Department of Oral and Craniofacial Biological Sciences, University of Maryland Dental School, Baltimore, Maryland 21201
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ABSTRACT |
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Andrew, David and
Joel D. Greenspan.
Peripheral Coding of Tonic Mechanical Cutaneous Pain:
Comparison of Nociceptor Activity in Rat and Human
Psychophysics.
J. Neurophysiol. 82: 2641-2648, 1999.
These
experiments investigated temporal summation mechanisms of tonic
cutaneous mechanical pain. Human volunteers provided psychophysical
estimates of pain intensity, which were compared with discharge
patterns of rat cutaneous nociceptors tested with identical stimulus
protocols. Human subjects made either intermittent or continuous
ratings of pain intensity during stimulation of the skin between the
thumb and first finger. Stimulus intensities of 25, 50, and 100 g
were applied with a probe of contact area of 0.1 mm2 for 2 min. Pain perception significantly increased during stimulation (temporal summation) for the 50- and 100-g stimulus intensities. Sequential conduction block of the myelinated fibers supplying the
stimulated skin was used to investigate the role of A-fiber mechanoreceptors and nociceptors in this temporal summation. Conduction block of the A fibers resulted in an increase in mechanically evoked
pain estimates and an increase in temporal summation, consistent with
loss of A
-mediated inhibition. When only conduction in the unmyelinated fibers remained, pain estimates were reduced to the preblock levels, but temporal summation was still present.
Electrophysiological recordings were made from filaments of the sciatic
nerve supplying receptors in the plantar skin of
barbiturate-anesthetized rats. Forty units fulfilled the identification
criteria for nociceptors: 20 A-fiber and 20 C-fiber nociceptors. Each
unit was characterized by recording its responses to graded mechanical
and heat stimuli. Nociceptors were also tested with stimuli identical
to those applied to the human subjects. The responses of all units to
sustained mechanical stimuli were adaptive
that is, they exhibited a
gradual decline in response with time. However, the time course of
adaptation varied among units. All the C-fiber nociceptors and one-half
of the A-fiber nociceptors had rapidly adapting responses. The
remainder of the A-fibers displayed slowly adapting responses.
One-third of all units also showed short-duration increases in firing
rate during stimulation. The latency after stimulus onset of this rate acceleration was inversely related to stimulus intensity. Despite the
apparent disparity between perceptual temporal summation and nociceptor
adaptation, central and peripheral mechanisms are proposed that can
reconcile the relationship between nociceptor activity and pain perception.
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INTRODUCTION |
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Adriansen et al. (1984) have
described a novel sensory paradox: Long-duration noxious mechanical
stimulation of human skin at constant intensity evokes a gradually
increasing perception of pain despite prominent adaptation of cutaneous
C-fiber nociceptors. Previous experiments on rat tail nociceptors have
demonstrated that A-fiber nociceptors adapt more slowly than C-fiber
nociceptors to such stimuli (Handwerker et al. 1987
).
However, the observation that some rat dorsal horn neurons maintain or
even increase their firing rate during comparable stimulation
(Cervero et al. 1988
) is discordant with the responses
of single nociceptors. The different time courses of C-fiber nociceptor
and large-diameter mechanoreceptor adaptation led Adriansen et
al. (1984)
to propose a pattern theory of central integration
of nociceptor and mechanoreceptor inputs, to explain the increase in
perceived pain. An alternative central mechanism could be
activity-dependent plasticity, involving summation of slow postsynaptic
potentials from unmyelinated fibers ("wind-up"; Mendell and
Wall 1965
). However, recent experiments (Garell et al.
1996
) have shown prominent differences in the mechanical
encoding properties of A- and C-fiber nociceptors in the hairy skin of cat. In addition, the A fibers have heterogeneous mechanical response properties, suggesting that different functional groups of fibers may
subserve separate roles for perception.
With this in mind, we have revisited the psychophysical and
electrophysiological experiments of Adriansen et al.
(1984) and Handwerker et al. (1987)
. In
particular, we have addressed the following issues. 1)
During long-duration mechanical stimulation of human skin does pain
intensity increase significantly over time? 2) Can these
perceptual changes be prevented by blocking conduction in one or more
groups of myelinated afferent fibers? 3) Is there a
population of A-fiber nociceptors that have mechanical adaptation
properties more consistent with evoked pain intensity?
