°C from a base temperature of 33°C led to reports of heat on more than 1/3 of trials, and cooling by just 3°C evoked heat on 75% of trials. Lowering the base temperature to 31 or 29°C increased reports of heat and burning but did not produce significant reports of pain. Perception of nonpainful heat at such mild temperatures indicates either that cold-sensitive nociceptors with thresholds very similar to cold fibers innervate hairy skin in humans, or that heat can result from integration of warm fiber and cold fiber activity, perhaps via convergence on nonspecific (e.g., WDR) neurons in the STT.     

Individual differences in temperature perception: evidence of common processing of sensation intensity of warmth and cold

The longstanding question of whether temperature is sensed via separate sensory systems for warmth and cold was investigated by measuring individual differences in perception of nonpainful heating and cooling. Sixty-two subjects gave separate ratings of the intensity of thermal sensations (warmth, cold) and nociceptive sensations (burning/stinging/pricking) produced by cooling (29 degrees C) or heating (37 degrees C) local regions of the forearm. Stimuli were delivered via a 4 x 4 array of 8 mm x 8 mm Peltier thermoelectric modules that enabled test temperatures to be presented sequentially to individual modules or simultaneously to the full array. Stimulation of the full array showed that perception of warmth and cold were highly correlated (Pearson r = 0.83, p < 0.05). Ratings of nonpainful nociceptive sensations produced by the two temperatures were also correlated, but to a lesser degree (r = 0.44), and the associations between nociceptive and thermal sensations (r = 0.35 and 0.22 for 37 and 29 degrees C, respectively) were not significant after correction for multiple statistical tests. Intensity ratings for individual modules indicated that the number of responsive sites out of 16 was a poor predictor of temperature sensations but a significant predictor of nociceptive sensations. The very high correlation between ratings of thermal sensations conflicts with the classical view that warmth and cold are mediated by separate thermal modalities and implies that warm-sensitive and cold-sensitive spinothalamic pathways converge and undergo joint modulation in the central nervous system. Integration of thermal stimulation from the skin and body core within the thermoregulatory system is suggested as the possible source of this convergence.     

The Sensory Effects of l-Menthol on Human Skin

Psychophysical measurements were made of the sensory effects of l-menthol applied topically to the forearm under controlled thermal conditions. In the first experiment, subjects judged the intensity and quality of sensations produced by warming or cooling the skin in the presence of menthol or the vehicle. During cooling, menthol intensified cutaneous sensations and increased reports of burning. During warming, menthol intensified sensations transiently at low temperatures and weakened them lastingly at higher temperatures; the frequency of reports of burning varied with intensity. A second experiment tested the hypothesis that menthol would lower the threshold for warmth and raise the threshold for heat pain. No change in either threshold was observed. The primary sensory effects of l-menthol on hairy skin are therefore to heighten the perception of cooling and to attenuate the perception of moderate warming. In contrast with other common chemical irritants, menthol's pungent qualities appear to be enhanced by cooling and suppressed by warming; this suggests that its sensory irritancy may be attributable to the stimulation of a population of high-threshold cold fibers or cold-sensitive nociceptors.     

Individual differences in temperature perception: Evidence of common processing of sensation intensity of warmth and cold

The longstanding question of whether temperature is sensed via separate sensory systems for warmth and cold was investigated by measuring individual differences in perception of nonpainful heating and cooling. Sixty-two subjects gave separate ratings of the intensity of thermal sensations (warmth, cold) and nociceptive sensations (burning/stinging/pricking) produced by cooling (29°C) or heating (37°C) local regions of the forearm. Stimuli were delivered via a 4?×?4 array of 8 mm?×?8?mm Peltier thermoelectric modules that enabled test temperatures to be presented sequentially to individual modules or simultaneously to the full array. Stimulation of the full array showed that perception of warmth and cold were highly correlated (Pearson r?=?0.83, p?<?0.05). Ratings of nonpainful nociceptive sensations produced by the two temperatures were also correlated, but to a lesser degree (r?=?0.44), and the associations between nociceptive and thermal sensations (r?=?0.35 and 0.22 for 37 and 29°C, respectively) were not significant after correction for multiple statistical tests. Intensity ratings for individual modules indicated that the number of responsive sites out of 16 was a poor predictor of temperature sensations but a significant predictor of nociceptive sensations. The very high correlation between ratings of thermal sensations conflicts with the classical view that warmth and cold are mediated by separate thermal modalities and implies that warm-sensitive and cold-sensitive spinothalamic pathways converge and undergo joint modulation in the central nervous system. Integration of thermal stimulation from the skin and body core within the thermoregulatory system is suggested as the possible source of this convergence.     

