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Query: UMLS:C0030193 (pain)
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Little is known concerning the mechanisms underlying the perception of cold pain in humans. An appreciation of these mechanisms is important to understand and possibly treat those disorders in which cold stimuli evoke unpleasant sensations. To study cold pain, I have conducted psychophysical experiments on 16 healthy subjects. A peltier-type stimulator (20 x 25 mm) was used to deliver stimuli to sites on the thenar eminence (glabrous skin) and volar forearm (hairy skin) of each arm. Each trial consisted of a 90 s, 2 degrees C stimulus that was preceded and followed by a 35 degrees C stimulus. A computer-based visual analog scale was used to collect continuous pain ratings throughout each trial. In experiment 1, nine subjects rated the overall evoked pain intensity (four trials/skin type) and the prickle component (four trials/skin type). Typically, subjects perceived the cold-evoked pain as prickly, cold/freezing and achy. The pain intensity and quality was similar for glabrous and hairy skin sites within individual subjects. Pain intensity gradually rose to a plateau by approximately 60 s into each trial. The prickle component differed amongst subjects due to its variable time course. Subjects consistently reported an intense, brief jab of prickle at both hairy and glabrous sites during the rewarming phase. In experiment 2, nine subjects rated the pain intensity during the cold stimulus before and during a compression-ischemic block of Abeta/Adelta fiber conduction. The dominant sensation evoked by the cold stimulus in the hairy and glabrous skin during the block was a sharp, hot/burning pain. The block did not consistently affect the total pain at the hairy sites. However, most subjects reported more pain during the block at the glabrous sites. These data suggest that noxious cold stimuli affect a mosaic of primary afferent input and central processing resulting in a complex pain experience which may differ in glabrous and hairy skin.
Pain 1998 Mar
PMID:Cold-induced pain and prickle in the glabrous and hairy skin. 953 73

To compare the heat responses of mechanically sensitive and mechanically insensitive A-fiber nociceptors, an electrical search technique was used to locate the receptive fields of 156 A-fibers that innervated the hairy skin in the anesthetized monkey (77 A beta-fibers, 79 A delta-fibers). Two-thirds of these afferents were either low-threshold mechanoreceptors (n = 91) or low-threshold cold receptors (n = 11). Nine A beta-fibers and 41 A delta-fibers were cutaneous nociceptors, and four A delta-fibers innervated subcutaneous tissue. The majority of cutaneous A-fiber nociceptors were heat sensitive (43/50 = 86%). Heat-insensitive cutaneous A-fiber nociceptors consisted of one cold nociceptor, three silent nociceptors, and three high-threshold mechanoreceptors. Two types of response were observed to an intense heat stimulus (53 degrees C, 30 s). Type I (n = 26) was characterized by a long latency (mean: 5 s) and a late peak discharge (16 s). Type II (n = 17) was characterized by a short latency (0.2 s) and an early peak discharge (0.5 s). Type I fibers exhibited faster conduction velocities (25 vs. 14 m/s) and higher heat thresholds (> 53 vs. 47 degrees C, 1-s duration) than type II fibers. The possibility that the type I heat response was a result of sensitization was tested in three fibers by determining the heat threshold to 30-s duration stimuli (42-46 degrees C). For this long stimulus duration heat thresholds were reproducible across multiple runs, and the threshold to the 1-s duration stimulus was not altered by these tests. Thus fibers with a type I heat response were not high-threshold mechanoreceptors that developed a heat response through sensitization. Fibers with a type II heat response had significantly higher mechanical thresholds (median: 15 bar) than fibers with a type I heat response (5 bar). This finding accounts for the observation that type II heat responses were infrequently observed in earlier studies wherein the search technique depended on mechanical responsiveness. Fibers with a type II response exhibited a graded response to heat stimuli, marked fatigue to repeated applications of heat stimuli, and adaptation to sustained heat stimuli similar to that seen in C-fiber nociceptors. First pain sensation to heat is served by type II A-fiber nociceptors that are mechanically insensitive. Type I A-fiber nociceptors likely signal pain to long-duration heat stimuli and may signal first pain sensation to mechanical stimuli.
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PMID:Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties. 974 23

