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1Department of Physiology and Experimental Pathophysiology, University of Erlangen/Nürnberg, 91054 Erlangen, Germany; and 2Department of Anesthesiology and Intensive Care Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany
Submitted 18 December 2002; accepted in final form 29 January 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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). This
"flare response" is dependent on the integrity of primary afferent
nerves but not on their central nervous connections. In addition, mechanical
hyperalgesia develops in the uninjured skin surrounding the injury. Two types
of mechanical hyperalgesia have been differentiated in neuropathic pain
patients: dynamic and static (Ochoa and
Yarnitsky 1993). Dynamic hyperalgesia denotes pain induced by
gentle stroking, while static hyperalgesia denotes hypersensitivity from
constant pressure. Both types of mechanical hyperalgesia can also be evoked in
healthy volunteers using topical application of alogogens, such as mustard oil
or capsaicin (Koltzenburg et al.
1992). The development of experimental models for the induction of
secondary hyperalgesia in human subjects and animals has provided the basis to
further explore the mechanisms of secondary hyperalgesia (Simone et al.
1989a,b).
Measurements of spatial extension and time course are different between
allodynia and punctate hyperalgesia. These differences suggest different
mechanisms (Baumann et al.
1991; Cervero et al.
1994; LaMotte et al.
1991; Simone et al.
1989a). Whereas A
-fibers have been suggested to mediate
allodynia (Torebjörk et al.
1992a), punctate hyperalgesia has recently been linked to
excitation of capsaicin-insensitive A
-fibers
(Fuchs et al. 2000;
Magerl et al. 2001;
Ziegler et al. 1999). Although
it is widely accepted that secondary mechanical hyperalgesia is due to
sensitization of spinal nociceptive neurons
(Koltzenburg 2000;
LaMotte et al. 1991;
Torebjörk et al. 1992b),
there are also reports suggesting that peripheral mechanisms are involved.
Axon reflex erythema and mechanical hyperalgesia have been identified to have
similar borders surrounding the injured tissue; this has led to the hypothesis
that the axon reflex mechanism may be linked to secondary hyperalgesia
(Serra et al. 1998). Moreover,
multiple intracutaneous injections of lidocaine, forming an "anesthetic
strip," after a nearby capsaicin injection, have not only been shown to
block the spreading of the axon reflex erythema but also the development of
punctuate hyperalgesia (LaMotte et al.
1991; Serra et al.
1998).
In this study, we used a newly developed model of electrically induced
secondary mechanical hyperalgesia (Koppert
et al. 2001) in which large and stable areas of allodynia and
punctate hyperalgesia are provoked for prolonged periods and are accompanied
by a large axon reflex erythema. Intradermal microdialysis was employed to
continuously deliver lidocaine in a narrow strip a length of 10 cm, thereby
providing a stable and narrow anesthetic strip. This experimental setup
enabled us to investigate the effects of the anesthetic strip on the
development of secondary mechanical hyperalgesia and the axon reflex
vasodilation (infrared thermography and laser Doppler scanning).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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In this study, 12 healthy volunteers (8 male, 4 female; mean age 26.7 ± 1 yr) participated after having given their informed consent. All subjects were informed about the general intention of the study but were naive to the specific experimental goals. They were free to withdraw from the experiments at any time. The local ethics committee approved the study. The volunteers were seated comfortably in a reclining chair with the left arm being placed in a relaxed position. The experimental sessions lasted 2.5 h.
Microdialysis
Three single plasmapheresis hollow fibers (0.4 mm in diameter, cutoff:
3,000 kDa; Asashi) were inserted intracutaneously
(Fig. 1A). All
microdialysis membranes were oriented transversally to the axis of the volar
forearm and were perfused at a constant flow rate of 5 µl/min via a Tygon
tubing (Novodirect) by a microdialysis pump (Pump 22, Harvard Apparatus). The
stimulation membrane was inserted over a length of 1.5 cm in the center of the
left volar forearm using a 25 G canula. No local anesthesia was required
during the insertion of the small-diameter canula. The remaining two membranes
were inserted a length of 
5 cm each a distance of 1 cm from the
stimulation site. These two membranes formed a line 10 cm long with an
overlap of 3–4 mm. They were separated from each other a distance of
<2 mm (Fig. 1A).