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METHODS |
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Experiments were performed on 31 male Sprague-Dawley rats (300-400 g; Harlan, Indianapolis, IN) and on 18 human subjects (10 males, 8 females; aged 25-54). The experimental protocols for the animal studies were approved by the University of Maryland Dental School Animal Care and Use Committee. These experiments were performed on cutaneous nociceptors supplying the plantar (glabrous) skin of the rat hindpaw. This site was chosen for reasons of mechanical stability, because it could be rigidly fixed and was a relatively flat surface. The experiments involving human subjects complied with the Declaration of Helsinki and were approved by the Institutional Review Board of the University of Maryland, Baltimore. Each subject gave informed consent and was free to withdraw from the experiment at any time. Subjects were paid $15 (testing only) or $25 (testing with nerve block) per experimental session.
Anesthesia and preparation of animals
Rats were initially anesthetized with sodium pentobarbital
(Nembutal, 50 mg/kg ip; Abbott, North Chicago, IL). Cannulae were inserted into the right jugular vein and carotid artery and into the
trachea. Anesthesia was maintained with additional doses of pentobarbital (15-20
mg·kg1 · h
1)
administered intravenously. Anesthetic depth was maintained so that the
animals were areflexic to pinching a paw. Blood pressure was recorded
with a pressure transducer connected to the arterial cannula. Body
temperature was maintained at 38.0 ± 0.5°C with an electric
blanket controlled from a rectal thermistor. The animals were
positioned prone and the hair over the dorsal surface of the right
hindlimb clipped short. The foot was securely held, plantar surface
uppermost, by fixing it with cyanoacrylate adhesive to a preformed
matrix of thermoplastic dental impression compound (Impression Compound
type 1; Kerr Manufacturing, Romulus, MI). The tibial and sciatic nerves
were exposed by an incision extending from just proximal to the ankle
to midthigh. To limit ongoing activity from other tissues the sural,
gastrocnemius, and posterior biceps femoris and semitendinosis nerves
were sectioned. The sciatic nerve was then cut as far centrally as
possible and its proximal end placed on a plastic dissecting platform.
A skin pool was formed from the surrounding tissues and filled with
warm (38°C) mineral oil. The tibial nerve was freed from the
surrounding tissues and placed on stimulating electrodes. The
connective tissue surrounding the cut end of the sciatic nerve was slit
with a chip of razor blade and fine filaments dissected from it with
sharpened forceps. Pairs of filaments were placed on a pair of platinum
wire electrodes (0.125-mm-diam), and differential recordings made from them.
Identification and characterization of nociceptors
Filaments were repeatedly subdivided until ideally only a single functional unit remained. More commonly, 2-4 units remained, and recordings were accepted only if the action potentials of the units were sufficiently different (e.g., size, polarity) to discriminate. Units were tested to determine their receptor type by stroking the skin with a camel's hair brush and by gentle squeezing with a pair of blunt forceps. A unit was classified as a nociceptor if it fulfilled the following criteria: 1) a sustained response to pinching a skin fold and 2) no response to brushing or gentle mechanical pressure with a blunt probe. Once a nociceptor was isolated, its latency at threshold and twice threshold was determined by constant current stimulation of the tibial nerve (0.1- or 0.5-ms stimulus duration, up to 10-mA intensity). The extent of a unit's receptive field was determined by squeezing small areas of skin with fine, smooth-tipped forceps (up to 10 stimuli per fiber, each of <1 s duration, repeated once every 5-10 s) and marked on the skin with ink. A glass probe with a smooth, curved tip (1-mm-diam) was also used similarly. Mechanical threshold was determined using calibrated monofilaments (Semmes-Weinstein; Stoelting, Chicago, IL). Threshold was defined as the minimum force that elicited impulses in 50% of trials. Once a unit had been characterized in this preliminary manner, no further stimuli were applied for 10-20 min to insure recovery from the preliminary testing protocol. All the nociceptors that were studied in detail had cutaneous receptive fields overlying the bones of the foot. Some nociceptors had to be discarded because the tissues beneath their receptive fields were unstable. These were usually on the tips and sides of digits, where controlled mechanical stimulation was impossible.
