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J Neurophysiol (May 1, 2003). 10.1152/jn.01139.2002
Submitted on Submitted 18 December 2002; accepted in final form 20 January 2003
1Department of Physiology and Experimental Pathophysiology, University of Erlangen/Nuremberg, D-91054 Erlangen, Germany; 2Department of Clinical Neurophysiology, University of Uppsala, S-75185 Uppsala, Sweden; 3Department of Basic Oral Sciences, Karolinska Institute, S-14104 Huddinge, Sweden; 4Department of Anesthesiology, Medical Faculty Mannheim, University of Heidelberg, 61087 Mannheim, Germany
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Schmelz, M.,
R. Schmidt,
C. Weidner,
Marita Hilliges,
H. E. Torebjörk, and
H. O. Handwerker.
Chemical Response Pattern of Different Classes of C-Nociceptors
to Pruritogens and Algogens.
J. Neurophysiol. 89: 2441-2448, 2003.
Vasoneuroactive substances were
applied through intradermal microdialysis membranes and characterized
as itch- or pain-inducing in psychophysical experiments. Histamine
always provoked itching and rarely pain, capsaicin always pain but
never itching. Prostaglandin E2 (PGE2) led
preferentially to moderate itching. Serotonin, acetylcholine, and
bradykinin induced pain more often than itching. Subsequently the same
substances were used in microneurography experiments to characterize
the sensitivity profile of human cutaneous C-nociceptors. The responses
of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMiHis
), and 24 mechanoinsensitive, histamine-positive (CMiHis+) units were
compared. CMiHis+ units were most responsive to histamine and to PGE2 and less to serotonin, ACh, bradykinin, and
capsaicin. CMH units (polymodal nociceptors) and CMiHis
units showed significantly weaker responses to histamine,
PGE2, and acetylcholine. Capsaicin and bradykinin responses
were not significantly different in the two classes of
mechano-insensitive units. We conclude that CMiHis+ units
are "selective," but not "specific" for pruritogenic substances
and that the pruritic potency of a mediator increases with its ability
to activate CMiHis+ units but decreases with activation of
CMH and CMiHis units.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The discovery of a
specialized subgroup of primary C-nociceptors driven by histamine
application has shed new light on peripheral itch mechanisms
(Schmelz et al. 1997b
). Activity in these units mirrored
the subjective itch sensations, and therefore these fibers were named
"itch" units. However, mediators other than histamine are known to
provoke itch, albeit with lower potency: prostaglandins of the E group
(Hägermark and Strandberg 1977; Woodward et
al. 1995), serotonin (Hägermark 1992;
Weisshaar et al. 1997), and acetylcholine
(Rukwied and Heyer 1999; Vogelgsang et al.
1995). Under certain conditions bradykinin
(Hägermark 1974; Rajakulasingam et al.
1991) and even capsaicin (Green and Shaffer
1993) may induce itch on topical application.
Here we have characterized pruritogenicity of these substances and studied the different C-fiber classes' sensitivity profile to these agents with different pruritogenic potency. The hypothesis was that the sensitivity of the applied substances, in histamine-responsive C-units (suggested "itch" fibers), should reflect the pruritogenic potency of these agents.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
None of the subjects showed signs of neurological or dermatological disease. Recordings were obtained from 132 subjects (86 male, 46 female, age 20-35 yr) in the microneurography laboratories at Uppsala and Erlangen. Microdialysis experiments were performed in 55 subjects (32 male, 23 female, age 22-36 yr).
The subjects were financially compensated for the time spent in the experiment. They were instructed that they could withdraw from the experiment at any time and this would not affect the financial compensation. All subjects gave their informed consent according to the Declaration of Helsinki and the study was approved by the local ethics committees in Erlangen and Uppsala.
Microdialysis experiments
As injection-related pain could inhibit the ensuing itch
sensation (Atanassoff et al. 1999) we used atraumatical
delivery of the mediators via intradermal microdialysis catheters to
assess their pruritogenicity. Microdialysis fibers (0.4 mm diam.,
cutoff 3,000 kDa, DermalDialysis, Erlangen, Germany) were inserted
intracutaneously at a length of 1.5 cm in the volar forearm using a
25-G cannula as previously described (Schmelz et al.