The two membranes were inserted randomly either distally or proximally from
the stimulation site. The stimulation membrane was perfused with Ringers
solution (Ringerlösung Fresenius), and the two catheters used to form the
anesthetic strip were perfused for the entire duration of the experiment with
2% lidocaine in Ringer solution. Insertion depth of the catheters was measured
sonographically (Dermascan C, Cortex Technologies) to be an average of 0.66 mm
(0.5–0.9 mm, minimum-maximum, n = 11). After the membranes were
passed through the skin, the membranes were inserted into glass capillaries
(150 µl, 1.0 mm ID; Servoprax, GLW) for the collection of the dialysate.
The capillaries were tilted at an angle of 5° to minimize the outflow
resistance. The length of the microdialysis fibers that was exposed to air was
<3 mm at both the inflow and outflow sites. The dialysate was taken from
the stimulation membrane every 15 min for a total duration of 75 min. The
samples were then stored in polyethylene cups. The experimental protocol is
depicted schematically in Fig.
1B.
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Electrical stimulation
After waiting a period of 60 min to establish a baseline, sensitivity of the skin above the lidocaine membranes was tested with light strokes and with pinpricks. After complete anesthesia was confirmed for the entire length of the two lidocaine catheters, transcutaneous electrical stimulation was applied between a stainless steel wire of 0.1 mm diam, inserted in the stimulation membrane (cathode), and a 1 cm2 TENS electrode attached epicutaneously above the membrane. Electrical stimulation was applied at a frequency of 1 Hz and with a pulse duration of 0.5 ms via a constant current stimulator (DS7A, Digitimer). Subjects were asked to numerically rate the electrically induced pain sensation on a scale from 0 to 10 (no pain to worst pain imaginable). Current was increased in 5-mA steps until the subject rated the electrically induced pain 5 of 10. During the first 15 min of stimulation, current intensity was increased at intervals of 2 min to maintain the same pain rating. The stimulus intensity was kept constant at this level for 15 min, and then the electrical stimulation was stopped.
Protein analysis
The dialysate samples were analyzed for total protein. Total protein
content was measured photometrically (MRX reader, Dynatech) according to
Bradford (Bradford 1976) using
Coomassie blue dye for the analysis and bovine serum albumin as normal
curve.
Vasodilation
Using a laser Doppler scanner (LDI, Moor instruments, Devon, UK), superficial blood flow was assessed at 5-min intervals, beginning at the lidocaine perfusion until the maximum current was reached (60-min baseline and 15 min during electrical simulation), in an area of 20 * 15 cm around the stimulation site (Fig. 1). Another single LDI scan was taken at the end of the electrical stimulation. The neurogenic flare was analyzed in the last scan of the series taken. The blood flux was evaluated in two rectangular areas (1 * 1.5 cm), which were positioned 2.5 cm distal and proximal from the stimulation site. One was positioned on the same side of the anesthetic strip as the stimulation (site A), and the other was positioned on the side of the anesthetic strip that was not stimulated (site B). Two additional sites on each side of the anesthetic strip were analyzed as controls for systemic responses (sites C and D; Fig. 1). Superficial blood flux (perfusion units, PU) in these areas was assessed after 30 min of electrical stimulation by dedicated software (MLDI, Moor instruments).
For the analysis of the flare size on either side of the anesthetic strip, the mean flux in perfusion units and its standard deviation were calculated for the baseline scan. Mean flux plus twice the standard deviation was used as the threshold for the flare reaction. Pixels exceeding the threshold were defined as flare and their areas were assessed on both sides of the anesthetic strip after 30 min of electrical stimulation. To enable in this analysis, a comparison of corresponding skin areas on either side of the anesthetic strip, only pixels at a distance of >1.5 cm from the stimulation site were included (Fig. 1). The mean flux of the pixels exceeding the flare threshold also were calculated.