Integration of temperature and olfactory information in cockroach antennal lobe glomeruli

Individual neurons in the antennal lobe of the cockroach not only respond to warming, cooling and the odor of lemon oil but they also integrate the responses to simultaneously occurring temperature and olfactory stimuli. This integration results in an increase or decrease of the neuron's activity as compared to its responses to the temperature stimuli presented alone. The mean gain for a change in temperature in the warm and cold direction is 9.5 (imp s(-1)) degrees C(-1) and 10.2 (imp s(-1)) degrees C(-1), respectively. Thus, the average neuron elevates its impulse frequency by 1 imp s(-1) when temperature is increased by 0.1 degree C or decreased by 0.09 degree C. Examination of response scatter reveals that the difference required between two warm or two cold stimuli to be discriminated is 0.5 degree C. Similar values for gain and resolving power are obtained for the enhanced responses to the warm-odor and the cold-odor stimulus combinations. The neurons described are: (1) local interneurons innervating a number of glomeruli distributed within the antennal lobe, and (2) projection neurons collecting information from single glomeruli at 140-280 microm from the surface of the antennal lobe and providing links with the calyces of the mushroom bodies and the lateral lobe of the protocerebrum.     

Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin

Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.     

Peripheral blood flow during rewarming from mild hypothermia in humans

During the initial stages of rewarming from hypothermia, there is a continued cooling of the core, or after-drop in temperature, that has been attributed to the return of cold blood due to peripheral vasodilatation, thus causing a further decrease of deep body temperature. To examine this possibility more carefully, subjects were immersed in cold water (17 degrees C), and then rewarmed from a mildly hypothermic state in a warm bath (40 degrees C). Measurements of hand blood flow were made by calorimetry and of forearm, calf, and foot blood flows by straingauge venous occlusion plethysmography at rest (Ta = 22 degrees C) and during rewarming. There was a small increase in skin blood flow during the falling phase of core temperature upon rewarming in the warm bath, but none in foot blood flow upon rewarming at room air, suggesting that skin blood flow seems to contribute to the after-drop, but only minimally. Limb blood flow changes during this phase suggest that a small muscle blood flow could also have contributed to the after-drop. It was concluded that the after-drop of core temperature during rewarming from mild hypothermia does not result from a large vasodilatation in the superficial parts of the periphery, as postulated. The possible contribution of mechanisms of heat conduction, heat convection, and cessation of shivering thermogenesis were discussed.     

Thermal balance and survival time prediction of man in cold water.

Metabolic rates and rectal temperatures were continuously monitored for humans immersed in cold ocean water (4.6--18.2 degrees C) under stimulated accident conditions. The subjects wore only light clothing and a kapok lifejacket while either holding-still or swimming. While holding-still, metabolic heat production (Hm,kcal-min--1) was inversely related to water temperature (Tw, degrees C) according to the equation Hm equals 4.19 minus-0.117 Tw. This temperature response pattern is shown to be similar to that for exposure to air of the same temperature when air velocity is just over 5 m.p.h. (2.24 m/s). The thermogenic response was one-third efficient in balancing the calculated heat loss in cold water, resulting in hypothermia at a rectal temperature cooling rate (C, degrees C-min--1) dependent on water temperature (Tw, degrees C) according to the relation C equal 0.0785 - 0.0034Tw. Although swimming increased heat production to 2.5 times that of holding-still at 10.5 degrees C water temperature, cooling rate was 35% greater while swimming. A prediction equation for survival time (ts, min) of persons accidentally immersed in cold water (Tw, degrees C) has the form ts equal 15 + 7.2/(0.0785-0.0034Tw), based on the findings of this study, and it is compared to pre-existing models.     