The responses of each unit were evaluated with graded mechanical
stimuli (5, 10, 20, 30, 45, 60, and 90 g; equivalent to 49, 98 196, 294, 441, 588, and 882 mN) that were applied to the most sensitive
region of a fiber's receptive field. Ramp-and-hold stimuli (ramp rate
75 g/s [735 mN/s], hold time 4.0 s, interstimulus interval 8.0 s) were delivered with a computer-controlled linear motor (Neurologic, Bloomington, IN; Barlow 1991) under force
feedback regulation (model 501 motor controller; Biocommunication
Electronics, Madison, WI) in order of increasing intensity. The probe
tip of the stimulator was interchangeable, allowing stimuli to be
delivered with probes of variable contact area (Garell et al.
1996
). In the current study cylindrical probes with a flat tip
of area 1.0 and 0.1 mm2 were used. Stimuli were
always applied to the same spot within a fiber's receptive field. The
adaptational properties of each unit were also studied. Stimuli of
intensity 25, 50, and 100 g (245, 490, and 980 mN) were applied
for 2 min with the 0.1-mm2 probe in order of
increasing intensity. For the 2-min, 100-g stimuli, tissue compliance
was measured by recording the probe's vertical position just before
stimulus onset and again just before stimulus offset. These two values
were subtracted to derive the amount of tissue displacement per 100-g
stimulus force. To prevent nociceptor sensitization or desensitization,
stimulus trials were widely separated in time (10-20 min). None of the
units became spontaneously active during testing, indicating that
sensitization did not occur within the time taken to evaluate the
receptor properties of a fiber (~60-80 min). However, in those
experiments in which more than one nociceptor was studied per animal,
care was taken to ensure that their receptive fields were separated to
preclude any possible effects of extended stimulation at one site.
After the mechanical stimulation testing, the heat sensitivity of each unit was evaluated using an ascending series of temperatures
(40-50°C in 2°C steps, from a baseline of 35°C), each applied
for 5 s, with a 25-s intertrial interval.
At the end of the experiment, the animals were killed with an overdose of anesthetic (100 mg/kg iv pentobarbital sodium).
Human psychophysics
Twelve subjects were initially tested to reproduce the
psychophysical findings reported by Adriansen et al.
(1984) and to establish that pain scores increased
significantly over time (temporal summation). Mechanical stimuli were
applied to the skin of the digital web between the thumb and first
finger of a subject's left hand. Here, the innervation is purely
cutaneous/subcutaneous, because the tissue does not overlay
deep tissues, such as bone or muscle. Each subject's hand was
supported, palmar surface downward, with a contoured, hard plastic mold
designed to separate the thumb and first finger. The mold also provided
a firm base against which stimuli could be delivered, thus making the
force-displacement relationship comparable with that of the animal
experiments. Mechanical stimuli were delivered in a manner identical
with those used in the rat experiments (25, 50, and 100 g applied
for 2 min with a 0.1-mm2 probe). Two methods of intensity
rating were used
intermittent and continuous. For intermittent rating,
the subject used a potentiometer connected to a pair of finger holders.
"No pain" was represented by apposing digits 1 and 2 ("closing"
the device), whereas "intolerable pain" was defined as maximal
separation of the two digits. Subjects rated their pain intensity
during the first 10 s of the stimulus presentation and were then
instructed to close the finger-span device. Subsequently, they were
given acoustic cues every 15 s as a signal to rate their perceived
pain intensity at that moment, and they then closed the finger-span
device until the next cue. For continuous ratings, the subjects used a
100-point visual analog scale (VAS) presented on a computer screen. A
computer mouse was used to adjust the height of an indictor bar on a
vertical scale. Descriptors such as faint, mild, and moderate along the
length of the scale were used to aid subjects in rating the intensity of their pain.
Eleven subjects also participated in a third experiment, when the
contribution of afferent fiber categories to the mechanically evoked
temporal summation of pain perception was investigated. Sequential
conduction block of the large- and then small-diameter myelinated
fibers was achieved by compression of the left superficial radial nerve
(MacKenzie et al. 1975; Torebjörk and
Hallin 1973
). At the beginning of the experiment, a pair of
stainless steel electrodes were fixed to the skin overlying the first
dorsal interosseous muscle. The electrodes were of 7-mm2
contact area. They were separated by 10 mm from their centers and made
electrical contact with the skin with conductive jelly (EC2 electrode
cream; Grass, West Warwick, RI). Trains of constant current stimuli
(200 Hz for 50-100 ms, pulse width 0.5 or 1.0 ms, repeated every
2 s) were applied between the electrodes with a photoelectric
isolation unit (model SIU 7, Grass). Stimulus intensity was gradually
increased (usually 1-5 mA) until the subjects reported a sharp
pricking or stinging sensation typical of first pain. This sensation is
considered to be mediated by finely myelinated (A
) nociceptors
(Campbell and LaMotte 1983
; Collins et al.