1997a). No local anesthesia was used. The fibers were perfused
with Ringer solution (Ringerlösung Fresenius) by a microdialysis
pump (Pump 22, Harvard Apparatus) at a constant flow rate of 4 µl/min
via a Tygon tubing (Novodirect). After a baseline period of 60 min,
stimulation was performed with either histamine (5 × 106 M), serotonin (104
M), bradykinin (104 M),
PgE2 (104 M),
acetylcholine (1%), or capsaicin (0.1%) for another 30 min (capsaicin, 5 min). The subjects noticed the switch of syringes but
were unaware of their content. Concentrations of mediators were based
on assessment of their dose-effect relation for the induction of pain
and itch as previously reported (Lischetzki et al. 2001;
Neisius et al. 2002). Pain and itch ratings were separately assessed on a numerical scale from 0 to 10. A value of
"0" indicated no sensation and "10" indicated the maximum
sensation the subject could imagine. For itch ratings a sensation
provoking the need to scratch should be rated as "3". Maximum pain
and itch ratings during application of the mediators were used for
statistical analysis.
Microneurography
Methods of microneurography employed in this study were
described in detail elsewhere (Schmelz et al. 1994;
Schmidt et al. 1995). Microelectrodes were inserted at
the level of the fibular head into the superficial branch of the
peroneal nerve. When a stable recording position in a nerve fascicle
was obtained, innervation territories of single C-units were searched
by transcutaneous electrical stimuli to avoid a bias toward
mechanically receptive units. When C-fiber responses were encountered,
a pair of needle electrodes, 0.2 mm diam., was inserted for
intracutaneous electrical stimulation of that site, tips 5 mm apart.
C-fiber responses were obtained to iterative constant current
stimulation (0.2 ms, 10-120 V, 4-s interstimulus interval) delivered
by the stimulus insulation unit of a Grass S88 stimulator.
"Marking" of activated C-units
When responses of one or several C-fibers to the intracutaneous
electrical stimulation were recorded, the "marking" technique was
used for characterizing the unit(s). This technique is based on the
slowing of conduction velocity in a C-fiber when it is activated by an
additional stimulus (Torebjörk 1974;
Torebjörk and Hallin 1974). Pronounced slowing
after repetitive firing is characteristic for nociceptive C-fibers
(Gee et al. 1996; Serra et al. 1999;
Thalhammer et al. 1994). The amount of the delay is
strongly correlated to the number of additional spikes (Schmelz et al. 1995). In this study the marking technique was used for semiquantitative assessment of the chemical responses.
The C-units were functionally tested in the following order.
MANEUVERS ELICITING SYMPATHETIC REFLEXES.
At first it was tested by maneuvers known to greatly increase the skin
sympathetic sudomotor and vasoconstrictor outflow in conscious man
(Hagbarth et al. 1970; Hallin and Torebjörk
1974; Torebjörk and Hallin 1970) whether
the C-units were possibly sympathetic efferents. For this purpose
sympathetic reflexes were provoked by loud unexpected noises or by
inciting the subject to laugh or to perform a deep inspiration. The
efficiency of these maneuvers was controlled by recording background
activity of sympathetic burst discharges. C-units that showed latency
increases related to sympathetic reflexes were classified as
sympathetic fibers (Hallin and Torebjörk 1974;
Schmelz et al. 1998).
NATURAL STIMULATION OF THE SKIN.
The receptive skin fields of C-units were poked with a 750-mN von Frey
nylon filament (Stoelting Co, Chicago, IL) to determine whether they
were responsive to mechanical stimulation. If that was the case, this
stimulus was also used for mapping the extension of their receptive
fields (Schmelz et al. 1994; Schmidt et al. 1997). In addition, thinner calibrated von Frey filaments were used for determining mechanical thresholds. Heat stimuli were delivered
by radiation from a halogen bulb focused to the receptive skin area and
feedback controlled from a thermocouple attached to the skin
(Beck et al. 1974). Mechanoresponsive units were tested inside their mechanoreceptive field and mechanoinsensitive units inside
their electroreceptive field (Schmelz et al. 1994). For testing heat responsiveness, the skin temperature was increased by
0.25°C/s, from an adapting temperature of 32°C. Heating was stopped
by the subject before the pain tolerance limit was reached (48-50°C). The cutoff temperature was 50°C.
