scholarly journals Enhanced brain responses to C-fiber input in the area of secondary hyperalgesia induced by high-frequency electrical stimulation of the skin

2014 ◽  
Vol 112 (9) ◽  
pp. 2059-2066 ◽  
Author(s):  
Emanuel N. van den Broeke ◽  
André Mouraux
Keyword(s):  
Electrical Stimulation ◽  
High Frequency ◽  
Reaction Times ◽  
Secondary Hyperalgesia ◽  
Brain Potentials ◽  
C Fibers ◽  
Brain Responses ◽  
C Fiber ◽  
Low Threshold ◽  
N2 Wave

High-frequency electrical stimulation (HFS) of the human skin induces an increase in both mechanical and heat pain sensitivity in the surrounding unconditioned skin. The aim of this study was to investigate the effect of HFS on the intensity of perception and brain responses elicited by the selective activation of C fibers. HFS was applied to the ventral forearm of 15 healthy volunteers. Temperature-controlled CO2 laser stimulation was used to activate selectively low-threshold C-fiber afferents without concomitantly activating Aδ-fiber afferents. These stimuli were detected with reaction times compatible with the conduction velocity of C fibers. The intensity of perception and event-related brain potentials (ERPs) elicited by thermal stimuli delivered to the surrounding unconditioned skin were recorded before (T0) and after HFS (T1: 20 min after HFS; T2: 45 min after HFS). The contralateral forearm served as a control. Mechanical hyperalgesia following HFS was confirmed by measuring the change in the intensity of perception elicited by mechanical punctate stimuli. HFS resulted in increased intensity of perception to mechanical punctate stimulation and selective C-fiber thermal stimulation at both time points. In contrast, the N2 wave of the ERP elicited by C-fiber stimulation (679 ± 88 ms; means ± SD) was enhanced at T1 but not at T2. The P2 wave (808 ± 105 ms) was unaffected by HFS. Our results suggest that HFS enhances the sensitivity to thermal C-fiber input in the area of secondary hyperalgesia. However, there was no significant enhancement of the magnitude of the C-fiber ERPs at T2, suggesting that quickly adapting C fibers do not contribute to this enhancement.

scholarly journals High frequency electrical stimulation induces a long-lasting enhancement of event-related potentials but does not change the perception elicited by intra-epidermal electrical stimuli delivered to the area of secondary mechanical hyperalgesia

2018 ◽  
Author(s):  
José Biurrun Manresa ◽  
Ole Kæseler Andersen ◽  
André Mouraux ◽  
Emanuel N. van den Broeke
Keyword(s):  
Electrical Stimulation ◽  
High Frequency ◽  
Event Related Potentials ◽  
Secondary Hyperalgesia ◽  
Brain Potentials ◽  
Brain Responses ◽  
Related Potentials ◽  
The Central Nervous System ◽  
Electrical Stimuli ◽  
N2 Wave

ABSTRACTHigh frequency electrical stimulation (HFS) of the skin induces increased pinprick sensitivity in the surrounding unconditioned skin (secondary hyperalgesia). Moreover, it has been shown that brief high intensity CO2 laser stimuli, activating both Aδ- and C-fiber nociceptors, are perceived as more intense when delivered in the area of secondary hyperalgesia. To investigate the contribution of A-fiber nociceptors to secondary hyperalgesia the present study assessed if the perception and brain responses elicited by low-intensity intra-epidermal electrical stimulation (IES), a method preferentially activating Aδ-fiber nociceptors, are increased in the area of secondary hyperalgesia. HFS was delivered to one of the two forearms of seventeen healthy volunteers. Mechanical pinprick stimulation and IES were delivered at both arms before HFS (T0), 20 minutes after HFS (T1) and 45 minutes after HFS (T2). In all participants, HFS induced an increase in pinprick perception at the HFS-treated arm, adjacent to the site of HFS. This increase was significant at both T1 and T2. HFS did not affect the percept elicited by IES, but did enhance the magnitude of the N2 wave of IES-evoked brain potentials, both at T1 and at T2. HFS induced a long-lasting enhancement of the N2 wave elicited by IES in the area of secondary hyperalgesia, indicating that HFS enhances the responsiveness of the central nervous system to nociceptive inputs conveyed by AMH-II nociceptors. However, we found no evidence that HFS affects the perception elicited by IES, which may suggest that AMH-II nociceptors do not contribute to HFS-induced secondary hyperalgesia.