Evidence suggests that nerve growth factor (NGF) is an important mediator in inflammatory pain states: NGF levels increase in inflamed tissue, and neutralization of endogenous NGF prevents the hyperalgesia which normally develops during inflammation of the skin. Here we asked whether NGF contributes to sensitization of primary afferent nociceptors, which are an important component of pain and hyperalgesia in inflamed tissue. An in vitro skin nerve preparation of the rat was used to directly record the receptive properties of thin myelinated (Adelta) and unmyelinated (C) nociceptors innervating normal hairy skin, carrageenan-inflamed skin and carrageenan-inflamed skin where endogenous NGF had been neutralized by application of a trkA-IgG (tyrosine kinase Aimmunoglobulin G) fusion molecule. Following carrageenan inflammation, there was a marked increase in the proportion of nociceptors which displayed ongoing activity (50% of nociceptors developed spontaneous activity compared to 4% of nociceptors innervating normal uninflamed skin), and this was reflected in a significant increase in the average ongoing discharge activity. Spontaneously active fibres were sensitized to heat and displayed a more than twofold increase in their discharge to a standard noxious heat stimulus. Furthermore, the number of nociceptors responding to the algesic mediator bradykinin increased significantly from 28% to 58%. By contrast, the mechanical threshold of nociceptive afferents did not change during inflammation. When the NGF-neutralizing molecule trkA-IgG was coadministered with carrageenan at the onset of the inflammation, primary afferent nociceptors did not sensitize and displayed essentially normal response properties, although the inflammation as evidenced by tissue oedema developed normally. We therefore conclude that NGF is a crucial component for the sensitization of primary afferent nociceptors associated with tissue inflammation.
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PMID:Neutralization of endogenous NGF prevents the sensitization of nociceptors supplying inflamed skin. 1021 23

Thermoregulatory and emotional sweating can be distinguished in humans. While the first is organized via feed back mechanisms involving thermoreceptors, thermoregulatory centers in the brain and the effector system (sympathetic nervous system and sweat glands), the latter is generated directly by cortical and limbic mechanisms without any feed back. Sweat glands on the hairy skin can be stimulated by thermoregulatory mechanisms (rising body temperature), the emotional sweating on the glabrous skin as a result of an arousal reaction and they can be stimulated by peripheral acting cholinergic agents, which initiate direct or axon reflex mediated sweating. To evaluate sweating there are qualitative methods that visualize the sweat response or indirect methods like the registration of skin potentials. Alternatively sweat output can be quantified by evaporative measurement. For best results these methods should be combined. In this way autonomic dysfunction e.g. after nerve lesions, in polyneuropathies, central lesions and certain pain disorders can be assessed. The sudomotor function tests complete the conventional electrophysiological methods.
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PMID:[The assessment of sudomotor function for diagnosis of autonomic diseases. Principles and methods]. 1044 39

Feedback-controlled laser heat was used to stimulate the hairy skin of the hand dorsum and forearm, and heat-evoked cerebral potentials were recorded at midline (Fz, Cz, Pz) and temporal (T3, T4) scalp positions. Based on data from primary afferent electrophysiology a stimulus level (40 degrees C) was chosen, which is above C-fiber heat threshold, but clearly below A delta-nociceptor heat threshold in order to excite selectively C-fibers without concomitant excitation of A delta-fibers. Feedback-controlled stepped heat stimuli to 40 degrees C elicited ultralate laser evoked potentials (LEPs) at the vertex in a high proportion of experiments (90%). Estimates of conduction velocity calculated from latency shifts between the hand and forearm sites of ultralate LEPs (2.4 m/s) and of reaction times (2.8 m/s) confirmed mediation of ultralate potentials by unmyelinated nerve fibers (nociceptors and/or warm fibers). The ultralate LEP could be differentiated from resolution of contingent negative variation (CNV), an endogenous potential related to expectation and response preparation, by its scalp topography. Strong heat stimuli of 48 degrees C, which is suprathreshold for most A delta- and C-fiber nociceptors, elicited the well-known late LEPs mediated by nociceptive Adelta-fibers confirming previous studies. The LEP waveform to strong heat stimuli also contained an ultralate component reminiscent of an ultralate LEP following the late LEP. Ultralate and late LEP had identical scalp topography. In conclusion, the method of temperature-controlled laser heat stimuli allows the selective and reliable examination of A delta- and C-fiber-mediated afferent pathways and the related cortical processing without the complication of dissociating A-fiber nerve blocks.
Pain 1999 Aug
PMID:C- and A delta-fiber components of heat-evoked cerebral potentials in healthy human subjects. 1046 18