1960
; Lewis and Pochin 1937
; Lundberg et
al. 1992
; Torebjörk and Ochoa 1990
). Loss
of the perception of electrically evoked first pain was used to
indicate conduction block of the A
fibers. This method appears to be
superior to that commonly used
the loss of cool perception
because
there is evidence that the A
nociceptors are more resistant to
compression block than are the A
cold-sensitive thermoreceptors and
would therefore still be capable of impulse conduction at the point at
which cool perception was lost (Ziegler et al. 1997
).
Initial pain ratings were recorded to graded mechanical stimuli (5-90 g) delivered with a probe of 0.1-mm2 tip area. Ratings were obtained with a VAS presented on a computer screen. Continuous ratings of the pain evoked by a 50-g stimulus delivered for 2 min were also obtained. Differential conduction block of the fibers of the superficial radial nerve was achieved by placing a 2.5-cm wide band over the wrist, with 700-g weights attached at each end (total weight 1.4 kg). Psychophysical evaluation was repeated when the subjects could no longer feel light stroking of the skin with a camel's hair brush and then again when the sensation of electrically evoked first pain disappeared. Conduction in unmyelinated fibers was always confirmed by determining that warmth perception was still present. Seven of the subjects who participated in the nerve block experiments also provided verbal descriptors of the quality of their pain sensations. The sensory-descriptive component of the McGill short-form questionnaire was used. After each series of magnitude scaling and temporal summation testing, subjects were asked which of the following adjectives described their sensations: "throbbing," "shooting," "stabbing," "sharp," "cramping," "gnawing," "hot-burning," or "aching." Subjects also rated the magnitude of each applicable sensation by describing it as "mild," "moderate," or "severe."
Data analysis
Electrophysiological data were displayed on an oscilloscope, recorded on magnetic tape, and digitized with a computer interface (model 1401 plus; Cambridge Electronic Design, Cambridge, UK). Neural records were sampled at 50 kHz, and records of force and tissue displacement were sampled at 1 kHz. These data were analyzed off-line, using Spike 2 display and analysis software (Cambridge Electronic Design). Unpaired t-tests were used to make statistical comparisons between two different receptor types, and an ANOVA was used to make comparisons among multiple receptor types. In the case of comparing latencies, when the data did not pass a normality test at the 95% level, a Mann-Whitney rank-sum test was used.
Pain rating data were evaluated with repeated-measures ANOVA. To evaluate the effects of time on pain scores evoked by sustained mechanical stimulation, a repeated-measures ANOVA was used that included a specific test for a linear trend over time. Tukey's LSD test was used to compare groups to one another if the ANOVA revealed significant differences between groups. P < 0.05 was considered significant.
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RESULTS |
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General properties of rat glabrous skin nociceptors
Recordings were made from 40 nociceptors innervating the plantar
skin of the rat hindpaw. Twenty of these were A-fibers and, 20 were
C-fibers; none was spontaneously active. The conduction velocities (cv)
of the A-fibers ranged from 5.0 to 32.0 m/s (16.5 ± 9.4 m/s,
mean ± SD), those of the C-fibers were 0.8-1.5 m/s (1.1 ± 0.2 m/s). Mean monofilament threshold of the A-fiber nociceptors was
926 kPa (820 ± 379 kPa, median ± SD; range 520-1639; 100 kPa = 1 bar = 10 g/mm2), and that of
the C fibers was 777 kPa (764 ± 432 kPa, range 156-1639). In
general, tibial nerve nociceptor-receptive fields were similar to those
described previously (Leem et al. 1993; Lynn and
Shakhanbeh 1988
). A-fibers had small multispot receptive fields
separated by insensitive zones (n = 8) or were a single sensitive spot (n = 12). C-fiber-receptive fields were
single spots. Sixteen of the C-fibers responded to heat as well as
mechanical stimuli and were classified as C mechanoheat nociceptors.
The remaining four were excited only by noxious mechanical stimuli and
were designated mechanical nociceptors. Only one of the A-fibers was
heat-sensitive in the range tested (up to 50°C), the remainder being
exclusively mechanosensitive (high-threshold mechanoreceptors; Burgess and Perl 1967
).