scholarly journals Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation

2018 ◽  
Author(s):  
E.N. van den Broeke ◽  
D.M. Hartgerink ◽  
J Butler ◽  
J Lambert ◽  
A Mouraux
Keyword(s):  
Electrical Stimulation ◽  
Central Sensitization ◽  
High Frequency ◽  
Similar Pattern ◽  
Pupil Size ◽  
Pupil Dilation ◽  
Negative Wave ◽  
Brain Potentials ◽  
Stimulation Intensity ◽  
Brain Responses

ABSTRACTHigh frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization, manifested as increased pinprick sensitivity of the skin surrounding the site at which HFS was applied. The aim of the present study was to compare the effects of HFS on pupil dilation and brain responses elicited by pinprick stimulation delivered in the area of increased pinprick sensitivity. In fourteen healthy volunteers HFS was applied to one of the two forearms. Before and twenty minutes after applying HFS, mechanical pinprick stimuli (64 mN and 96 mN) were delivered to the area surrounding the site at which HFS was applied as well as the contralateral control arm. During pinprick stimulation both the pupil size and electroencephalogram were recorded. HFS induced a clear and comparable increase in pinprick sensitivity for both the 64 and 96 mN stimulation intensity. Both pinprick stimulation intensities elicited a greater pupil dilation response when delivered to the area of increased pinprick sensitivity. However, this greater pupil dilation response was larger for the 64 mN compared to the 96 mN stimulation intensity. A similar pattern was observed for the negative wave of the pinprick-evoked brain potentials (PEPs), however, the increase was not significant for the 96 mN and showed only a trend towards significance for the 64 mN. These results show that there is a correspondence between the increase in pupil dilation and the increase in PEPs, but that pupil size is a more sensitive measure for detecting the effects of central sensitization than PEPs.

Characterization of Long-Term Potentiation of C-Fiber–Evoked Potentials in Spinal Dorsal Horn of Adult Rat: Essential Role of NK1 and NK2 Receptors

1997 ◽  
Vol 78 (4) ◽  
pp. 1973-1982 ◽  
Author(s):  
X.-G. Liu ◽  
J. Sandkühler
Keyword(s):  
Dorsal Horn ◽  
High Intensity ◽  
High Frequency ◽  
Spinal Dorsal Horn ◽  
Long Term Potentiation ◽  
Field Potentials ◽  
Spinal Dorsal ◽  
C Fibers ◽  
Evoked Field Potentials ◽  
C Fiber