The psychophysical responses to noxious cold stimulation of the skin in normal human subjects are not well understood. Continuous pain ratings with the visual analogue scale is an important method to assess these responses. In this study, we addressed several important issues about the parameters with which stimuli are delivered: the type of skin stimulated, the rate with which the stimulus temperature decreases, and the dimension of the pain rated by subjects. Cold stimuli were delivered to the thenar eminence (glabrous skin) and the dorso-lateral hand (hairy skin) via a 4 cm(2) Peltier-type stimulator. Cold and pain thresholds were determined by the method of limits (MOL). A computerized visual analogue scale (VAS) was used to obtain continuous ratings of pain intensity and affect. The McGill Pain Questionnaire (MPQ) was used to assess the quality of cold-evoked pain. Supra-threshold stimuli (34 degrees C base) were delivered at 0.5, 1 or 2 degrees C/s to 2 degrees C, held for 20s and returned to baseline at 9 degrees C/s. These studies revealed: (1) Cold thresholds, measured with MOL, were lower (i.e. occurred at higher absolute temperatures) for the hairy skin of the dorso-lateral hand compared to the glabrous skin of the thenar eminence. (2) A similar pattern was evident for cold induced pain thresholds with MOL at 1.5 degrees C/s and with intensity and affect VAS scales at 0.5 and 1 degrees C/s. (3) Exponents for supra-threshold ratings fit to power functions were larger for the glabrous skin site than the hairy skin site regardless of cooling rate or dimension of pain measured. (4) All pain indices were higher for slower cooling rates. (5) No significant differences were found in the pain indices for pain ratings of intensity and affect. (6) A substantial proportion of subjects chose words representing paradoxical heat with the MPQ. (7) Painful paradoxical heat sensations occurred most often during cooling, while innocuous warm sensations mainly occurred during the rewarming phase.
Pain 1999 Nov
PMID:Cold-evoked pain varies with skin type and cooling rate: a psychophysical study in humans. 1053 83

In the skin, noxious heating induces an axon reflex response which is commonly accepted to be due to the release of vasodilatory neuropeptides from polymodal nociceptors. In the present study, the quantitative assessment of calcitonin gene-related peptide (CGRP) release from rat skin serves as an integrative measure of primary afferent activation by noxious heat and the presumed sensitising action of bradykinin and an activator of protein kinase C (PKC). The isolated rat hairy skin of either hind paw was mounted on acrylic rods and exposed for 5 min periods to synthetic interstitial fluid of either 32 degrees C for control or of higher temperatures up to 59 degrees C during stimulation. In addition, experiments were performed in calcium free solution (containing 10 mM EGTA) or the skin was preloaded with the membrane permeant calcium chelator BAPTA-AM (1 mM). To look for modulatory effects on the heat responses, bradykinin or polymyristate-acetate (PMA) were added during heat stimulation in further experiments. Heating the skin induced a temperature-dependent release of CGRP from a threshold of 43 degrees C which was absent in calcium free solution. Only at the highest temperatures (55 and 59 degrees C) was a partially calcium-independent release observed. Inhibition of the release was also obtained with the intracellular calcium buffer BAPTA-AM. Bradykinin 10 but not 1 microM as well as PMA 1 and 10 microM significantly facilitated the heat-induced CGRP release at 47 degrees C whereby BK caused a marginal and PMA a significant CGRP release by itself. Our results indicate that moderate noxious heat induces calcium-dependent CGRP release and this can be facilitated by bradykinin and by the activation of PKC. This suggests the same sensitising mechanism that affects nociceptor heat responses.
Pain 1999 Nov
PMID:Heat-induced release of CGRP from isolated rat skin and effects of bradykinin and the protein kinase C activator PMA. 1053 1