Responses to mechanical stimuli and adaptive properties of nociceptors
The responses of the A- and C-fiber nociceptors to
mechanical stimulation with discrete forces applied with probes of 1- and 0.1-mm2 contact area are shown in Fig.
1. Nociceptor discharge frequency increased with stimulus intensity and also showed the expected relationship between firing and probe size. A-fiber nociceptors were
more responsive than C-fiber nociceptors; that is, for a given force
and probe size the mean firing rate of the A-fiber nociceptors was
higher than that of the C-fiber nociceptors. In these respects rat
glabrous skin nociceptors are similar to cat hairy skin nociceptors
(Garell et al. 1996).
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The responses of units to sustained mechanical stimulation fell into one of two categories (Fig. 2): 1) those units that rapidly adapted to the stimulus (Fig. 2, B and C), or 2) units that adapted much more slowly (Fig. 2A). All the C fibers exhibited rapidly adapting responses to suprathreshold stimuli (e.g., Fig. 2C). After the dynamic response associated with stimulus onset, impulse generation was irregular and seldom exceeded 1 Hz (Fig. 3C). A-fiber nociceptors responded similarly to C-fiber units (A-rapidly adapting nociceptors, A-HT[RA], n = 10; Figs. 2B and 3B) or showed sustained firing throughout the duration of the mechanical stimulus (A-slowly adapting nociceptors, A-HT[SA], n = 10; Figs. 2A and 3A). Despite prominent differences in the adaptive properties of A-fiber nociceptors, neither their cvs (A-HT[RA] nociceptors: 19.2 ± 8.6 m/s, A-HT[SA] nociceptors 15.3 ± 7.3 m/s) nor their thresholds to monofilament stimulation (threshold for A-HT[RA] nociceptors 1005 ± 441 kPa; threshold for A-HT[SA] nociceptors 848 ± 317 kPa) were significantly different (cv: P = 0.3, unpaired t-test; threshold: P > 0.4, unpaired t-test).
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The major difference in nociceptor response across fibers to sustained mechanical stimulation was not dependent on differences in receptive field site; thus, it was not due to systematic variations in tissue compliance. Tissue displacement was measured for each stimulation site with the 100-g, 2-min stimulus. There were no significant differences among the mean tissue compliances of receptive fields of A-HT[RA] nociceptors (315 ± 87 µm/100 g, mean ± SD), A-HT[SA] nociceptors (344 ± 39µm/100 g), or C-fiber nociceptors (297 ± 70 µm/100g; P > 0.2, ANOVA).
The classification of A-fibers into slowly adapting and rapidly
adapting groups was based on their instantaneous firing rate evoked by
the 25-g, 2-min stimulus. Firing frequency was measured well after the
dynamic component of their response was over (25 s after stimulus
onset). The firing frequencies of all the slowly adapting A-fiber
nociceptors were 5 Hz; those of the rapidly adapting nociceptors were
much lower, usually <1 Hz. When the A-fiber nociceptors were divided
into A-HT[RA] and
A-HT[SA] nociceptors and their mechanical
intensity-coding properties replotted, an obvious difference between
the two groups was observed (Fig. 4). The
response of A-HT[RA] nociceptors to
stimulation with a probe of tip area 0.1 mm2
plateaued at stimulus intensities close to pain threshold reported for
humans (median 35 g, 1st quartile; 25 g, 3rd quartile,
65 g with a probe of 0.1 mm2 tip
area, Greenspan and McGillis 1991
, 1994
); whereas
A-HT[SA] nociceptors continued to increase
their discharge monotonically as stimulus intensity increased above
pain threshold.
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One frequent observation (shown in Figs. 2 and 3) was an abrupt increase in firing rate of a unit during the plateau phase of stimulation. This was observed in 14 units (6 C fibers, 6 A-HT[RA] nociceptors, and 2 A-HT[SA] nociceptors). There was no tendency for such units to differ in conduction velocity, threshold, or suprathreshold sensitivity from nociceptors that did not exhibit such increases in discharge rate. The increase in firing frequency was usually observed with the more intense stimuli (50 and 100 g), and its latency from stimulus onset was dependent on stimulus intensity (latency for 50-g stimulus: 70.4 ± 32.5 s, mean ± SD; latency for 100-g stimulus: 50.8 ± 24.9 s; P < 0.05, Mann-Whitney rank-sum test).