, 2000). Activity-dependent slowing of conduction velocity was assessed as absolute increase of response latency after 70 activations as described previously (Weidner et
al. 1999).
TRANSCUTANEOUS ELECTRICAL STIMULATION. For searching and identifying mechanoinsensitive units, transcutaneous electrical stimuli (0.2 ms, 30-50 mA) were delivered from a pointed surface electrode gently pressed to the skin. This surface electrode was also used for assessment of the innervation territory (electroreceptive field) of mechanoinsensitive units.
ELECTRICAL THRESHOLDS.
A Digitimer DS7 constant current stimulator was used for measuring the
electrical threshold of the units to current application through a
standardized probe. For this purpose, single pulses, 0.2 ms in
duration, were delivered through a specially designed, hand-held
applicator containing a round cotton disc, 5 mm diam., soaked in saline
(Magerl et al. 1990). A large (5 × 10 cm) metal plate attached to the skin on the lower leg served as reference electrode.
CHARACTERIZATION ACCORDING TO HISTAMINE RESPONSE.
The technique of iontophoretic application of histamine has been used
by our group in several studies (Magerl et al. 1990). Histamine dihydrochloride (1%) was dissolved in a gel of 2.5% methylcellulose in distilled water. The 50-µl cavity of a 5-mm-diam. acrylic applicator was filled with this jelly. Current of 1 mA was
delivered for 20 s from a silver-silverchloride electrode in this
applicator to a large reference electrode applied to the skin distally
and outside the territory of the peroneal nerve. According to the
number of markings, the units were classified as histamine responsive
(>40 markings) or histamine insensitive (<20 markings). Sustained
histamine responses were restricted to mechanoinsensitive units, which
resulted in three categories of C-fibers: 1)
mechanoresponsive ("polymodal nociceptors," all histamine
negative), 2) mechanoinsensitive histamine-positive ("itch
fibers"), and 3) mechanoinsensitive histamine-negative units. Responsiveness to ACh, PGE2, serotonin, bradykinin, and capsaicin was assessed and compared between these three fiber classes.
Saline (0.9%) injections were used as vehicle controls.
RESPONSIVENESS TO INFLAMMATORY MEDIATORS.
The inflammatory mediators PgE2, serotonin, and
bradykinin were dissolved in saline solution at concentration of
10-5M and kept frozen at 
20°C until use.
Capsaicin solutions (0.1%) were prepared in saline containing Tween 80 (LaMotte et al. 1991). For the injections 28-G needles
and 0.3-ml syringes (Becton Dickinson) were used. Injections (20 µl)
were given in the previously mapped innervation territory. Injection
sites in one innervation territory were spaced by 
1.5 cm. Pain
sensations induced by the insertion of the needle and by the injection
were assessed psychophysically. Subjects were asked to rate the
sensation numerically on a scale from 0 to 10, in which 0 equaled "no
pain" and 10 equaled "unbearable pain." Maximum pain sensation
induced by the injection was used for statistical analysis. Mechanical
and heat thresholds at the injection sites were determined before and 5 min after the injection.
20 µl)
(LaMotte et al. 1991) (i.e., a maximal dose of 20 µg)
was injected intracutaneously inside the electrically mapped
innervation territory. The injection was performed slowly (10 s) to
allow the subject to rate continuously the increase of pain magnitude
on a 10-point scale (0 = no pain, 10 = unbearable pain).
Injection was stopped immediately when the subject reported a pain
intensity of "5" to prevent losing the unit due to unintentional
pain-provoked movements of the subject. Capsaicin was delivered from a
100-µl Hamilton syringe (Hamilton Bonaduz AG, Basel, Switzerland)
with 1 µl partitions through a sterile nylon microfilter with
0.22-µm pores (Micron Separations Inc.), using a 27-G needle.
Data acquisition and analysis
C-unit responses to intracutaneous electrical stimulation were
recorded on-line by a PC computer via an interface card (DAP, Microstar) using the SPIKE/SPIDI software package (Forster and Handwerker 1990). A suitable time segment of the recording
following each electrical stimulus pulse was displayed and subsequent
traces were written from top to bottom on the computer screen for
on-line assessment of latency shifts of the activated C-units. Digital matched filtering was implemented to facilitate the tracking of the
latency shifts (Hansson et al. 1998). In addition, the
recordings were stored on hard disk for off-line analysis.