Temporal summation of pain is suggested to be an important factor during various clinical conditions. Controversies exist as to whether temporal summation exists for Adeltafibre-mediated first pain. The aim of the present human experimental study was to investigate the importance of stimulus configuration (intensity, inter-pulse interval, location) for temporal summation of radiant (laser)- and contact-heat-induced pain. Consecutive stimuli were applied to the same or to adjacent skin locations. Both stimulation techniques evoked rapid temperature changes, which is an important parameter for recruitment of specific cutaneous nociceptors (Adelta and C fibres). Psychophysical thresholds and intensity ratings were used to assess the pain evoked by repeated stimuli applied to the hairy skin of nine volunteers. Inter-pulse interval (IPI) and stimulus intensity were important and interrelated parameters for temporal summation of pain. An increase in IPI resulted in a decreased summation, whereas increased stimulus intensity resulted in increased summation. Brief heat pulses evoked both first and second pain, and summation of the different pain qualities was investigated. Taking the latency from stimulation to perception into consideration, we were able to differentiate and find summation of first (Adeltafibre-mediated) and second pain (C fibre-mediated). Summation of first pain was more pronounced for high (38 degrees C) than for low (30-32 degrees C) baseline temperature. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
Eur J Pain 1998
PMID:The importance of stimulus configuration for temporal summation of first and second pain to repeated heat stimuli. 1070 Mar 28

Based on a hypothesis of neural system involvement in the initial absorption and further processing of the millimeter electromagnetic waves (MW) signal, we reproduced, quantitatively assessed and compared the analgesic effect of a single MW treatment, exposing areas of skin possessing different innervation densities. The cold water tail flick test (cTFT) was used to assess experimental pain in mice. Three areas of exposure were used: the nose, the glabrous skin of the right footpad, and the hairy skin of the mid back at the level of T5-T10. The MW exposure characteristics were: frequency = 61.22 GHz; incident power density = 15mW/cm2; and duration = 15 min. The maximum hypoalgesic effect was achieved by exposing to MW the more densely innervated skin areas--the nose and the footpad. The hypoalgesic effect in the cTFT after MW exposure to the murine back, which is less densely innervated, was not statistically significant. These results support the hypothesis of neural system involvement in the systemic response to MW.
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PMID:Hypoalgesic effect of millimeter waves in mice: dependence on the site of exposure. 1082 49

1. With the argon laser technique cutaneous nociceptors can be activated with high specificity and reproducibility making it a useful tool in psychophysical pain studies. This study was designed to examine and compare two different psychophysical methods combined with the argon laser technique. 2. Pain thresholds on different locations of the body and on different skin types were measured with (i) the method of limits and (ii) the forced choice method. 3. A significant correlation between the pain thresholds measured with the two different methods was detected on feet and hands. The method of limits yielded significantly higher pain thresholds in glabrous skin than hairy skin. Higher pain thresholds were also detected on the right side of the body. No statistically significant difference between sexes was found. A high reproducibility over time as well as in-between investigators was found for the method of limits. 4. Its concluded that the argon laser for pain threshold measurement with the method of limits is useful and preferred to the forced choice, since the method of limits is easier to perform and also less time consuming.
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PMID:Pain threshold measurements with cutaneous argon laser, comparing a forced choice and a method of limits. 1083 88


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