Deep interscapular temperature and thermogenesis of brown fat during sleep

Deep interscapular temperature measured just below the brown fat lobes was studied in rats during sleep at two ambient temperatures (24 degrees C and 4 degrees C) before and after adaptation (9 days) to cold (4 degrees C). The results show that in the cold ambient deep interscapular temperature decreases during desynchronized sleep independently of adaptation. Such change in temperature is probably the result of the depression in sympathetic vasoconstrictor influences on heat exchangers producing blood and brown fat cooling in sequence during this stage of sleep.     

Cortical activation changes during repeated laser stimulation: a magnetoencephalographic study

Repeated warm laser stimuli produce a progressive increase of the sensation of warmth and heat and eventually that of a burning pain. The pain resulting from repetitive warm stimuli is mediated by summated C fibre responses. To shed more light on the cortical changes associated with pain during repeated subnoxious warm stimulation, we analysed magnetoencephalographic (MEG) evoked fields in eleven subjects during application of repetitive warm laser stimuli to the dorsum of the right hand. One set of stimuli encompassed 10 laser pulses occurring at 2.5 s intervals. Parameters of laser stimulation were optimised to elicit a pleasant warm sensation upon a single stimulus with a rise of skin temperature after repeated stimulation not exceeding the threshold of C mechano-heat fibres. Subjects reported a progressive increase of the intensity of heat and burning pain during repeated laser stimulation in spite of only mild (4.8°C) increase of skin temperature from the first stimulus to the tenth stimulus. The mean reaction time, evaluated in six subjects, was 1.33 s, confirming involvement of C fibres. The neuromagnetic fields were modelled by five equivalent source dipoles located in the occipital cortex, cerebellum, posterior cingulate cortex, and left and right operculo-insular cortex. The only component showing statistically significant changes during repetitive laser stimulation was the late component of the contralateral operculo-insular source peaking at 1.05 s after stimulus onset. The amplitude increases of the late component of the contralateral operculo-insular source dipole correlated with the subjects' numerical ratings of warmth and pain. Results point to a pivotal role of the contralateral operculo-insular region in processing of C-fibre mediated pain during repeated subnoxious laser stimulation.     

Modulation of oral heat and cold pain by irritant chemicals

Common food irritants elicit oral heat or cool sensations via actions at thermosensitive transient receptor potential (TRP) channels. We used a half-tongue, 2-alternative forced-choice procedure coupled with bilateral pain intensity ratings to investigate irritant effects on heat and cold pain. The method was validated in a bilateral thermal difference detection task. Capsaicin, mustard oil, and cinnamaldehyde enhanced lingual heat pain elicited by a 49 degrees C stimulus. Mustard oil and cinnamaldehyde weakly enhanced lingual cold pain (9.5 degrees C), whereas capsaicin had no effect. Menthol significantly enhanced cold pain and weakly reduced heat pain. To address if capsaicin's effect was due to summation of perceptually similar thermal and chemical sensations, one-half of the tongue was desensitized by application of capsaicin. Upon reapplication, capsaicin elicited little or no irritant sensation yet still significantly enhanced heat pain on the capsaicin-treated side, ruling out summation. In a third experiment, capsaicin significantly enhanced pain ratings to graded heat stimuli (47 degrees C to 50 degrees C) resulting in an upward shift of the stimulus-response function. Menthol may induce cold hyperalgesia via enhanced thermal gating of TRPM8 in peripheral fibers. Capsaicin, mustard oil, and cinnamaldehyde may induce heat hyperalgesia via enhanced thermal gating of TRPV1 that is coexpressed with TRPA1 in peripheral nociceptors.     

