Brain, Vol. 122, No. 12, 2237-2244,
December 1999
© 1999 Oxford University Press
Review article |
Does sympathetic nerve discharge affect the firing of polymodal C-fibre afferents in humans?
1 Institute for Clinical Neuroscience, Department of Clinical Neurophysiology, Sahlgren University Hospital, S-413 45 Göteborg, Sweden and 2 Department of Physiology, University of Iceland, Reykjavik, Iceland
Correspondence to:
Dr Mikael Elam, Department of Clinical Neurophysiology, Sahlgren University Hospital, S-413 45 Göteborg, Sweden E-mail: mikael.elam{at}nfys.gu.se
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Abstract |
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Experimental and clinical studies in animals and humans have indicated that nociceptive nerve fibres can acquire sensitivity to norepinephrine after injury or chemical sensitization. To evaluate the functional relevance of such sensitization, we recorded the activity of single polymodal C-fibre afferents in healthy human volunteers and investigated whether intense physiological sympatho-excitation could affect their firing properties. This was studied before and after chemical sensitization of receptive fields by topical application of mustard oil. All afferent C fibres investigated (11 units in 10 subjects) were mechano-heat-sensitive, and four of seven fibres subjected to mustard oil were also chemosensitive. Putative sensitivity to sympathetic stimulation was investigated during low-frequency (0.25 Hz) electrical stimulation of the unit receptive field at a threshold intensity sufficient to evoke an action potential in the afferent fibre after every second to third stimulus. Following a prolonged period of silent rest, sympathoexcitation was elicited by forced mental arithmetic for 60 s, again followed by a long silent rest period. During stress, sympathetic nerve traffic increased to 625 ± 146% of the control level, while firing of the afferent units remained unchanged. There was no sign of sympathetically mediated direct activation of afferent units and no change in the relative amounts of afferent activations caused by the background electrical stimulation. Results were similar for all units, both before (seven units in six subjects) and after (seven units in seven subjects) chemical sensitization of their cutaneous receptive field. The results suggest that if chemical sensitization of nociceptive C afferent neurons with mustard oil does induce sensitivity to noradrenaline in humans, it is not sufficient to make C nociceptive fibres respond to short-lasting physiological variations in sympathetic outflow.
sympathetic; C afferent; single-unit; microneurography; mustard oil
GSR = galvanic skin response
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Introduction |
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The question of whether sympathetic nerve activity may affect the firing of unmyelinated nociceptive nerve fibres remains controversial, despite much attention over the years. In animals, most studies indicate that the activity of polymodal C afferent fibres is unaffected by sympathetic stimulation under normal conditions (Roberts and Elardo, 1985
; Shea and Perl, 1985; Barasi and Lynn, 1986), but neural injury may induce sensitivity to sympathetic/adrenergic stimulation. Thus, both electrical stimulation of the sympathetic trunk and intravenous or intraarterial administration of adrenoceptor agonists have been shown to elicit discharge from C nociceptors in several nerve injury models, including partial and complete nerve lesions (Blumberg and Jänig, 1984; Häbler et al., 1987; Sato and Perl, 1991; O'Halloran and Perl, 1997). Chemical sensitization of afferent C fibres may induce similar adrenergic/sympathetic sensitivity (Hu and Zu, 1989; Sato et al., 1993). The in vitro finding that the discharge pattern of chemically sensitized C fibre afferents is unchanged after sympathectomy may, however, question the physiological relevance of this adrenergic sensitization (Koltzenburg et al., 1992).