Thermography
The skin temperature was assessed using an infrared thermocamera (AGEMA
Thermovision ® Scanner 900 SW/TE). The temperature resolution of the
device was 0.1°C, spatial resolution was 1.5 mm (248 * 108 pixel), and
individual scans were taken at a frequency of 3 Hz. Averages of 32 successive
scans were stored on a hard disk at 15-s intervals for offline analysis. Skin
temperature was scanned for 15 min from the start of electrical stimulation.
In an offline analysis (Greiner et al.
1995), the "thermographic flare" reaction was
assessed. An increase in skin temperature of ≥0.6°C was set as the
threshold for detecting the thermographic axon reflex by computer assisted
analysis (Greiner et al. 1995).
Only pixels a distance of >1.5 cm from the stimulation site were included
to enable comparison of the corresponding skin areas (see
Fig. 1). Time course of the
temperature increase was measured after a 15-min stimulation within the area
of the largest flare on the stimulation side of the anesthetic strip and its
mirror image opposite of the anesthetic strip
(Fig. 1A). In
addition, control areas (2 * 2 cm) on each side of the anesthetic strip,
chosen outside the flare area (sites C and D), were analyzed
for temperature changes.
Psychophysics
The allodynic area was delineated by light strokes with a cotton swab. The strokes were applied perpendicular to the direction from either the wrist or the cubital fossa towards the stimulation site. These strokes were applied in 0.5-cm steps at a frequency of 1 Hz in three lines on either side of the anesthetic strip. The subjects were instructed to indicate when the evoked sensation changed from touch to pain or to the sensation of soreness. The borders of the allodynic areas were marked on the skin.
After the current was switched off, the time course of the decline of allodynia was measured. The extension of allodynia along the central trajectory was tested and marked at 30-s intervals on either side of the anesthetic strip until there was no longer a feeling of allodynia. The measurements on the side treated with lidocaine were stopped 3 mm from the lidocaine membrane as touch was not felt in the region above the membrane.
When allodynia was no longer detectable, the area of punctate hyperalgesia using a von Frey filament (bending force 250 mN, Stoelting) was assessed analogous to the allodynia test. Subjects were instructed to indicate when the painful stimulus became notably more painful. The borders of the punctate hyperalgesia were marked on the skin. All marks on the skin were transferred to a transparency at the end of the experiment, which was digitized and analyzed off line.
Statistics
For statistical evaluation, an ANOVA for repeated measures was calculated using protein concentration, superficial blood flow, or temperature as dependent variables. Normalized data were used if not indicated otherwise. Scheffé's post hoc test was employed to identify significant differences. Paired t-tests were used to compare hyperalgesic areas and vasodilation on both sides of the anesthetic strip. P values <5% were considered significant. All values are given as means ± SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The mean maximum current during stimulation was 49.6 ± 2.3 mA. Maximum pain rating was 5.3 ± 0.3 on a scale from 0 to 10. The current needed to induce a pain rating of 5 was independent of the side of the lidocaine strip (t-test, n.s.). The quality of the electrically evoked pain was reported as burning and stinging.
Protein extravasation
After insertion of the canula, we detected protein concentrations in the dialysate of the stimulation membrane of 0.89 ± 0.06 mg/ml, which exponentially declined after 60 min to a stable baseline of 0.43 ± 0.04 mg/ml. Electrical stimulation did not result in any increase in protein concentration (0.40 ± 0.03 mg/ml after 75 min).
Vasodilation
Insertion flare declined to baseline blood flow during the 1 h of baseline
perfusion with Ringer solution. Vasodilation of 3 mm in width was
observed above the lidocaine membranes. This area of vasodilation did not
subside during the 60-min baseline. A flare reaction developed on the control
side during the electrical stimulation, but this did not extend beyond the
anesthetic strip (Fig. 2). When
electrical stimulation had reached the final current, a flare reaction was
detected which differed significantly in size and intensity on both sides of
the anesthetic strip (Fig.
3).