Thermosensory intensity and affect throughout the perceptible range

The thermosensory system was evaluated psychophysically in 12 healthy volunteers, spanning the full range of tolerable temperatures. Subjects provided ratings of (1) perceived thermal intensity, (2) perceived pleasantness or unpleasantness, and (3) perceived pain intensity after placing either one hand or foot in a temperature controlled water bath. Of particular interest were the interrelationships among the three perceptual measures, and differences between heat and cold. The relationship between perceived intensity and (un)pleasantness was different for hot vs cold stimuli. Specifically, for a given perceived thermal intensity, cold stimuli were rated as less pleasant or more unpleasant than hot stimuli. Similarly, for a given pain intensity, cold stimuli were rated as more unpleasant than hot stimuli. As warm temperatures increased and as cold temperatures decreased, stimuli were perceived as being unpleasant before they were perceived as being painful. The difference in transition temperatures for unpleasantness vs pain for heat averaged 1.4 degrees C, while the same difference for cold averaged 5.6 degrees C. Thus, there was a fourfold difference in the range of unpleasant but non-painful cold vs hot temperatures. Pain intensity and unpleasantness ratings were significantly higher for heat stimuli applied to the foot vs hand. In contrast, there was no significant body site difference for pain intensity or unpleasantness ratings of cold stimuli. All of these results reveal important differences in the processing of cold vs hot stimuli. These differences could be exploited to differentiate processing relevant to discriminative vs affective components of somesthetic perception, in both the innocuous and noxious ranges.     

Depression of sublingual temperature by cold saliva.

Sublingual and oesophageal temperatures were compared at various air temperatures in 16 subjects. In warm air (25-44 degrees C) sublingual temperatures stabilized within plus or minus 0-45 degrees C of oesophageal temperatures, but in air at room temperature (18-24 degrees C) they were sometimes as much as 1-1 degrees C below and in cold air (5-10 degrees C) as much as 4-4 degrees C below oesophageal readings. The sublingual-oesophageal temperature difference in cold air was greatly reduced by keeping the face warm, but it was not reduced in two patients breathing through tracheostomies and thereby eliminating cold air flow from the nose and pharynx. Parotid saliva temperature was low and saliva flow high during exposure, and cold saliva seemed to be mainly responsible for the erratic depression of sublingual temperature in the cold. These results indicate hazards in the casual use of sublingual temperatures, and indicate that external heat may have to be supplied to enable them to give reliable clinical assessments of body temperature.     

Site-dependent and subject-related variations in perioral thermal sensitivity

The Marstock method of limits was used to obtain thresholds for detection of cooling, warming, cold pain and heat pain for 34 young adults, upon eight spatially matched sites on the left and right sides of the face, the right ventral forearm and the scalp. Male and female subjects were tested by both a male and a female experimenter. Neither the experimenter nor the gender of the subject individually influenced the thresholds. The thermal thresholds varied greatly across facial sites: sixfold and tenfold for cool and warmth, respectively, from the most sensitive sites on the vermilion to the least sensitive facial site, the preauricular skin. Warm thresholds were 68% higher than cool thresholds, on average, and 12% higher on the left compared to the right side of the face. The mean cold pain threshold increased from 21.0 degrees C on the hairy upper lip to 17.8 degrees C on the preauricular skin. Sites on the upper lip were also most sensitive to noxious heat with pain thresholds of 42-43 degrees C. The scalp was notably insensitive to innocuous and noxious changes in temperature. For the sensations of nonpainful cool and warmth, the more sensitive a site, the less the estimates of the thresholds differed between subjects. In contrast, for heat pain, the more sensitive a site, the more the estimates differed between subjects. Subjects who were relatively more sensitive to cool tended to be relatively more sensitive to warmth. Subjects' sensitivities to nonpainful cool and warmth were less predictive of their sensitivities to painful cold and heat, respectively. Short-term within-subject variability increased with the magnitude of the thresholds. The lower the threshold, the more similar were repeated measurements of it, within a 5-25 s period.     

Procedures for handling fresh stallion semen

Handling procedures for semen to be used at the stud-farm and for transport are reviewed. Proper handling of semen is required throughout the entire process, from semen collection to the insemination of the mare. Semen shall not be exposed to mechanical damage, light, cold or heat. All equipment that comes in contact with semen must be warm, clean, dry and free from toxic residues. Skim-milk extender appears to be the medium best suited for the preservation of stallion semen during cooling and storage. When used immediately, semen is usually extended 1:1 (v:v), but for transport, concentrations of 25 to 100 x 10(6) spermatozoa/mL are recommended. The proportion of semen plasma should be reduced to < 20%. by centrifuging, by collecting only the first 3 sperm-rich fractions, or by substantially diluting of the ejaculate. The storage temperature can be between 20 to 15 degrees C, if shipment time is no more than 12 h; for longer storage, temperatures < 10 degrees C are recommended. Semen can be cooled rapidly from 35 to 19 degrees C. In the temperature zone between 19 and 8 degrees C, stallion spermatozoa are sensitive to cold shock, and the cooling rate should be slowed to 0.05 degrees C/min. Rapid cooling can be resumed below 8 degrees C. At low temperatures, removal of oxygen-rich air is beneficial for the survival of spermatozoa. The Equitainer transport container keeps a constant temperature of 5 degrees C for 48 h and is therefore recommended for transportation lasting over 24 h.     