In man, injection of noradrenaline around the stump neuroma of an amputated limb has been found to cause intense pain (Chabal et al., 1992). Intraoperative stimulation of the sympathetic chain has been reported to elicit immediate augmentation of pain in patients with causalgia (Walker and Nulsen, 1948; White and Sweet, 1969), and intracutaneous administration of noradrenaline in a causalgic area has been demonstrated to rekindle pain (Wallin et al., 1976; Torebjörk et al., 1995), supporting the concept of adrenergic sensitization of afferent nerve fibres after nerve injury. On the other hand, simultaneous bilateral recordings of sympathetic nerve outflow to affected and unaffected limbs showed normal and symmetrical sympathetic activity in causalgia patients (Elam, 1997) without an obvious relationship between the degree of sympathetic discharge and the level of perceived pain. This lack of relationship is in agreement with previous unilateral sympathetic nerve recordings in causalgia patients (Wallin et al., 1976; Casale and Elam, 1992). Furthermore, a human case of painful neuropathy with sensitized nociceptors that did not modify their activity during reflex sympathetic activation has been reported (Ochoa et al., 1996). Thus, in humans also it remains unclear whether physiological variations in sympathetic outflow may modulate clinical pain transmission/perception.
Experimental topical administration of chemical irritants such as capsaicin has been shown to induce adrenergic sensitization of nociceptor afferents also in humans (Drummond, 1995). Furthermore, pain elicited by capsaicin has been demonstrated to decrease after subcutaneous (Kinnman et al., 1997) or systemic intravenous (Liu et al., 1996) 
-receptor blockade.
The aim of the present study was to investigate whether the activity of single cutaneous C polymodal afferents in man can be modulated by physiological variations in sympathetic nerve discharge, both afferent and efferent nerve activity being recorded from the same nerve fascicle. This was tested in healthy volunteers, under normal conditions and/or after acute chemical sensitization of the sensory units. Sensitization was achieved by topical application of mustard oil in the receptive field of the units, a procedure known to directly activate C mechano-heat-sensitive afferents (Handwerker et al., 1991) and alter their afferent properties (Olausson, 1998a). Preliminary obseervations have been reported Elam et al., 1997).
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Subjects
Data were obtained from 11 experiments in 10 healthy volunteers (mean age 28 years, range 22–45 years; six males, four females) recruited among students and hospital staff. Each subject gave informed written consent to the procedures, which were approved by the human ethics committee of the University of Göteborg.
General procedures
Experiments were performed in the morning, ~2 h after a light breakfast. The ECG was monitored via standard Ag/AgCl chest electrodes and respiratory movements (to identify inadvertent sympathetic stimulations due to Valsalva manoeuvres or deep inspiratory gasps) were monitored with a strain-gauge transducer attached to a strap around the chest. With the subjects in a comfortable, supine position, the thigh was supported by a vacuum cast and the common peroneal nerve was located behind the fibular head by palpation and electrical stimulation via a surface probe. A low-impedance electrode (i.e. one with a large uninsulated tip) was placed subcutaneously a few centimetres from the estimated position of the nerve, to serve as the reference electrode. A high-impedance tungsten microelectrode (type 25-10-1; Frederick Haer Co., Brunswick, Me., USA) was then inserted into the peroneal nerve, initially guided by low-voltage electrical stimulation through the electrode. Cutaneous nerve fascicles were identified by three criteria: (i) electrical stimuli through the electrode elicited skin paraesthesias in the receptive field of the impaled fascicle; (ii) neural activity was evoked by touch stimuli within the receptive field; and (iii) spontaneous nerve activity with a firing pattern characteristic of skin sympathetic nerve fibres was often recorded. In fact, the strategy commonly used to find single C afferent fibres was to manipulate the intraneural microelectrode until well-defined bursts of sympathetic efferent C-fibre activity were recorded, and then to search for single C afferent fibres at this recording site. Afferent units were detected by searching in the receptive field of the impaled nerve fascicle with an electrode giving transcutaneous electrical stimuli (0.3 Hz, 0.5 ms, 50–150 V). When an afferent unit with stable response latency (see below) was found, transcutaneous stimulation with the same electrode was used to define its receptive field. Subsequently, two tungsten electrodes (0.2 mm diameter) with large uninsulated tips were placed intracutaneously in the centre of the receptive field (5–10 mm apart) and stimulated (0.25 Hz, 0.5 ms) with a constant-current stimulator (Grass S88, Quincy, Mass, USA).