The amount of activation of C-units was documented by parameters derived from the marking response: the intensity and duration of the response was assessed by analyzing the number of traces in which the conduction delay of the respective unit was abruptly increased (activation periods, see Fig. 1). The period of injection or iontophoresis itself was excluded from this analysis, because activation by the needle or the current could not be differentiated from responses to the chemicals.
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Statistics
Intensity ratings and number of activation periods following chemical stimulation were evaluated by Kruskal-Wallis ANOVA and Mann-Whitney U tests as post hoc tests. Differences in conduction velocity and electrical threshold were calculated by ANOVA and Scheffé post hoc tests.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Psychophysics
MICRODIALYSIS. Application of various agents via intradermal microdialysis fibers provoked different intensities of itch and pain sensations. Maximum itch and pain ratings for each substance are shown in Fig. 1.
ITCH SENSATION.
Histamine had the highest pruritic potency, significantly higher than
each of the other mediators (P < 0.05; Kruskal Wallis ANOVA, Mann Whitney U test as post hoc test). The difference
in itch intensity induced by PgE2, serotonin, and
acetylcholine did not reach statistical significance (P > 0.2, Mann Whitney U test). Capsaicin did not induce itch
sensations at all. Regarding the average itch responses one may put the
"itching potency" of the tested substances in the following rank
order: histamine 
PgE2 = serotonin = acetylcholine > bradykinin > capsaicin.
PAIN SENSATION. Capsaicin provoked the highest pain ratings, significantly higher than each of the other mediators (P < 0.05; Kruskal Wallis ANOVA, Mann Whitney U test as post hoc test). PgE2 induced pain ratings did not significantly differ from those provoked by histamine and serotonin but they were lower as compared with acetylcholine, bradykinin and capsaicin (P < 0.05, Mann Whitney U test) (see Fig. 1). The tentative pain inducing potency of the tested substances on the basis of the average ratings is: capsaicin > acetylcholine = bradykinin > serotonin > histamine. Generally itch ratings diminished with increasing pain ratings and only 7 subjects reported a combination of itch and pain sensation (see Fig. 1).
INJECTION PAIN. Postinjection pain after bradykinin (2.5, 1-5; median, quartiles) and serotonin (2, 1-4) was significantly higher compared with saline (1.5, 1-2) (P < 0.05; Kruskal Wallis ANOVA, Mann Whitney U test as post hoc test). Pain ratings after PgE2 injection (2, 1-3) did not significantly differ from that after saline and was significantly lower compared with bradykinin (P < 0.05; Kruskal Wallis ANOVA, Mann Whitney U test as post hoc test). Capsaicin injection provoked intense pain sensation (5, 4-6; median, quartiles) that by far exceeded the ratings for the other mediators.
Sample of C-nociceptors
89 mechano-responsive C-units (CMH), 52 mechano-insensitive
histamine-negative (CMiHis-) and 24 mechano-insensitive histamine-positive C-units
(CMiHis+) were studied. Conduction velocity of the CMH
units was significantly higher as compared with the mechano-insensitive fibers (P < 0.001; ANOVA, Scheffé post hoc
test). Within the mechano-insensitive group
CMiHis+ had significantly lower conduction
velocities than CMiHis- units (P = 0.01; ANOVA, Scheffé post hoc test) (Fig.
2A). Transcutaneous electrical
thresholds and the activity dependent decrease in conduction velocity
("slowing"), did not differ significantly between the histamine
positive and negative CMi units, whereas both
parameters clearly differentiated between mechano-insensitive and
mechano-responsive units (Fig. 2B,C) (Weidner et al.
1999).
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Responses of C-fibers
PROSTAGLANDIN E2, ACETYL CHOLINE AND SEROTONIN RESPONSES CMH and CMiHis- units were largely unresponsive to PgE2 injection, or showed only spurious activation. In contrast, most of CMiHis+ units were clearly activated and showed prolonged responses. A specimen of such a response is shown in Fig. 3.