Effects of heating and cooling on nerve terminal impulses recorded from cold-sensitive receptors in the guinea-pig cornea

An in vitro preparation of the guinea-pig cornea was used to study the effects of changing temperature on nerve terminal impulses recorded extracellularly from cold-sensitive receptors. At a stable holding temperature (31-32.5 degrees C), cold receptors had an ongoing periodic discharge of nerve terminal impulses. This activity decreased or ceased with heating and increased with cooling. Reducing the rate of temperature change reduced the respective effects of heating and cooling on nerve terminal impulse frequency. In addition to changes in the frequency of activity, nerve terminal impulse shape also changed with heating and cooling. At the same ambient temperature, nerve terminal impulses were larger in amplitude and faster in time course during heating than those recorded during cooling. The magnitude of these effects of heating and cooling on nerve terminal impulse shape was reduced if the rate of temperature change was slowed. At 29, 31.5, and 35 degrees C, a train of 50 electrical stimuli delivered to the ciliary nerves at 10-40 Hz produced a progressive increase in the amplitude of successive nerve terminal impulses evoked during the train. Therefore, it is unlikely that the reduction in nerve terminal impulse amplitude observed during cooling is due to the activity-dependent changes in the nerve terminal produced by the concomitant increase in impulse frequency. Instead, the differences in nerve terminal impulse shape observed at the same ambient temperature during heating and cooling may reflect changes in the membrane potential of the nerve terminal associated with thermal transduction.     

Nociceptor activation and pain

This paper reviews advances in our knowledge on the physiological properties of human nociceptors and their capacity to signal pain. Conventional microneurography was used in combination with intraneural microstimulation in subjects who estimated the magnitude of pain from nociceptor stimulation. The experimental evidence favours the notion that C polymodal nociceptors can provide a peripheral neuronal basis for determination of heat pain threshold and also an essential peripheral code for suprathreshold magnitude judgments of heat pain. Furthermore, sensitized C polymodal nociceptors can contribute to hyperalgesia after a mild heat injury to hairy skin. Temporal summation is documented for dull, delayed C fibre pain, which is different in quality and less accurately projected than the fast, sharp pain from high-threshold A delta nociceptors. A segmental organization is shown for projected and referred pain from deep structures. Examples are given of central inhibition of pain by a prostaglandin synthetase inhibitor, and by physical manoeuvres such as vibration and cooling. Recent reports on microneurographic findings after nerve injury indicate that the technique may be useful for future studies on pathophysiological pain mechanisms.     

Acclimation of entomopathogenic nematodes to novel temperatures: trehalose accumulation and the acquisition of thermotolerance