Identification and characterization of afferent units
Although the SC/ZOOM software used for analysis of unit activity (see below) incorporates a spike recognition facility for off-line analysis of the morphology of every spike of a candidate unit, the low signal-to-noise ratio in recordings from single C-fibre afferents in human nerves may not allow the unequivocal identification of single sensory units. Therefore, a method described by Torebjörk and Hallin was adopted to identify single units and establish their afferent characteristics (Torebjörk and Hallin, 1974). Briefly, the receptive field of the recorded sensory unit was stimulated by low-amplitude, low-frequency electrical pulses (0.25 Hz) and the arrival latency of the action potentials at the intraneural electrode at the fibular head was established (Fig. 1). Since all our receptive fields were situated on the dorsum of the foot, latencies of 400–500 ms for all units included in the study indicated conduction velocities in the C-fibre range (~1 m/s). C afferent units show a stable latency to low-frequency intradermal electrical stimulation, whereas sympathetic C efferent units show a highly variable latency due to their spontaneous activity (Hallin and Torebjörk, 1974). This enables the identification of single C afferent units on strict latency criteria and also provides a basis for the characterization of afferents. Thus, while a stable latency to ongoing low-frequency electrical stimulation is being recorded, a natural stimulus (mechanical, thermal or chemical) is added in the receptive field to test whether it can activate the unit. If so, the extra discharges lead to a slowing of conduction velocity, resulting in a transient prolongation of the latency of electrically induced potentials (Fig. 1A), thus marking or disclosing the sensitivity of the afferent unit to that particular type of natural stimulus. Mechanical stimuli were delivered with von Frey hairs, thermal stimuli with an argon laser heat source (Olausson, 1998b) and chemical stimulation by the topical application of mustard oil (Handwerker et al., 1991).
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Sensitivity of afferent units to sympathetic stimulation
After the thermal and mechanical afferent characterization, the intensity of the low-frequency electrical stimulation of the receptive field was reduced until only every second or third stimulus activated the afferent unit, the remainder of stimuli thus being subthreshold (Fig. 1A
). The stimulation was maintained at this near-threshold level for 10–15 min, the subject relaxing without any communication with the experimenters. Subsequently, in order to achieve a temporally defined and intense physiological sympatho-excitation, a 1 min period of mental stress (in which the subject was required to carry out repeated mental subtraction of the number 17 or 13, starting at 1000, while being verbally harassed) was introduced, followed by another 15–20 min of complete relaxation. Sympathetic multifibre activity to the receptive field under investigation was quantitated from the mean voltage neurogram (Fig. 1B; see below). A putative sympathetic modulation of afferent unit activity was evaluated by (i) comparing the latencies of electrically evoked potentials during stress with those during relaxation (a prolonged latency indicating direct activation of the sensory unit) and (ii) comparing the relative proportion of potentials elicited by the near-threshold electrical stimulation (spike incidence) at rest and during stress (increased incidence suggesting lowered threshold for activation).
Data recording and analysis
Neural activity was amplified (5 x 104 to 25 x 104), filtered (0.1–8.0 kHz), audio-monitored, digitized at 12.8 kHz (12 bits) and stored on disk by means of the SC/ZOOM data acquisition and analysis system (Department of Physiology, University of Umeå, Sweden), for off-line analysis of the firing of single C-fibre afferents. The amplified (5 x 104) and filtered (0.7–2.0 kHz) nerve signal was also led through a resistance-capacitance circuit (time constant 100 ms). The output of this circuit (mean voltage nerve signal) was dominated by multifibre sympathetic efferent activity whereas the contribution from the sensory afferents was negligible. This signal was digitized at 800 Hz, stored as 8 bits and recorded on a VHS tape recorder (V-Store; Racal, Southampton, UK) together with all other physiological variables (see above and below). The sympathetic nerve discharge in the investigated fascicle was estimated from the mean voltage neurogram (area under the curve) using analysis software developed in our laboratory (Wallin and Elam, 1997). Sympathetic activity was expressed in arbitrary units/min and presented as the percentage change from control. For the recording of sympathetic effector function within the receptive field, skin perfusion was measured by laser Doppler flowmetry (Periflux; Perimed AB, Järfälla, Sweden). Sudomotor function was evaluated by recording changes in skin resistance [galvanic skin responses (GSR)], with a modified van Gough GSR module (type IGSR/7A) using Ag/AgCl electrodes (Medicotest A/S, Ølstykke, Denmark).