Human psychophysics and the effects of differential nerve block
Pain was reported by four of the subjects for the 25-g stimulus; by seven of them for the 50-g stimulus, and by all subjects for the 100-g stimulus (n = 12). Subjective magnitude scaling of the pain intensity showed that pain scores increased significantly over time for both the 50-g (P < 0.02, ANOVA) and 100-g forces (P < 0.001, ANOVA; Fig. 5). No significant increase in pain occurred with the 25-g force (P > 0.13, ANOVA). There was no significant difference between pain scores, depending on which method of scaling was used (intermittent versus continuous; P > 0.4, 2-factor ANOVA). After the initial dynamic response associated with stimulus onset, pain scores tended to increase smoothly (Fig. 5B), and there were no abrupt increases in pain ratings that may have been associated with rapid increases in nociceptor firing.
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Compression of the superficial radial nerve produced sequential
conduction block of myelinated fibers. Loss of the perception of light
touch occurred within 24-51 min (mean 39 min), and loss of the
sensation of electrically evoked first pain took an additional 17-45
min (mean 27 min). The mean latency to achieve full A-fiber block was
64 min (range 41-90 min). Abolition of conduction in A
mechanoreceptors caused a significant increase in magnitude estimates
of mechanical pain (Fig. 6A;
P < 0.001, 2-factor ANOVA). Whereas magnitude
estimates of the pain evoked by the same stimuli obtained after A
fiber block were not significantly different from controls
(P > 0.05, 2-factor ANOVA). The rate of temporal summation of pain caused by sustained stimulation was assessed by
fitting a power function to each subject's ratings versus time for the
first 30 s of stimulation (i.e., during the time of most rapid
perceptual change). The exponents of these power functions were not
significantly different between control conditions and during
conduction block of the A
fibers (t = 1.23;
P > 0.20), or between control and A
block
conditions (t = 0.69; P > 0.50; Fig.
6B). Thus, although the absolute pain ratings were
significantly higher during the A
fiber block, the rate of pain
increment over time was not found to be significantly different. Verbal
descriptors taken after each series of psychophysical evaluations for
seven subjects showed that the quality of the evoked sensations changed from sharp (42% of subjects) and stabbing (57% of subjects) during the control and A
block testing, to throbbing (71% of subjects), aching (42% of subjects), and, occasionally, burning (28% of
subjects) after A
block.
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DISCUSSION |
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We have described the stimulus-response properties of rat glabrous
skin nociceptors to mechanical stimuli and also their adaptive responses to sustained mechanical stimulation. The differential coding
of both stimulus intensity and stimulus area (probe size) of A- and
C-fibers is similar to cat hairy skin nociceptors (Garell et al.
1996) and monkey cutaneous nociceptors (Slugg et al.
1994
), indicating that rat glabrous skin is a suitable
mammalian model for mechanical nociception. There is also a similar
distribution of nociceptor mechanical thresholds in rat, primate, and
man (Lynn 1994
) which further underscores the validity
of this preparation. This is not the case for all aspects of
nociception, because heat responses from rat myelinated nociceptors are
rarely found, if at all, whereas in the monkey they are the norm. Among
the A-fiber nociceptor population there is a group the mechanical
adaptation properties of which are distinctly different from those of
other A-fiber nociceptors and from C-fiber nociceptors. Although the responses of these units, which we termed
A-HT[SA] nociceptors, are somewhat better
related to human pain intensity than others, their discharge still
adapts during stimulation while perceived pain increases. These
A-HT[SA] units continued to increase their
discharge in an approximately linear fashion as stimulus intensity
increased; the remainder of the A-fiber nociceptor population (A-HT[RA] nociceptors) had stimulus-response
functions that plateaued at stimulus intensities close to the average
threshold for pain in humans (Greenspan and McGillis 1991
,
1994
). This plateau response and the rapid adaptation to
long-duration mechanical stimuli indicates that these
A-HT[RA] nociceptors are unlikely to contribute
much to the painfulness of such stimuli.