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The size of the flare on the control side was 12.4 ± 2.3 cm2, whereas beyond the lidocaine strip the flare was 3.5 ± 1.2 cm2 (t-test, P < 0.001, n = 12). The superficial blood flows inside the flare on the control side and in the area beyond the anesthetic strip (mean flux in entire flare area) were 426 ± 24 and 257 ± 21 PU, respectively (t-test, P < 0.001, n = 12). The radius of the flare erythema was 4.6 ± 0.3 cm on the control side. In five of the subjects, the block of the flare erythema beyond the anesthetic strip was not complete. Elevated superficial blood flow was detected in this area beyond the anesthetic strip. In these five subjects, the area of this erythema was 6.0 ± 1.9 cm2 and its intensity was 299 ± 31 PU. Even in these cases, the reduction of flare size and intensity was significant (t-test, P < 0.05; n = 5). In those seven subjects in which no visible erythema developed beyond the area treated with lidocaine, the flare area, as assessed by the laser Doppler, was 1.1 ± 0.3 cm2 with a mean intensity of 214 ± 18 PU (data not shown). When comparing superficial blood flow in the two 1.5 cm2 areas on each side of the lidocaine strip, the highest flux was found within the flare on the control side (511 ± 66 PU, site A; Fig. 3). The flare in site A was significantly higher as compared to control areas (111 ± 13 PU, site C) and the areas beyond the anesthetic strip (184 ± 24 PU in the hypothetical flare; site B vs. 99 ± 10 PU in the 2nd control area; site D, ANOVA, Scheffé's post hoc test). No significant differences in flux were observed between the control areas (sites C and D) and the area inside the hypothetical flare beyond the anesthetic strip (site B).
Infrared thermography
Before stimulation, we observed a baseline skin temperature of 32.0 ± 0.1°C without significant differences between the four analyzed areas. Electrical stimulation provoked a significant increase of skin temperature of 1.1 ± 0.1°C only on the stimulation side of the anesthetic strip (P < 0.05, ANOVA, Scheffé's post hoc tests; n = 12; Figs. 2 and 4). No major changes in temperature were observed in the corresponding area beyond the anesthetic strip or in the two remote control areas (sites C and D; Fig. 4). There was no significant difference whether the lidocaine strip was distal or proximal of the stimulation membrane in this temperature increase (data not shown).
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Psychophysics
The integrity of the anesthetic strip was tested several times prior to electrical stimulation by applying punctate stimuli above and in the vicinity of the lidocaine membranes. The anesthetized area covered the length of the lidocaine membranes and extended 2 mm on each side of the membranes. This anesthetized area was stable during the 30-min lidocaine perfusion. Areas of allodynia and hyperalgesia were assessed at the end of the electrical stimulation (Fig. 5). Subjects reported a clear difference between normal skin and allodynic or hyperalgesic areas. Allodynia was described as a slightly burning, unpleasant, or sore sensation evoked by brushing. Hyperalgesia was described as a heightened pain response to a pricking with a von Frey hair. The maximum extent of the allodynic and hyperalgesic areas was slightly smaller beyond the anesthetic strip, but these differences were not significant. The mean maximum radius of the area of allodynia was 7.4 ± 0.7 and 8.6 ± 0.9 cm, and the area of hyperalgesia was 7.6 ± 0.7 and 8.7 ± 0.9 cm. There was no significant difference between the sides of the lidocaine strip (t-test, n.s.). The areas of allodynia and hyperalgesia were significantly larger than the area of erythema on either side of the anesthetic strip (ANOVA, P < 0.001).
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In the five subjects whose flare reaction was not completely blocked beyond the lidocaine strip, we compared the maximum radius of areas of allodynia and hyperalgesia. In the seven subjects whose flare reaction was completely blocked by the lidocaine strip, there was no significant difference between the extent of allodynia (9.86 ± 1.18 vs. 8.06 ± 0.96 cm mean maximum radius) and the area of punctate hyperalgesia (9.51 ± 1.21 vs. 8.13 ± 0.89 cm mean maximum radius) on either side of the anesthetic strip (t-test, n.s.). We did not attempt to quantify the intensity of the secondary mechanical hyperalgesia.
After the end of the electrical stimulation, we assessed the time course of allodynia on each side of the anesthetic strip separately. The decrease of allodynic areas was rapid and occurred symmetrically (Fig. 5). The allodynia beyond the anesthetic strip had subsided after 157 ± 18 s and on the control side after 172 ± 15 s (ANOVA, n.s.).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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High intensity transcutaneous electrical stimulation was used for the
induction of the axon reflex flare reaction. The short distance of <1 mm
between the stimulation electrodes provided a high current density, which is
necessary to excite mechano-insensitive ("silent") C nociceptors.