Statistics
All values are expressed as means and standard error of the mean unless otherwise stated. Spike incidence was analysed with ANOVA (analysis of variance) for repeated measurements and Huynh-Feldt adjustment of degrees of freedom (Ludbrook, 1994), using STATISTICA for Windows v. 5.1 (StatSoft Inc., Tulsa, Okla., USA). P values <0.05 were considered significant.
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Results |
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Number of units and their afferent characteristics
The effect of sympatho-excitation on sensory C-fibre firing was tested before application of mustard oil on seven afferent units in six subjects (one subject was used in two recording sessions on separate days). In three of these subjects, the sympatho-excitation protocol was repeated on the same C afferent fibre after induction of neurogenic inflammation in its receptive field. In the remaining four subjects, the afferent unit was lost before application of mustard oil. In four other subjects, the mustard oil was applied immediately after the mechanical and thermal afferent characterization of the unit, and then sympathetic activation was initiated. Thus, a total of seven afferent units in seven subjects were tested for sympathetic modulation after neurogenic inflammation of their receptive fields. All 11 C afferent units included in this study responded to both mechanical and thermal stimuli (see example in Fig. 1A
). Three out of seven units responded to mustard oil application with robust activation, whereas three units showed no overt chemosensitivity. The remaining unit showed a short and weak activation, rendering impossible the unequivocal distinction between chemosensitivity and mechanosensitivity (mild tactile stimulation during topical application).
Effects of sympatho-excitation
Before application of mustard oil, the resting level of sympathetic nerve activity was consistently low. During the mental stress period the sympathetic activity (one subject shown in Fig. 1B) increased to 625 ± 146% of the control level and then subsided within 2 min after termination of stress (Fig. 2). Concomitantly, the number of GSR increased from <1/min at rest to >9/min during stress, and then returned to the resting level within 2 min. In a few experiments the sympatho-excitation during stress was also associated with a reduction in skin perfusion, illustrating the well-known fact that mental stress activates both vaso- and sudomotor sympathetic fibres (Wallin and Elam, 1997). In most experiments, however, baseline skin perfusion in the receptive fields was usually under the detection limit of laser Doppler flowmetry, precluding general assessment of cutaneous vasomotor function. As a further indication of the autonomic nervous system response to stress, average heart rate increased from 58 beats/min at rest to 75 beats/min during stress. Throughout the period of sympathetic excitation, the latency of potentials elicited by the near-threshold low-frequency electrical stimuli remained unaffected, as did the relative spike incidence (Fig. 2).
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Effect of chemical sensitization
After application of mustard oil within the receptive field of the recorded afferent unit, the mental stress period was not initiated until the mustard oil-induced excitation of C afferent units had subsided and the afferent unit responded to electrical stimuli with a relative spike incidence of ~30–40%. Regardless of whether mustard oil elicited pain or only a mild sense of irritation in the treated area, sympathetic nerve activity rapidly returned to a low level at rest. During the subsequent mental stress period, sympathetic outflow increased to 669 ± 316% of the control level and subsided within 2 min, i.e. there was no difference compared with the effect before sensitization. Also, the increases in GSR (from 1–2/min to >7/min), and average heart rate (from 60 to 69 beats/min) were similar to those before sensitization. A tendency for all three autonomic variables to remain slightly elevated after stress in the mustard oil protocol was not statistically significant. Just as without inflammation of their receptive fields, the firing properties of C afferent units remained unaffected during marked physiological shifts in sympathetic outflow, as shown by consistently unaltered response latencies and no significant changes in relative spike incidences (Fig. 2
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Discussion |
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The main findings of this study are that (i) no evidence of sympathetic modulation of polymodal C-fibre afferent unit firing characteristics was found, and (ii) the absence of sympathetic modulation of the afferent C-fibre activity persisted after induction of acute neurogenic inflammation in the cutaneous receptive fields with mustard oil. If anything, there was a weak tendency towards a lower spike incidence of the afferent C fibres during sympatho-excitation after mustard oil application. Thus, although chemically sensitized C afferent fibres may be equipped with
receptors (see Introduction), the present results suggest that in humans these receptors may not respond to physiological variation in neurally derived norepinephrine.