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Bradykinin and capsaicin responses
Activation of nociceptors by bradykinin lasted shorter compared with activation by the above mediators. No significant differences between the nociceptor classes were observed. Injection of capsaicin activated virtually all nociceptors. The response pattern differed strikingly between the mechano-responsive and -insensitive group, with intense, but short-lasting activation in all the mechano-responsive units. Mechano-insensitive nociceptors showed longer lasting responses. A tendency for more activation periods were observed following injection in the histamine-negative subpopulation, but this difference was not significant (P = 0.2; Kruskal Wallis ANOVA, Mann Whitney U test as post hoc test) (Fig. 4).
Sensitization
Mechanical thresholds to probing with von Frey hairs were unchanged in CMH units following injections of PgE2 (30, 18-47 mM vs. 30, 14-32 mN) (median, quartiles; before vs. after injection), serotonin (30, 30-32 mM vs. 30, 12-32 mN), bradykinin (30, 14-65 mM vs. 30, 14-65 mN) and saline (30, 30-49 mM vs. 30, 12-46 mN). No originally mechano-insensitive fiber was sensitized to mechanical stimuli following PgE2.
Heat thresholds did not change significantly following injections of saline and serotonin. Bradykinin slightly lowered heat thresholds in CMH units from 41.0 ± 3.0°C to 40.5 ± 2.9°C (mean ± SD; n = 31), in CMiHis+ from 48.6 ± 3.5°C to 47.7 ± 1.4°C (n = 4), and from 48.1 ± 3.8°C to 48.0 ± 3.0°C (n = 7) in CMiHis- units. None of these differences was statistically significant. Two previously heat-insensitive, mechano-insensitive units were sensitized to heat by bradykinin (heat thresholds 48 and 50°C).
PgE2 injection slightly decreased heat thresholds in mechano-responsive units from 40.8 ± 3.1°C to 40.2 ± 2.4°C (mean ± SD; n = 28; P = 0.25, t-test). The drop in heat thresholds was by far more pronounced in CMiHis+ units, namely from 47.0 ± 1.2°C to 42.0 ± 1.6°C (n = 4, P < 0.01) and in histamine-negative mechano-insensitive units from 47.7 ± 2.6°C to 45.4 ± 2.3°C (n = 7, P < 0.05). Four initially heat insensitive mechano-insensitive units were sensitized to heat following PgE2 injection (heat thresholds 45, 47, 49 and 49°C) (Fig. 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present results shed new light on the peripheral mechanisms of itch and pain sensations in healthy human skin. Mechano-insensitive nociceptors with a sustained response to histamine presented a graded response to pruritogenic substances such as prostanglandin E2 and serotonin, but were also excited by the algogenic substances bradykinin and capsaicin. In contrast, mechano-responsive C-fibers and histamine-insensitive CMi units were insensitive to PgE2 or showed spurious responses. They were, however, readily activated by algogenic substances.
Sensitization
Bradykinin did not sensitize C-nociceptors to mechanical stimuli,
as could be expected from psychophysical investigations: intracutaneous
injections of bradykinin did not induce mechanical hyperalgesia
(Manning et al. 1991). However, in this in vivo
investigation heat pain thresholds dropped by about 1°C in the
subjects, which correlates well to animal data (Beck and
Handwerker 1974). Interestingly, bradykinin-induced
sensitization to heat is much more prominent under in vitro conditions
(Jeftinija 1994; Khan et al. 1992;
Koltzenburg et al. 1992; Liang et al.
2001; Mizumura et al. 1992; Rueff and Dray 1993), possibly because of lack of degrading enzymes.
Prostaglandin E2 induced clear heat sensitization, but no
drop in mechanical thresholds or sensitization of mechano-insensitive nociceptors. These results are compatible with some in vitro data in
rat skin (Lang et al. 1990). Recently, mechanical
sensitization following PgE2 injection has been
described in rat skin in vivo (Chen et al. 1999). The
drop in mechanical threshold above saline control observed in this
study was about 15%. As we used a series of calibrated v.Frey hairs
with steps of more than 30% such a modest difference could not be
detected in our study.