Liu, X.-G. and J. Sandkühler. Characterization of long-term potentiation of C-fiber–evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors. J. Neurophysiol. 78: 1973–1982, 1997. Impulses in afferent C fibers, e.g., during peripheral trauma, may induce plastic changes in the spinal dorsal horn that are believed to contribute to some forms of hyperalgesia. The nature of lasting changes in spinal nociception are still not well understood. Here we characterized the long-term potentiation (LTP) of spinal field potentials with a negative focus in superficial spinal dorsal horn evoked by supramaximal electrical stimulation of the sciatic nerve in urethan-anesthetized adult rats. The field potentials studied in this work had high thresholds (≥7 V, 0.5 ms), long latencies (90–130 ms), and long chronaxy (1.1 ms) and were not abolished by muscle relaxation and spinalization. Thus they were evoked by afferent C fibers. In response to 1-Hz stimulation of afferent C fibers, amplitudes of C-fiber–evoked field potentials remained constant, whereas number of action potentials of some dorsal horn neurons increased progressively (wind-up). In all 25 rats tested, high-frequency, high-intensity stimulation (100 Hz, 30–40 V, 0.5 ms, 400 pulses given in 4 trains of 1-s duration at 10-s intervals) always induced LTP (to ∼200% of control), which consistently lasted until the end of recording periods (4–9 h). This tetanic stimulation also significantly decreased mean threshold of C-fiber–evoked field potentials. The C-fiber volley, which was recorded simultaneously in sural nerve, was, however, not affected by the same tetanic stimulation. High-frequency, low-intensity stimulation (100 Hz, 3 V, 0.5 ms) never induced LTP in six rats tested. At an intermediate frequency, high-intensity stimulation (20 Hz, 40 V, 0.5 ms, 400 pulses given in 4 trains of 5 s at 10-s intervals) induced LTP in four out of six rats, which lasted until end of recording periods (3–6 h). In the remaining two rats, no LTP was induced. Low-frequency, high-intensity stimulation (2 Hz, 30–40 V, 0.5 ms, 400 pulses) induced LTP that lasted for 2–8 h in four out of five rats. Intravenous application of neurokinin 1 (NK1) or neurokinin 2 (NK2) receptor antagonist RP 67580 (2 mg/kg, n = 5) or SR 48968 (0.3 mg/kg, n = 5) 30 min before high-frequency, high-intensity stimulation blocked the induction of LTP in all rats tested. In contrast, the same dose of their inactive enantiomers RP 68651 ( n = 5) or SR 48965 ( n = 5) did not affect the induction of LTP. Spinal superfusion with RP 67580 (1 μM) from 30 min before to 30 min after high-frequency, high-intensity stimulation blocked induction of LTP in all five rats tested. Spinal application of SR 48968 (10 nM) prevented LTP in five out of seven rats. However, when spinal superfusions with RP 67580 (1 μM, n = 3) or SR 48968 (10 nM, n = 3) were started 1 h after high-frequency, high-intensity stimulation, established LTP was not affected. Thus the activation of neurokinin receptors is necessary for the induction but not for the maintenance of LTP of C-fiber–evoked field potentials in spinal dorsal horn. This model may be useful to study plastic changes in spinal cord induced by peripheral C-fiber stimulation. The LTP of C-fiber–evoked field potentials may be a mechanism underlying some forms of hyperalgesia.

Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys

1979 ◽  
Vol 42 (5) ◽  
pp. 1354-1369 ◽  
Author(s):  
J. M. Chung ◽  
D. R. Kenshalo ◽  
K. D. Gerhart ◽  
W. D. Willis
Keyword(s):  
Dynamic Range ◽  
High Threshold ◽  
Mechanical Stimuli ◽  
Spinothalamic Tract ◽  
Noxious Heat ◽  
C Fibers ◽  
C Fiber ◽  
Excitatory Action ◽  
Low Threshold ◽  
Lateral Nucleus

1. The responses of spinothalamic tract cells in the lumbosacral spinal cords of anesthetized monkeys were examined following electrical stimulation of the sural nerve or the application of noxious thermal and mechanical stimuli to the skin on the lateral aspect of the foot. 2. The spinothalamic tract neurons were classified as wide dynamic range (WDR), high-threshold (HT), or low-threshold (LT) cells on the basis of their responses to mechanical stimuli. 3. All of the WDR and HT spinothalamic tract cells tested responded to volleys in A- and C-fibers. However, strong C-fiber responses were more common in HT than in WDR cells. 4. The responses atributed to C-fibers were graded with the size of the C-fiber volley. The latencies of the responses attributed to C-fibers indicated that the fastest afferents involved had a mean conduction velocity of 0.9 m/s. The responses remained after anodal blockade of conduction in A-fibers. 5. Temporal summation of the responses of spinothalamic tract cells was demonstrated both to brief trains of stimuli at 33 Hz and to single stimuli repeated at 1- to 2-s intervals. The latter phenomenon is often called "windup." 6. The responses of several spinothalamic tract cells to noxious heat pulses could still be elicited during anodal blockade of conduction in A-fibers. Similarly, it was possible to demonstrate an excitatory action of noxious mechanical stimuli despite interference with conduction in A-fibers by anodal current. 7. The cells investigated were located either in the marginal zone or in the layers of the dorsal horn equivalent to Rexed's laminae IV-VI in the cat. The cells were generally activated antidromically from the caudal part of the ventral posterior lateral nucleus of the thalamus.