This class of nociceptors is characterized by very high electrical excitation
thresholds (Weidner et al.
1999) and large innervation territories
(Schmidt et al. 2002). This
nociceptor class has also been shown to mediate the visible axon reflex
erythema (Schmelz et al.
2000a). Anesthetic strips achieved by multiple small injections of
a local anesthetic have been used before to block the development of the
neurogenic axon flare reaction (LaMotte et
al. 1991; Serra et al.
1998). In this study, intradermal microdialysis was used to
deliver lidocaine. Due to the limited diffusion, the anesthetic strip achieved
by microdialysis is very narrow (<5 mm), which can be maintained over a
prolonged period. In 7 of 12 experiments, the block of the axon reflex was
complete, i.e., even with the very sensitive methods of LDI and infrared
thermography no increase in temperature or superficial blood flow was
detectable. In those cases in which we were not able to block the development
of the flare completely, the anesthetic strip might not have been evenly
distributed over the entire length of the microdialysis catheter, although the
mechanical testing prior to electrical stimulation indicated complete
anesthesia. As the remaining flare beyond the strip developed close to the
overlap of the two membranes delivering lidocaine, some collaterals might have
remained unaffected by the lidocaine. This result confirms the concept that
the axon reflex is the underlying mechanism for neurogenic erythema. An
alternative explanation for the incomplete blockade could be arborizations of
C fibers, which separate from the parent axon proximally and reach their
innervation territory in the skin by a different path. Proximal branching in
nociceptors has been shown previously in monkey skin
(Peng et al. 1999). Also, in
human skin, there is evidence for extensive branching of cutaneous C fibers;
however, it is unclear how proximal these arborizations occur
(Weidner et al. 2000b). In
most of the subjects, the blockade of the flare was complete, suggesting there
are too few of these proximally branching units to produce a neurogenic
vasodilation beyond the anesthetic strip.
Excitation of mechano-insensitive C nociceptors has been linked to
induction of central sensitization
(LaMotte et al. 1991;
Schmelz et al. 2000b). Taking
into account the high electrical thresholds of these fibers, high-intensity
electrical stimulation has been successfully used to provoke stable areas of
secondary mechanical hyperalgesia (punctate hyperalgesia and allodynia)
(Koppert et al. 2001). The
spatial extent of this hyperalgesia is comparable to the one observed after
the injection of 100 µg capsaicin
(Simone et al. 1989b). In our
study, areas of allodynia and punctate hyperalgesia developed symmetrically on
both sides of the stimulation electrode and were not blocked by the anesthetic
strip. Even under the condition of a complete block of the axon reflex flare,
we did observe symmetrical development of punctate hyperalgesia and allodynia
beyond the anesthetic strip. This indicates that no peripheral coupling is
needed to provoke secondary mechanical hyperalgesia. This result is at
variance with previous reports of capsaicin-induced mechanical hyperalgesia
(LaMotte et al. 1991;
Serra et al. 1998). In these
studies, punctate hyperalgesia was not observed beyond the anesthetic strip.
The contradictory results might be explained by either the differences between
capsaicin and electrically induced hyperalgesia or between the application
techniques of the block. The spatial extent of the electrically induced
hyperalgesia and allodynia is equivalent to the one induced by injection of
100 µg capsaicin and therefore cannot account for the variant results.
However, the two models differ in the time course of allodynic areas: in the
electrical model, allodynic areas are constant, whereas in the capsaicin
model, allodynia follows a similar time course as the capsaicin-induced pain
(Koltzenburg et al. 1994;
LaMotte et al. 1991). The
extent of allodynic areas might therefore be more problematic to assess in the
capsaicin model. However, capsaicin-induced punctate hyperalgesia has a
prolonged time course and can be measured several hours after the
injection.