Responses of different classes of C-nociceptors and psychophysics
In our study chemical responsiveness was tested in various spots
inside the innervation territories of nociceptors. Although there is a
fairly pronounced heterogeneity of heat thresholds in
mechano-insensitive units (Schmidt et al. 2002),
chemical responsiveness was fairly homogenous; however, as there could
be also spots inside the innervation territory which are insensitive to
histamine, a negative histamine provocation does not prove that a unit
is indeed histamine-insensitive in its entire receptive field thereby blurring our classification. However, our results show that only histamine-positive mechano-insensitive "itch" units showed strong and sustained responses to PgE2, whereas the
other nociceptor classes were more or less unresponsive. Interestingly,
also conventional mechano-heat sensitive nociceptors from rodents have
been found largely unresponsive to PgE2
(Lang et al. 1990; Mizumura et al. 1987;
Rueff and Dray 1993). Activation of nociceptors by
PgE2 has been reported only from nociceptive
joint afferents in the cat (Schaible and Schmidt 1988;
Schepelmann et al. 1992). The excitatory effect of
PgE2 on histamine-positive mechano-insensitive nociceptors is therefore a novel finding, though it fits well with
psychophysical observations that PgE2 applied by
intradermal injection (Hägermark and Strandberg
1977) and by topic application in the conjunctivae
(Woodward et al. 1995) causes itch. Taking into account
the histamine sensitivity of these units, indirect activation via
histamine released from mast cells has to be considered. Intradermal
injection of PgE2 has been reported to induce
only marginal whealing (Juhlin and Michaelsson 1969;
Kingston and Greaves 1985), however, it provoked a
small, albeit significant protein extravasation in other studies
(Sabroe et al. 1997; Sciberras et al.
1987). Recently, dermal application of
PgE2 via microdialysis has been combined with
measurement of local protein extravasation and local blood flow
(Neisius et al. 2002). In this study
PgE2 did not increase protein extravasation, even
at a concentration of 10-4M, but provoked a weak
itch sensation and a pronounced vasodilation. In contrast, histamine
provokes protein extravasation at lower concentrations as compared with
the induction of itch (Lischetzki et al. 2001). Thus
rather than being mediated by histamine release, the pruritic effect of
PgE2 is most probably due to direct excitation of
the CMihis+ units.
A direct comparison between psychophysics and nociceptor discharge is problematic as mediators were administered via different routes, i.e., iontophoresis and injection for electrophysiology and microdialysis for psychophysics. Microdialysis was chosen because it avoids the interaction of injection pain with the ensuing itch sensation. However, application of mediators via microdialysis catheters in the setting of microneurography is not feasible because of the time consuming procedure. Despite these limitations it appears reasonable to compare the response patterns of different nociceptor classes for a given mode of application.
Interaction of pain and itch
Although the responses in "itch units" reflected the pruritic
potency of the mediators tested in this study, the strong activation of
these units by capsaicin and bradykinin seems to contradict a specific
role of these units in itch, since both substances are mainly algogenic
and not pruritogenic. The ambiguity of "itch unit" discharge to
pruritics and algogens may be solved by the central inhibition of itch
by pain: it is common knowledge that scratching relieves itching. Thus
it can be assumed that activity in mechano-sensitive nociceptors
suppresses itch. To date there are many reports on itch suppression
exerted by painful stimuli. These stimuli include electrical
stimulation (Nilsson et al. 1997) or treatment with
capsaicin (Brull et al. 1999). Recently, also the
opposite effect, i.e., increasing of itch sensation by pain reduction
has been clearly shown (Atanassoff et al. 1999). On a
spinal level, opioids inhibit pain processing and thereby may provoke
itch (Schmelz 2001). This mechanism is probably the
basis for the antipruritic action of opioid antagonist like naloxone or
naltrexone (Odou et al. 2001; Wolfhagen et al.
1997). However, it has to be stated that currently available
data on central interactions of pain and itch are mainly based on
psychophysics and therefore have to treated with caution.
The inhibition of itch by painful stimuli has to be taken into
consideration when activity in "itch" units is correlated to the
pruritic potency of the tested mediator (Schmelz 2001).
Prostaglandin E2 exclusively excited "itch" nociceptors in our
study, whereas acetylcholine activated a considerable number of nonitch
nociceptors. Thus the pruritic effect of PgE2 can
be explained by the activation of "itch" units and simultaneous the
absence of activity in itch suppressing nociceptors. Conversely, the
activation of "itch" units by acetylcholine does not provoke itch
because simultaneously activated nonitch nociceptors suppress the itch
and the perceived sensation is pain. Accordingly, capsaicin that
readily activates itch and nonitch units, provokes strong pain and no
itch sensation. Although our data support this concept, experimental
proof for it can only be obtained in recordings from second order
neurons. Noteworthy, acetylcholine provokes itch instead of pain in
patients suffering from atopic dermatitis (Groene et al.