High-frequency electrical stimulation of the human skin induces heterotopical mechanical hyperalgesia, heat hyperalgesia, and enhanced responses to nonnociceptive vibrotactile input

2014 ◽  
Vol 111 (8) ◽  
pp. 1564-1573 ◽  
Author(s):  
Emanuel N. van den Broeke ◽  
André Mouraux
Keyword(s):  
Electrical Stimulation ◽  
Human Skin ◽  
High Frequency ◽  
Time Course ◽  
Mechanical Hyperalgesia ◽  
Relative Contribution ◽  
Brain Responses ◽  
Before And After ◽  
Nociceptive Afferents ◽  
Heat Hyperalgesia

High-frequency electrical stimulation (HFS) of the human skin induces increased pain sensitivity in the surrounding unconditioned skin. The aim of the present study was to characterize the relative contribution of the different types of nociceptive and nonnociceptive afferents to the heterotopical hyperalgesia induced by HFS. In 17 healthy volunteers (9 men and 8 women), we applied HFS to the ventral forearm. The intensity of perception and event-related brain potentials (ERPs) elicited by vibrotactile stimuli exclusively activating nonnociceptive low-threshold mechanoreceptors and thermonociceptive stimuli exclusively activating heat-sensitive nociceptive afferents were recorded before and after HFS. The previously described mechanical hyperalgesia following HFS was confirmed by measuring the changes in the intensity of perception elicited by mechanical punctate stimuli. HFS increased the perceived intensity of both mechanical punctate and thermonociceptive stimuli applied to the surrounding unconditioned skin. The time course of the effect of HFS on the perception of mechanical and thermal nociceptive stimuli was similar. This indicates that HFS does not only induce mechanical hyperalgesia, but also induces heat hyperalgesia in the heterotopical area. Vibrotactile ERPs were also enhanced after HFS, indicating that nonnociceptive somatosensory input could contribute to the enhanced responses to mechanical pinprick stimuli. Finally, the magnitude of thermonociceptive ERPs was unaffected by HFS, indicating that type II A-fiber mechano-heat nociceptors, thought to be the primary contributor to these brain responses, do not significantly contribute to the observed heat hyperalgesia.

Spastic Long-Lasting Reflexes in the Awake Rat After Sacral Spinal Cord Injury

2004 ◽  
Vol 91 (5) ◽  
pp. 2247-2258 ◽  
Author(s):  
D. J. Bennett ◽  
L. Sanelli ◽  
C. L. Cooke ◽  
P. J. Harvey ◽  
M. A. Gorassini
Keyword(s):  
Spinal Cord ◽  
Electrical Stimulation ◽  
Nerve Trunk ◽  
Motoneuron Excitability ◽  
C Fiber ◽  
Low Threshold ◽  
Acute Spinal Rats ◽  
Fiber Stimulation ◽  
Sacral Spinal Cord ◽  
Stimulation Of