Electrical current and capsaicin may also activate different sets of
nociceptors. It has been shown that especially high-threshold mechanoreceptors
are nonresponsive to capsaicin in rat skin
(Seno and Dray 1993). However,
capsaicin-induced punctate hyperalgesia has been shown to cross an anesthetic
strip, which was applied by dermal microdialysis
(Schmelz et al. 1999). Thus
the controversial results might be attributed to the mode of application of
the lidocaine strip (injection vs. microdialysis). Although the spread of
substances applied via intradermal microdialysis is restricted to the
immediate vicinity of the probe (Weidner
et al. 2000a), repeated intracutaneous injections might cause some
uncontrolled spread of the anesthetic and thereby interfere with the
psychophysical test for mechanical hyperalgesia.
The areas of punctate hyperalgesia and allodynia were slightly smaller
beyond the anesthetic strip. We did not test for the intensity of the
hyperalgesia, thus we cannot exclude a reduction by the anesthetic strip. Our
data are therefore not at variance with a block of some widely branched
chemonociceptors, which pass the anesthetic strip before heading centrally. As
proposed by LaMotte, this mechanism would result in less noxious inputs to the
spinal cord from the skin area beyond the anesthetic strip; this could lead to
less pronounced hyperalgesia in this area as proposed before
(LaMotte et al. 1991).
However, the arborization of the unblocked chemonociceptors is wide enough to
compensate for the decreased input, at least as far as the spatial extent of
the hyperalgesia and allodynia is concerned.
Although we could not confirm the hypothesis that widely branched
chemonociceptors would not only initiate neurogenic inflammation but also be
sensitized in this process (Serra et al.
1998), our results substantiate the crucial role of this class of
nociceptors in both processes: the induction of neurogenic inflammation in the
periphery and in the induction of hypersensitivity in the spinal cord. Our
data therefore add to the prevailing view of a central mechanism of secondary
mechanical hyperalgesia (Koltzenburg
2000).
In this study, we observed a rapid decrease in allodynia after electrical
stimulation was switched off. After 4 min, allodynia was not detected on
either side of the lidocaine strip, whereas punctate hyperalgesia had a more
prolonged time course. The maintenance of allodynia requires ongoing noxious
input to the spinal cord (Koltzenburg et al.
1992,
1994;
LaMotte et al. 1991). The
magnitude, duration, and area of allodynia are closely related to the
magnitude and duration of ongoing pain after capsaicin injection
(Simone et al. 1989b),
although allodynia can be observed for some time after the spontaneous pain
has subsided. Ongoing activity in mechano-insensitive C nociceptors after
capsaicin injection has been proposed to generate this noxious input
(Schmelz et al. 2000b). The
capsaicin-induced allodynia has been reported to last for 2 h
(LaMotte et al. 1991) after
capsaicin injection with the area decreasing rapidly after the
capsaicin-induced pain has subsided. Capsaicin-induced activity in
mechano-insensitive chemonociceptors can be recorded for prolonged periods
after the injection (Ringkamp et al.
2001; Schmelz et al.
2000b), exceeding the period in which pain is perceived. Thus the
time course of nociceptor activity rather than the time course of pain
sensation matches the time course of allodynia. In our model of electrically
evoked allodynia and hyperalgesia, termination of the electrical stimulation
will instantaneously stop the noxious input to the spinal cord and thereby
facilitate the studies of the time course for resolving hyperalgesia. The
rapid decline in allodynia and the prolonged time course of punctate
hyperalgesia observed in this study confirm the view that ongoing input from
nociceptors is required to maintain allodynia, whereas punctate hyperalgesia
does not depend on it.
In conclusion, this study confirms the peripheral origin of the axon reflex and provides strong evidence to the central origin of secondary mechanical hyperalgesia without peripheral coupling.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was supported by Deutsche Forschungsgemeinschaft Grant, SFB 535.
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FOOTNOTES |
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Address for reprint requests: M. Schmelz, Dept. Anesthesiology and Intensive Care Medicine, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany (E-mail: martin.schmelz{at}anaes.ma.uni-heidelberg.de).
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, the radius of allodynia on the stimulation side; 
, the
area beyond the anesthetic strip (mean ± SE, n = 12). The
radius of the punctate hyperalgesia (bars on the right) was tested after
allodynia had ceased,