2001; Vogelgsang et al. 1995) indicating, that
pain induced inhibition of itch might be compromised in these patients.
Activation of histamine-positive chemonociceptors by
PgE2 is inline with the pruritogenic effects of
prostaglandins. As PgE2 is only a weak pruritic it is not
clear, whether positive PgE2 responses can be regarded
characteristic for "itch-units" and thus could be useful to
separate between pain and itch fibers. However, the histamine-positive
fibers might not be classified as "itch specific", because they are
also excited by pure algogens and thus might rather be termed "itch
selective" (McMahon and Koltzenburg 1992). Further
support for the "specificity", or rather "selectivity theory"
comes from second order neurons in the cat that have recently been
recorded. These neurons cannot be excited by mechanical stimulation,
but are activated by histamine iontophoresis with a similar time course
as compared with the primary afferents (Andrew and Craig
2001). Interestingly, conduction velocity in the primary
afferents innervating these neurons was particularly low. In addition,
their thalamic projection differed significantly from the conventional
nociceptor specific and wide dynamic range neurons. From these results
it appears that finally there is strong evidence to suggest that a
subpopulation of nociceptors exist, which is responsible for the
induction of itch and conveys their information in an itch specific
central pathway.
In summary, the pruritic potency of inflammatory mediators is characterized by their ability to activate histamine positive mechano-insensitive C-nociceptors. However, concomitant activation of mechano-sensitive and mechano-insensitive histamine negative nociceptors will decrease the itch. Therefore the itch sensation is based on both, activity in the "itch-pathway" and absence of activity in the "pain-pathway".
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ACKNOWLEDGMENTS |
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This work was supported by a Max Planck Award to H. E. Torebjörk, by the Deutsche Forschungsgemeinschaft, SFB 353, by the Swedish Medical Council, Project 5206 and a grant to R. Schmidt from the Swedish Foundation for Brain Research.
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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, 61087 Mannheim, Germany (E-mail: martin.schmelz{at}anaes.ma.uni-heidelberg.de).
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 T. Akiyama, A. W. Merrill, K. Zanotto, M. I. Carstens, and E. Carstens Scratching Behavior and Fos Expression in Superficial Dorsal Horn Elicited by Protease-Activated Receptor Agonists and Other Itch Mediators in Mice J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 945 - 951. [Abstract] [Full Text] [PDF]
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 M. S. Gurun, R. Parker, J. C. Eisenach, and M. Vincler The Effect of Peripherally Administered CDP-Choline in an Acute Inflammatory Pain Model: The Role of {alpha}7 Nicotinic Acetylcholine Receptor Anesth. Analg., May 1, 2009; 108(5): 1680 - 1687. [Abstract] [Full Text] [PDF]
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 R. H. LaMotte, S. G. Shimada, B. G. Green, and D. Zelterman Pruritic and Nociceptive Sensations and Dysesthesias From a Spicule of Cowhage J Neurophysiol, March 1, 2009; 101(3): 1430 - 1443. [Abstract] [Full Text] [PDF]
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 B. Namer, B. Barta, K. Orstavik, R. Schmidt, R. Carr, M. Schmelz, and H. O. Handwerker Microneurographic assessment of C-fibre function in aged healthy subjects J. Physiol., January 15, 2009; 587(2): 419 - 428. [Abstract] [Full Text] [PDF]
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B. Namer, R. Carr, L. M. Johanek, M. Schmelz, H. O. Handwerker, and M. Ringkamp Separate Peripheral Pathways for Pruritus in Man J Neurophysiol, October 1, 2008; 100(4): 2062 - 2069. [Abstract] [Full Text] [PDF]