Following chronic sacral spinal cord transection in rats the affected tail muscles exhibit marked spasticity, with characteristic long-lasting tail spasms evoked by mild stimulation. The purpose of the present paper was to characterize the long-lasting reflex seen in tail muscles in response to electrical stimulation of the tail nerves in the awake spastic rat, including its development with time and relation to spasticity. Before and after sacral spinal transection, surface electrodes were placed on the tail for electrical stimulation of the caudal nerve trunk (mixed nerve) and for recording EMG from segmental tail muscles. In normal and acute spinal rats caudal nerve trunk stimulation evoked little or no EMG reflex. By 2 wk after injury, the same stimulation evoked long-lasting reflexes that were 1) very low threshold, 2) evoked from rest without prior EMG activity, 3) of polysynaptic latency with >6 ms central delay, 4) about 2 s long, and 5) enhanced by repeated stimulation (windup). These reflexes produced powerful whole tail contractions (spasms) and developed gradually over the weeks after the injury (≤52 wk tested), in close parallel to the development of spasticity. Pure low-threshold cutaneous stimulation, from electrical stimulation of the tip of the tail, also evoked long-lasting spastic reflexes, not seen in acute spinal or normal rats. In acute spinal rats a strong C-fiber stimulation of the tip of the tail (20 × T) could evoke a weak EMG response lasting about 1 s. Interestingly, when this C-fiber stimulation was used as a conditioning stimulation to depolarize the motoneuron pool in acute spinal rats, a subsequent low-threshold stimulation of the caudal nerve trunk evoked a 300–500 ms long reflex, similar to the onset of the long-lasting reflex in chronic spinal rats. A similar conditioned reflex was not seen in normal rats. Thus there is an unusually long low-threshold polysynaptic input to the motoneurons (pEPSP) that is normally inhibited by descending control. This pEPSP is released from inhibition immediately after injury but does not produce a long-lasting reflex because of a lack of motoneuron excitability. With chronic injury the motoneuron excitability is increased markedly, and the pEPSP then triggers sustained motoneuron discharges associated with long-lasting reflexes and muscle spasms.

Sensory receptors with unmyelinated (C) fibers innervating the skin of the rabbit's ear

1985 ◽  
Vol 54 (3) ◽  
pp. 491-501 ◽  
Author(s):  
V. K. Shea ◽  
E. R. Perl
Keyword(s):  
Mechanical Stimulation ◽  
Receptive Fields ◽  
High Threshold ◽  
Cutaneous Stimulation ◽  
Great Auricular Nerve ◽  
C Fibers ◽  
C Fiber ◽  
Back Ground ◽  
Low Threshold ◽  
Stimulation Of

The cutaneous receptive properties of unmyelinated (C) fibers of the rabbit's great auricular nerve were determined by single-unit recordings. The majority of C-fiber units could be excited by cutaneous stimulation, and such sensory units fell into three major categories on the basis of responses to mechanical and thermal stimulation of their cutaneous receptive fields: low-threshold mechanoreceptors, nociceptors, or specific thermoreceptors. The majority of afferent elements were nociceptive, and all nociceptors responded to strong mechanical stimulation. Three types of nociceptors could be distinguished by their responses to thermal stimuli. Polymodal nociceptors responded to heat with thresholds of 40-55 degrees C and typically displayed enhanced responses or sensitization after noxious heating of their receptive fields. High-threshold mechanoreceptors failed to respond promptly to heat before noxious cutaneous stimulation which, however, elicited subsequent back-ground activity or sensitivity to heat. A third type of nociceptor responded to cold but not to heat. Low-threshold mechanoreceptors were identified by their brisk responses to very gentle, slowly moving mechanical stimulation of their receptive fields, and were readily distinguished from any element classified as nociceptive by their lower mechanical thresholds. Rapid innocuous warming or cooling excited some of the low-threshold mechanoreceptors. Specific thermoreceptors, both warming and cooling types, were rare, insensitive to mechanical stimulation, and responded to very slight changes in temperature. In contrast to the sensitization to heat, which was characteristic of most nociceptors, specific warming receptors displayed depressed thermal responses after noxious heating of their receptive fields. These results provide further evidence of the similarity of C-fiber receptors innervating hairy skin of different species. Some differences from past reports and additional features are described.