Although the effect of nerve injury on afferent nerve fibre properties may differ from that of chemical sensitization, our findings agree with the limited number of intraneural recordings of sympathetic nerve traffic performed in patients with injury-related neuropathic pain (Wallin et al., 1976; Casale and Elam, 1992; Elam, 1997). In these studies there was no clear relationship between the strength of the sympathetic nerve traffic and the level of perceived pain. In the study by Wallin and colleagues, this lack of relationship contrasted with the ability of intracutaneously administered norepinephrine to rekindle or exacerbate pain in the affected region (Wallin et al., 1976). From a clinical point of view, this finding raises the possibility that adrenoceptor antagonists, such as phentolamine (Olsson et al., 1990; Arnér, 1991; Raja et al., 1991), may also have analgesic properties when sympathetic nerve blocks are inefficient. This adds another level of complexity to the interpretation of studies of the analgesic properties of sympathetic blocks.
The clinical experience from various sympatho-inhibitory procedures has fuelled rather than resolved the controversy concerning sympathetic involvement in pain. Although many pain clinicians and researchers maintain the traditional view (Nathan, 1947; Richards, 1967; Roberts, 1986) that sympathetic blockade may be beneficial in neuropathic syndromes involving an element of sympathetically dependent pain (Treede et al., 1991; cf. Jänig and Schmidt, 1992; Jänig and Stanton-Hicks, 1996), the analgesic efficacy or specificity of sympathetic blocks has been seriously questioned recently (Verdugo and Ochoa, 1994; Schott, 1995; Max and Gilron, 1999). Earlier reports on strong placebo effects after sympathetic nerve blocks (Brena et al., 1980) also illustrate the difficulty of evaluating physiological mechanisms based on clinical therapeutic results, and raise serious doubts regarding the interpretation of a large number of studies on the analgesic effects of sympathetic blocks (Kingery, 1997). The present results, as well as previous sympathetic nerve recordings in causalgic patients (Wallin et al., 1976; Casale and Elam, 1993; Elam, 1997), suggest that, even though an analgesic effect of a postsynaptic sympathetic block (i.e. an -adrenoceptor antagonist such as phentolamine) has been verified in a placebo-controlled protocol, this does not necessarily mean that a sympathetic nerve blockade or a surgical sympathectomy would be beneficial. In fact, destructive procedures must be seriously questioned since sympathectomy alone, without concomitant injury of afferent nerve fibres, can sensitize C nociceptive fibres to locally administered norepinephrine (Bossut et al., 1996). The clinical relevance of this experimental finding is illustrated by several reports of neuralgia after sympathectomy (Tracy and Cockett, 1957; Litwin, 1962; Raskin et al., 1974; Churcher, 1984).
Limitations of the study
In the present study, intracutaneous electrical stimulation via needle electrodes placed within the receptive field was used to activate the afferent C fibres. With this mode of stimulation, some nerve fibres may have been activated at the end and others a short distance from the end. We cannot exclude the possibility that natural stimulation of only the ends of the fibres would give different results. However, sympathetic stimulation has been found to facilitate electrically evoked C afferent nerve activity in the rabbit peroneal nerve, both before (Shyu et al., 1989a, b) and after experimental nerve compression (Shyu et al., 1990), suggesting that adrenoceptors are present on unmyelinated axons. Therefore, it seems likely that changes in excitability due to noradrenaline-induced changes of membrane properties would be detectable regardless of whether or not the stimulation activated the end of the fibre or the distal axon.
Mustard oil activated only half of the mechano-heat-sensitive C afferent units that were tested, in agreement with previous studies (Beck and Handwerker, 1974; Lang et al., 1990; Koltzenburg et al., 1992). It may be argued that those afferent C fibres that were not overtly activated by mustard oil were not sensitized by the procedure. This possibility cannot be excluded, but all subjects reported a local burning sensation within 1–2 min of application, and topical mustard oil has been found to alter the sensory characteristics of afferent units independently of whether they are directly activated (Olausson, 1998a). Therefore, we chose to include units regardless of whether or not they were overtly affected by mustard oil.