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 L. M. Johanek, R. A. Meyer, R. M. Friedman, K. W. Greenquist, B. Shim, J. Borzan, T. Hartke, R. H. LaMotte, and M. Ringkamp A Role for Polymodal C-Fiber Afferents in Nonhistaminergic Itch J. Neurosci., July 23, 2008; 28(30): 7659 - 7669. [Abstract] [Full Text] [PDF]
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S. Davidson, X. Zhang, C. H. Yoon, S. G. Khasabov, D. A. Simone, and G. J. Giesler Jr The Itch-Producing Agents Histamine and Cowhage Activate Separate Populations of Primate Spinothalamic Tract Neurons J. Neurosci., September 12, 2007; 27(37): 10007 - 10014. [Abstract] [Full Text] [PDF]
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W.-S. Shim, M.-H. Tak, M.-H. Lee, M. Kim, M. Kim, J.-Y. Koo, C.-H. Lee, M. Kim, and U. Oh TRPV1 Mediates Histamine-Induced Itching via the Activation of Phospholipase A2 and 12-Lipoxygenase J. Neurosci., February 28, 2007; 27(9): 2331 - 2337. [Abstract] [Full Text] [PDF]
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A. George, J. Serra, X. Navarro, and H. Bostock Velocity recovery cycles of single C fibres innervating rat skin J. Physiol., January 1, 2007; 578(1): 213 - 232. [Abstract] [Full Text] [PDF]
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T. Ohta, Y. Ikemi, M. Murakami, T. Imagawa, K.-i. Otsuguro, and S. Ito Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons J. Physiol., November 1, 2006; 576(3): 809 - 822. [Abstract] [Full Text] [PDF]
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 H. Y. FU, S. J. CHEN, R. F. CHEN, W. H. DING, L. L. KUO-HUANG, and R. N. HUANG Identification of Oxalic Acid and Tartaric Acid as Major Persistent Pain-inducing Toxins in the Stinging Hairs of the Nettle, Urtica thunbergiana Ann. Bot., July 1, 2006; 98(1): 57 - 65. [Abstract] [Full Text] [PDF]
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D. A. Bereiter, K. Okamoto, A. Tashiro, and H. Hirata Endotoxin-Induced Uveitis Causes Long-Term Changes in Trigeminal Subnucleus Caudalis Neurons J Neurophysiol, December 1, 2005; 94(6): 3815 - 3825. [Abstract] [Full Text] [PDF]
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K. K. Rau, R. D. Johnson, and B. Y. Cooper Nicotinic AChR in Subclassified Capsaicin-Sensitive and -Insensitive Nociceptors of the Rat DRG J Neurophysiol, March 1, 2005; 93(3): 1358 - 1371. [Abstract] [Full Text] [PDF]
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D. A. Simone, X. Zhang, J. Li, J.-M. Zhang, C. N. Honda, R. H. LaMotte, and G. J. Giesler Jr. Comparison of Responses of Primate Spinothalamic Tract Neurons to Pruritic and Algogenic Stimuli J Neurophysiol, January 1, 2004; 91(1): 213 - 222. [Abstract] [Full Text] [PDF]
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H. Nojima, C. T. Simons, J. M. Cuellar, M. I. Carstens, J. A. Moore, and E. Carstens Opioid Modulation of Scratching and Spinal c-fos Expression Evoked by Intradermal Serotonin J. Neurosci., November 26, 2003; 23(34): 10784 - 10790. [Abstract] [Full Text] [PDF]
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P. M. Lang, R. Burgstahler, W. Sippel, D. Irnich, B. Schlotter-Weigel, and P. Grafe Characterization of Neuronal Nicotinic Acetylcholine Receptors in the Membrane of Unmyelinated Human C-Fiber Axons by In Vitro Studies J Neurophysiol, November 1, 2003; 90(5): 3295 - 3303. [Abstract] [Full Text] [PDF]
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 S. Stander, M. Steinhoff, M. Schmelz, E. Weisshaar, D. Metze, and T. Luger Neurophysiology of Pruritus: Cutaneous Elicitation of Itch Arch Dermatol, November 1, 2003; 139(11): 1463 - 1470. [Abstract] [Full Text] [PDF]
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A. Ikoma, R. Rukwied, S. Stander, M. Steinhoff, Y. Miyachi, and M. Schmelz Neurophysiology of Pruritus: Interaction of Itch and Pain Arch Dermatol, November 1, 2003; 139(11): 1475 - 1478. [Abstract] [Full Text] [PDF]
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