Regeneration of cutaneous afferent unmyelinated (C) fibers after transection

1985 ◽  
Vol 54 (3) ◽  
pp. 502-512 ◽  
Author(s):  
V. K. Shea ◽  
E. R. Perl
Keyword(s):  
Thermal Hyperalgesia ◽  
Nerve Transection ◽  
Specific Receptor ◽  
Normal Range ◽  
Great Auricular Nerve ◽  
C Fibers ◽  
C Fiber ◽  
Low Threshold ◽  
Noxious Mechanical Stimulation ◽  
Mechanical Thresholds

The cutaneous receptive properties of C-fiber units were studied 1-8 mo after transection and repair of the rabbit's great auricular nerve. The proportions of C-fiber units that could be excited by the cutaneous stimuli known to excite normal C-fiber afferent elements of the same nerve increased with time of recovery and approached the normal range within 5 mo after transection. No evidence was obtained that suggests that any specific receptor type regenerated more rapidly than others. No differences were established between the cutaneous receptive properties of normal and regenerated low-threshold mechanoreceptors or specific thermoreceptors. However, the properties of regenerated polymodal nociceptors were different from those of normal polymodal nociceptors. Mechanical thresholds for regenerated polymodal nociceptors were greater than normal at 2 mo after transection but not later, and nearly 20% of regenerated polymodal units had heat thresholds lower than normal. It is argued that the abnormal properties of some regenerated polymodal nociceptors could explain, in part, the elevated thresholds to noxious mechanical stimulation and the thermal hyperalgesia reported during recovery from nerve transection in man.

Two Types of C Nociceptors in Human Skin and Their Behavior in Areas of Capsaicin-Induced Secondary Hyperalgesia

2004 ◽  
Vol 91 (6) ◽  
pp. 2770-2781 ◽  
Author(s):  
Jordi Serra ◽  
Mario Campero ◽  
Hugh Bostock ◽  
José Ochoa
Keyword(s):  
Electrical Stimulation ◽  
Discrete Series ◽  
Intradermal Injection ◽  
Repetitive Stimulation ◽  
Mechanical Stimuli ◽  
Secondary Hyperalgesia ◽  
Stimulation Protocol ◽  
C Fiber ◽  
Primary Hyperalgesia ◽  
Stimulation Of

Peripheral nociceptor sensitization is accepted as an important mechanism of cutaneous primary hyperalgesia, but secondary hyperalgesia has been attributed to central mechanisms since evidence for sensitization of primary afferents has been lacking. In this study, microneurography was used to test for changes in sensitivity of C nociceptors in the area of secondary hyperalgesia caused by intradermal injection of capsaicin in humans. Multiple C units were recruited by electrical stimulation of the skin at 0.25 Hz and were identified as discrete series of dots in raster plots of spike latencies. Nociceptors slowed progressively during repetitive stimulation at 2 Hz for 3 min. According to their response to mechanical stimulation, nociceptors could be classified as either mechano-sensitive (CM) or mechano-insensitive (CMi). These two nociceptor subtypes had different axonal properties: CMi units slowed by 2% or more when stimulated at 0.25 Hz after a 3-min pause, whereas CM units slowed by <1%. This stimulation protocol was used before capsaicin injection to identify nociceptor subtype without repeated probing, thus avoiding possible mechanical sensitization. Capsaicin, injected 10–50 mm away from the site of electrical stimulation, had no effect on any of 29 CM units, but induced bursts of activity in 11 of 15 CMi units, after delays ranging from 0.5 to 18 min. The capsaicin injections also sensitized a majority of the CMi units, so that 11 of 17 developed immediate or delayed responsiveness to mechanical stimuli. This sensitization may contribute a peripheral C fiber component to secondary hyperalgesia.

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