In the light of our finding that acute chemical irritation of their receptive fields with mustard oil did not sensitize C nociceptors in healthy humans to sympathetic modulation, a possible extension of the present experiments would have been to study patients with neuropathic pain and evidence for chronic sensitization. However, given the fact that these pain syndromes are often initiated by a rather limited trauma, and that the present type of single-unit approach of microneurography often involves a prolonged intraneural search procedure, we decided against including pain patients.
Although our physiological sympatho-excitation was vigorous compared with the normal physiological variations in sympathetic traffic seen in non-stressed subjects, it could be argued that the duration of our stress protocol (1 min) and the resulting sympatho-excitation (2 min) was too short to reveal sympathetic modulation. However, the recent finding that prolonged, cooling-induced cutaneous sympathetic vasoconstriction does not influence capsaicin-induced pain in humans (Baron et al., 1999) suggests that the duration of the sympatho-excitation may not be a critical factor.
In conclusion, the activity of single cutaneous polymodal C-fibre afferents in healthy humans is not affected by marked physiological variation in sympathetic nerve activity. This absence of sympathetic modulation remains after mustard oil-induced acute neurogenic inflammation of sensory unit receptive fields, indicating that this widely used model for chemical sensitization of C nociceptors does not involve acquired sensitivity to neurally released catecholamines.
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Acknowledgments |
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We with to thank Tomas Karlsson and Göran Pegenius for excellent technical assistance. This study was supported by the Swedish Medical Research Foundation (projects 3546, 11009 and 12170), the Medical Faculty of Göteborg, The University of Iceland Research Foundation and the Icelandic Council of Science.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Arnér S. Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 1991; 46: 17–22.[Web of Science][Medline]
Barasi S, Lynn B. Effects of sympathetic stimulation on mechanoreceptive and nociceptive afferent units from the rabbit pinna. Brain Res 1986; 378: 21–7.[Web of Science][Medline]
Baron R, Wasner G, Borgstedt R, Hastedt E, Schulte H, Binder A, et al. Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation. Neurology 1999; 52: 923–32.
Beck PW, Handwerker HO. Bradykinin and serotonin effects on various types of cutaneous nerve fibers. Pflügers Arch 1974; 347: 209–22.[Web of Science][Medline]
Blumberg H, Jänig W. Discharge pattern of afferent fibers from a neuroma. Pain 1984; 20: 335–53.[Web of Science][Medline]
Bossut DF, Shea VK, Perl ER. Sympathectomy induces adrenergic excitability of cutaneous C-fiber nociceptors. J Neurophysiol 1996; 75: 514–7.
Brena SF, Wolf SL, Chapman SL, Hammonds WD. Chronic back pain: electromyographic, motion and behavioral assessments following sympathetic nerve blocks and placebos. Pain 1980; 8: 1–10.[Web of Science][Medline]
Casale R, Elam M. Normal sympathetic nerve activity in a reflex sympathetic dystrophy with marked skin vasoconstriction. J Auton Nerv Syst 1992; 41: 215–9.[Web of Science][Medline]
Chabal C, Jacobson L, Russell LC, Burchiel KJ. Pain response to perineuromal injection of normal saline, epinephrine, and lidocaine in humans. Pain 1992; 49: 9–12.[Web of Science][Medline]
Churcher MD. Algodystrophy after aortic bifurcation surgery. Lancet 1984; 2: 131–3.[Web of Science][Medline]
Drummond PD. Noradrenaline increases hyperalgesia to heat in skin sensitized by capsaicin. Pain 1995; 60: 311–5.[Web of Science][Medline]
Elam M. Is reflex sympathetic dystrophy a valid concept? Behav Brain Sci 1997; 20: 447–8.
Elam M, Skarphedinsson JO, Olausson B, Wallin BG. No apparent sympathetic modulation of single C-fiber afferent transmission in human volunteers [abstract]. In: Abstracts of the 8th World Congress on Pain. Seattle: IASP Press; 1996. p. 398.