Adaptation is a general property of sensory receptors (Adrian
1928), and it would have been surprising if we had observed units that increased their firing during sustained stimulation. In this
respect peripheral mechanisms would be unlikely to explain the increase
in pain that sustained mechanical stimulation causes. However, we
observed primary afferent properties that could contribute to pain
intensity increases with sustained stimulation. Thirty-five percent of
nociceptors showed transient increases in their firing rates during
long-duration stimulation (e.g., Fig. 2, A and
B). This delayed excitation could contribute to temporal
summation if several units, each showing delayed excitation at
different latencies, converged onto the same central neuron that also
received unmyelinated fiber inputs. However, it is unclear whether
sufficient summation occurs for such events to influence CNS responses,
and ultimately, perception. We did not observe any units that were excited at long latency by subthreshold stimuli (see Fig. 3,
inset) as reported by White et al. (1991)
in
rat hairy skin. The difference between the results of White et
al. (1991)
and those reported here is partly technical. Even
our weakest stimulus (25 g) was suprathreshold for almost all units.
However, it may be that the delayed nociceptor excitation reported here
is mechanistically similar to the long-latency excitation seen with
subthreshold stimuli described by White et al. (1991)
.
The delayed excitation of some nociceptors may have been caused by one
or more chemical mediators released from the surrounding tissues (e.g.,
prostaglandins, bradykinin), although this is unlikely, given the short
duration of the effect. In addition, the long-latency, subthreshold
excitation phenomenon reported by White et al. (1991) was not affected
by prostaglandin E2, a known
nociceptor-sensitizing agent (see Kress and Reeh 1996
and Levine and Taiwo 1994
for recent reviews). It
remains to be determined whether other putative chemical modulators of
nociceptor sensitivity, such as neuropeptides, produce similar effects
on nociceptor responses as the kinins or prostanoids. Such agents may
cause effects similar to the short-duration firing increases that were
observed, given their short half-lives.
That pain perception still continued to increase during sustained
stimulation when conduction in the A fibers of the superficial radial nerve was blocked argues against the theory that perceptual temporal summation results from gradually changing A
-fiber input relative to A
- and C-fiber input (Adriansen et al.
1984
). Indeed, pain perception approximately doubled after A
block, consistent with the well-known phenomenon of
mechanoreceptor-mediated inhibition (Brown et al. 1973
;
Handwerker et al. 1975
; Hillman and Wall
1969
). Temporal summation was still evident when only the
unmyelinated fibers were capable of impulse conduction. This summation
could have both peripheral and central components. Delayed excitation of mechanically insensitive C-fiber nociceptors, including
C-heat nociceptors, by tonic pressure has recently been reported in
humans (Schmelz et al. 1997
), with such units showing
increasing firing rates during a response. Reeh et al.
(1987)
have reported recruitment of A
nociceptors in the
rat's tail by long-duration mechanical stimuli applied with a large
probe outside their receptive fields. We were unable to reproduce this
finding, because, occasionally, stimuli were inadvertently applied to
areas just outside a unit's receptive field because of small lateral
movements of the stimulator's probe between stimulus blocks. Under
these conditions the fiber under study was never excited by the
stimulus. Also, there are substantial differences in method between the
stimuli applied by Reeh et al. (1987)
and those used in
the current study, which may underlie the differing results. Summation
of inputs by central neurons is also likely to be involved in mediating
the increases in pain sensation that tonic mechanical stimuli of
noxious intensity causes. Wind-up (Mendell and Wall
1965
) of deep dorsal horn neurons, caused by summation of slow
potentials from unmyelinated inputs, increases their responsiveness to
subsequent afferent inputs for tens of seconds or even minutes
(Woolf and King 1987
; Woolf et al. 1988
).
There is also evidence of summation of A-fiber inputs. Cervero
et al. (1988)
reported that some dorsal horn neurons (both "wide dynamic range" and nociceptive-specific) increase their discharge rate during long-duration mechanical stimuli, regardless of
whether they receive C-fiber inputs or not. Perhaps these cells, whose
responses parallel our psychophysical data, receive strong inputs from
A-HT[SA] nociceptors, many of which show the
delayed excitation phenomenon.
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ACKNOWLEDGMENTS |
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This work was supported by National Science Foundation Grant IBN-9696127 and National Institute of Neurological Disorders and Stroke Grant NS-28559 to J. D. Greenspan. D. Andrew was a Senior International Scholar of the Fulbright Commission during this research.
Current address of D. Andrew: Division of Neurosurgery, Barrow Neurological Institute, 350 W. Thomas Rd., Phoenix, AZ 85013.
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FOOTNOTES |
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Address reprint requests to J. D. Greenspan, Dept. OCBS, Room 5-A-12, University of Maryland Dental School, 666 W. Baltimore St., Baltimore, MD 21201.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 26 August 1998; accepted in final form 16 July 1999.
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REFERENCES |
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