The effect of thermal acclimation on trehalose accumulation and the acquisition of thermotolerance was studied in three species of entomopathogenic nematodes adapted to either cold or warm temperatures. All three Steinernema species accumulated trehalose when acclimated at either 5 or 35 degrees C, but the amount of trehalose accumulation differed by species and temperature. The trehalose content of the cold adapted Steinernema feltiae increased by 350 and 182%, of intermediate Steinernema carpocapsae by 146 and 122% and of warm adapted Steinernema riobrave by 30 and 87% over the initial level (18.25, 27.24 and 23.97 microg trehalose/mg dry weight, respectively) during acclimation at 5 and 35 degrees C, respectively. Warm and cold acclimation enhanced heat (40 degrees C for 8h) and freezing (-20 degrees C for 4h) tolerance of S. carpocapsae and the enhanced tolerance was positively correlated with the increased trehalose levels. Warm and cold acclimation also enhanced heat but not freezing tolerance of S. feltiae and the enhanced heat tolerance was positively correlated with the increased trehalose levels. In contrast, warm and cold acclimation enhanced the freezing but not heat tolerance of S. riobrave, and increased freezing tolerance of only warm acclimated S. riobrave was positively correlated with the increased trehalose levels. The effect of acclimation on maintenance of original virulence by either heat or freeze stressed nematodes against the wax moth Galleria mellonella larvae was temperature dependent and differed among species. During freezing stress, both cold and warm acclimated S. carpocapsae (84%) and during heat stress, only warm acclimated S. carpocapsae (95%) maintained significantly higher original virulence than the non-acclimated (36 and 47%, respectively) nematodes. Both cold and warm acclimated S. feltiae maintained significantly higher original virulence (69%) than the non-acclimated S. feltiae (0%) during heat but not freezing stress. In contrast, both warm and cold acclimated S. riobrave maintained significantly higher virulence (41%) than the non-acclimated (14%) nematodes during freezing, but not during heat stress. Our data indicate that trehalose accumulation is not only a cold associated phenomenon but is a general response of nematodes to thermal stress. However, the extent of enhanced thermal stress tolerance conferred by the accumulated trehalose differs with nematode species.     

Thermoelastic properties of uniaxially deformed lung strips

We examined the temperature dependence of small degassed hamster lung strip mechanics to develop insights into the molecular basis of lung elasticity. Quasi-static length-tension curves of adapted lung strips were generated at 10, 23, 37, 50, and 80 degrees C; quasi-static tension-temperature plots (QSTT) at strains of 0.5, 0.75, and 1.0 were then formulated. Static tension-temperature (STT) plots at strain 1 were independently generated from other strips. Stress relaxation was evaluated as a function of temperature at different strains; hysteresis ratio was calculated as a parameter of mechanical efficiency. Between 23 and 37 degrees C, the slopes of the QSTT plots at the different strains were close to zero. The slope of the STT plot was slightly positive, indicating that the tension developed by a stretched strip was primarily due to entropic changes with length, suggesting that strips behave like rubber polymers near physiological temperature. Between 10 and 23 degrees C, the slope of the QSTT curve was zero at the two lowest strains but was negative at strain 1; and slope of the STT curve was zero at strain 1. These data indicated that collagen fiber and possibly glycosaminoglycan function was abnormally affected at 10 degrees C. Between 50 and 80 degrees C at strain 1, the slopes of both the QSTT and STT plots at all strains were positive. These data suggested that elastic fiber function was altered between 50 and 80 degrees C such that both internal energetic and entropic contributions to the tension were changed. Stress relaxation and hysteresis data were consistent with these findings.(ABSTRACT TRUNCATED AT 250 WORDS)     

Capsaicin and nociception

The antinociceptive effect of capsaicin to noxious chemical stimuli has been invariably verified. As to thermal or mechanical nociception, however, routine pharmacological methods resulted in conflicting findings. Therefore, using new techniques the nociceptive thresholds of different stimuli were determined on the hindpaw of the rat. After systemic (400 mg/kg s.c.), perineural (1% on the sciatic nerve) and local (5 micrograms into the hindpaw) application of capsaicin the threshold for noxious heat (47.4 +/- 0.08) was shifted upwards by 3.3 degrees C, 4.1 degrees C and 2.9 degrees C, respectively. The changes in mechanonociceptive threshold evoked by pin prick (186 +/- 9 mN force) were more variable. The response to percutaneous xylene application was abolished or markedly inhibited. After systemic application the responsiveness to noxious heat recovered faster than the effect of xylene. C-polymodal nociceptors and some A-delta mechanoheat-sensitive nociceptors isolated from the saphenous nerve of the rat were activated by capsaicin in nanogram doses given close arterially. Five micrograms capsaicin excited few slowly adapting A mechanoreceptors after a long latency, but not A-delta mechanonociceptors or other cutaneous receptors. Proportion of C-polymodal nociceptors was decreased, that of the C-mechanoreceptors was increased after systemic treatment. The role of polymodal-type nociceptors, interaction of other nociceptors, as well as secondary dynamic changes are stressed to explain the antinociceptive effect of capsaicin.