Häbler HJ, Jänig W, Koltzenburg M. Activation of unmyelinated afferents in chronically lesioned nerves by adrenaline and excitation of sympathetic efferents in the cat. Neurosci Lett 1987; 82: 35–40.[Web of Science][Medline]
Hallin RG, Torebjörk HE. Methods to differentiate electrically induced afferent and sympathetic C unit responses in human cutaneous nerves. Acta Physiol Scand 1974; 92: 18–31.
Handwerker HO, Forster C, Kirchhoff C. Discharge patterns of human C-fibers induced by itching and burning stimuli. J Neurophysiol 1991; 66: 307–15.
Hu SJ, Zhu J. Sympathetic facilitation of sustained discharges of polymodal nociceptors. Pain 1989; 38: 85–90.[Web of Science][Medline]
Jänig W, Schmidt RF. Reflex sympathetic dystrophy: pathophysiological mechanisms and clinical implications. Weinheim: VCH; 1992.
Jänig W, Stanton-Hicks M. Reflex sympathetic dystrophy: a reappraisal. Seattle: IASP Press; 1996.
Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. [Review]. Pain 1997; 73: 123–39.[Web of Science][Medline]
Kinnman E, Nygards EB, Hansson P. Peripheral alpha-adrenoreceptors are involved in the development of capsaicin induced ongoing and stimulus evoked pain in humans. Pain 1997; 69: 79–85.[Web of Science][Medline]
Koltzenburg M, Kress M, Reeh PW. The nociceptor sensitization by bradykinin does not depend on sympathetic neurons. Neuroscience 1992; 46: 465–73.[Web of Science][Medline]
Lang E, Novak A, Reeh PW, Handwerker HO. Chemosensitivity of fine afferents from rat skin in vitro. J Neurophysiol 1990; 63: 887–901.
Litwin MS. Postsympathectomy neuralgia. Arch Surg 1962; 84: 591–5.
Liu M, Max MB, Parada S, Rowan JS, Bennett GJ. The sympathetic nervous system contributes to capsaicin-evoked mechanical allodynia but not pinprick hyperalgesia in humans. J Neurosci 1996; 16: 7331–5.
Ludbrook J. Repeated measurements and multiple comparisons in cardiovascular research. [Review]. Cardiovasc Res 1994; 28: 303–11.
Max MB, Gilron I. Sympathetically maintained pain: has the emperor no clothes? Neurology 1999; 52: 905–7.
Nathan PW. On the pathogenesis of causalgia in peripheral nerve injuries. Brain 1947; 70: 145–70.
Ochoa JL, Serra J, Campero M. Pathophysiology of human nociceptor function. In: Belmonte C, Cervero F, editors. Neurobiology of nociceptors. Oxford: Oxford University Press; 1996. p. 489–516.
O'Halloran KD, Perl ER. Effects of partial nerve injury on the responses of C-fiber polymodal nociceptors to adrenergic agonists. Brain Res 1997; 759: 233–40.[Web of Science][Medline]
Olausson B. Recordings of human polymodal single C-fiber afferents following mechanical and argon-laser heat stimulation of inflamed skin. Exp Brain Res 1998a; 122: 55–61.[Web of Science][Medline]
Olausson B. Recordings of polymodal single C-fiber nociceptive afferents following mechanical and argon-laser heat stimulation of human skin. Exp Brain Res 1998b; 122: 44–54.[Web of Science][Medline]
Olsson GL, Arnér S, Hirsch G. Reflex sympathetic dystrophy in children. In: Tyler DC, Krane EJ, editors. Pediatric pain. Advances in pain research therapy, Vol. 15. New York: Raven Press; 1990. p. 323–31.
Raja SN, Treede RD, Davis KD, Campbell JN. Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology 1991; 74: 691–8.[Web of Science][Medline]
Raskin NH, Levinson S, Hoffman PM, Pickett JB 3rd, Fields HL. Postsympathectomy neuralgia. Amelioration with diphenylhydantoin and carbamazine. Am J Surg 1974; 128: 75–8.[Web of Science][Medline]
Richards RL. Causalgia. A centennial review. Arch Neurol 1967; 16: 339–50.
Roberts WJ. A hypothesis on the physiological basis for causalgia and related pains. [Review]. Pain 1986; 24: 297–311.[Web of Science][Medline]
Roberts WJ, Elardo SM. Sympathetic activation of unmyelinated mechanoreceptors in cat skin. Brain Res 1985; 339: 123–5.[Web of Science][Medline]
Sato J, Perl ER. Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 1991; 251: 1608–10.
Sato J, Suzuki S, Iseki T, Kumazawa T. Adrenergic excitation of cutaneous nociceptors in chronically inflamed rats. Neurosci Lett 1993; 164: 225–8.[Web of Science][Medline]
Schott GD. An unsympathetic view of pain. [Review]. Lancet 1995; 345: 634–6.[Web of Science][Medline]
Shea VK, Perl ER. Failure of sympathetic stimulation to affect responsiveness of rabbit polymodal nociceptors. J Neurophysiol 1985; 54: 513–9.
Shyu BC, Olausson B, Huang KH, Widerstrom E, Andersson SA. Effects of sympathetic stimulation on C-fibre response in rabbit. Acta Physiol Scand 1989a; 137: 73–84.[Web of Science][Medline]
Shyu BC, Olausson B, Andersson SA. Sympathetic and noradrenaline effects on C-fibre transmission: single-unit analysis. Acta Physiol Scand 1989b; 137: 85–91.[Web of Science][Medline]
Shyu BC, Danielsen N, Andersson SA, Dahlin LB. Effects of sympathetic stimulation on C-fibre response after peripheral nerve compression: an experimental study in the rabbit common peroneal nerve. Acta Physiol Scand 1990; 140: 237–43.[Web of Science][Medline]
Torebjörk HE, Hallin RG. Responses in human A and C fibres to repeated electrical intradermal stimulation. J Neurol Neurosurg Psychiatry 1974; 37: 653–64.
Torebjörk E, Wahren L, Wallin G, Hallin R, Koltzenburg M. Noradrenaline-evoked pain in neuralgia [see comments]. Pain 1995; 63: 11–20. Comment in: Pain 1995; 63: 1-2.[Web of Science][Medline]
Tracy GD, Cockett FB. Pain in the lower limb after sympathectomy. Lancet 1957; 272: 12–4.
Treede RD, Raja SN, Davis KD, Meyer RA, Campbell JN. Evidence that peripheral alpha-adrenergic receptors mediate sympathetically maintained pain. In: Bond MR, Charlton JE, Woolf CJ, editors. Proceedings of the VIth World Congress on Pain. Amsterdam: Elsevier; 1991. p. 377–82.
Verdugo RJ, Ochoa JL. `Sympathetically maintained pain'. I. Phentolamine block questions the concept [see comments]. Neurology 1994; 44: 1003–10. Comment in: Neurology 1995; 45: 1235-7.
Walker AE, Nulsen F. Electrical stimulation of the upper thoracic portion of the sympathetic chain in man. Arch Neurol Psychiatr 1948; 59: 559–60.
Wallin BG, Elam M. Cutaneous sympathetic nerve activity in humans. In: Gibbins IL, Morris JL, editors. Autonomic innervation of the skin. Australia: Harwood Academic: 1997; p. 111–32.
Wallin BG, Torebjörk E, Hallin R. Preliminary observations on the pathophysiology of hyperalgesia in the causalgic pain syndrome. In: Zotterman Y, editor. Sensory functions of the skin in primates, with special reference to man. Oxford: Pergamon Press; 1976. p. 489–502.
White JC, Sweet WH. Pain and the neurosurgeon. Springfield (IL): Charles C. Thomas; 1969.
Received February 23, 1999. Revised May 26, 1999. Accepted June 2, 1999.
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 P. D. Drummond, P. M. Finch, S. Skipworth, and P. Blockey Pain increases during sympathetic arousal in patients with complex regional pain syndrome Neurology, October 9, 2001; 57(7): 1296 - 1303. [Abstract] [Full Text] [PDF]
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