 |
 Previous Article | Next Article 
The Journal of Neuroscience, November 1, 1998, 18(21):8947-8959
Intradermal Injection of Capsaicin in Humans Produces
Degeneration and Subsequent Reinnervation of Epidermal Nerve Fibers:
Correlation with Sensory Function
Donald A.
Simone1, 2,
Maria
Nolano3,
Timothy
Johnson4,
Gwen
Wendelschafer-Crabb4, and
William R.
Kennedy4
Departments of 1 Psychiatry, 2 Preventive
Sciences, and 4 Neurology, University of Minnesota,
Minneapolis, Minnesota 55455, and 3 Salvatore Maugeri
Foundation, Campoli M.T. (BN), Italy
 |
ABSTRACT |
The ability of capsaicin to excite and subsequently to desensitize
a select group of small sensory neurons has made it a useful tool to
study their function. For this reason, application of capsaicin to the
skin has been used for a variety of painful syndromes. We examined
whether intradermal injection of capsaicin produced morphological
changes in cutaneous nerve fibers that would account for its analgesic
properties by comparing cutaneous innervation in capsaicin-treated skin
with psychophysical measures of sensation. At various times after
capsaicin injection, nerve fibers were visualized immunohistochemically
in skin biopsies and were quantified. In normal skin the epidermis is
heavily innervated by nerve fibers immunoreactive for protein gene
product (PGP) 9.5, whereas fibers immunoreactive for substance P (SP)
and calcitonin gene-related peptide (CGRP) are typically associated
with blood vessels. There was nearly complete degeneration of epidermal
nerve fibers and the subepidermal neural plexus in capsaicin-treated
skin, as indicated by the loss of immunoreactivity for PGP 9.5 and
CGRP. The effect of capsaicin on dermal nerve fibers immunoreactive for
SP was less obvious. Capsaicin decreased sensitivity to pain produced by sharp mechanical stimuli and nearly eliminated heat-evoked pain
within the injected area. Limited reinnervation of the epidermis and
partial return of sensation occurred 3 weeks after treatment; reinnervation of the epidermis was ~25% of normal, and sensation improved to 50-75% of normal. These data show that sensory
dysfunction after capsaicin application to the skin results from rapid
degeneration of intracutaneous nerve fibers.
Key words:
pain; analgesia; protein gene product 9.5; intracutaneous
nerves; immunohistochemistry; confocal microscopy
| |
INTRODUCTION |
Capsaicin, the active pungent
ingredient in hot peppers, is a unique tool used to study the functions
of a subset of sensory neurons, including nociceptive neurons. Early
studies focused on the neurotoxic actions of capsaicin applied
systemically in high doses to neonatal or adult rats (for
review, see Nagy, 1982 ; Fitzgerald, 1983; Russell and Burchiel,
1984; Buck and Burks, 1986; Holzer, 1991). It was found that capsaicin
destroys a subset of small diameter primary afferent fibers and their
cell bodies.
Topical application of capsaicin evokes burning pain, neurogenic
inflammation (vasodilatation and plasma extravasation), and hyperalgesia to heat and mechanical stimuli (Szolcsányi, 1977; Carpenter and Lynn, 1981; Culp et al., 1989; Simone and Ochoa, 1991).
After repeated applications, the treated area becomes less sensitive to
pain. This desensitizing action has made capsaicin attractive for use
as a peripherally acting analgesic for chronic painful syndromes
(Capsaicin Study Group, 1991; Fusco and Giacovazzo, 1997).
Intradermal injection of capsaicin quickly deposits a quantified amount
directly into human skin. This produces a sensation of intense burning
pain and hyperalgesia to heat and mechanical stimuli (Simone et al.,
1987, 1989; LaMotte et al., 1991, 1992), followed by a rapid
desensitization characterized by diminished pain sensation at the site
of application (LaMotte et al., 1991). Electrophysiological studies
have shown that shortly after intradermal injection of capsaicin,
C-fiber polymodal nociceptors can become insensitive to mechanical and
heat stimuli (Baumann et al., 1991). Furthermore, this effect of
capsaicin is well localized to the injection site because only the
portion of the receptive field exposed to capsaicin becomes
desensitized. Thus, diminished pain sensation at the site of capsaicin
injection is attributed to desensitization of nociceptors.
The mechanisms underlying rapid desensitization and hypalgesia after
local capsaicin application in humans are unclear. Desensitization of
capsaicin-sensitive afferent fibers involves a continuum of physiological and morphological changes that are dependent on capsaicin
dose and route of administration. The effects of capsaicin on neural
function, whether applied systemically or locally, have been
categorized into various stages in animal studies and range from
conduction block with reversible ultrastructural changes in peripheral
nociceptive endings to irreversible degeneration of nociceptive neurons
and their processes (Szolcsányi, 1993). For example, although
systemic application of high doses of capsaicin destroys certain
sensory neurons, capsaicin applied to the peripheral nerve endings in
the cornea produces swelling of mitochondria and a reduction in the
number of microvesicles in unmyelinated nerve endings without evidence
of axonal degeneration (Szolcsányi et al., 1975). Morphological
correlates of functional desensitization after capsaicin application to
skin are unknown. Although topical capsaicin decreased the number of
nerve fibers in the epidermis as observed in a blister roof (Reilly et
al., 1997), this was not verified by skin biopsy or sensory testing.
Therefore, in this correlative study in humans, psychophysical measures
of cutaneous sensation and immunohistochemical techniques were used to
determine whether the hypalgesia after intradermal injection of
capsaicin could be attributed to morphological changes in epidermal
nerve fibers (ENFs).
A preliminary report has been published previously (Simone et al.,
1996).
| |
MATERIALS AND METHODS |
Subjects. Eight subjects (six male and two female)
ranging in age from 24 to 69 years participated. Each subject provided informed consent to a protocol that was approved by the Institutional Review Board Human Subjects Committee of the University of
Minnesota.
Intradermal injection of capsaicin. Capsaicin was dissolved
in a vehicle containing 7.5% Tween 80 in saline as described
previously (Simone et al., 1987, 1989; LaMotte et al., 1991). All
injections were given into test areas (5 mm in diameter) marked on the
lateral aspect of the upper arm. Capsaicin doses of either 0.2, 2, or 20 µg in a volume of 20 µl or an equal amount of the vehicle was injected into each site using a 0.5 ml insulin syringe. A maximum of
seven injections were given into each shoulder. Before each injection,
the skin was anesthetized with an intradermal injection of 1%
lidocaine (0.3-0.5 ml).
Psychophysical measures of cutaneous sensation. Heat pain,
pricking pain, cold sensation, and tactile threshold were evaluated within each 5-mm-diameter test site. Thermal stimuli of 5 sec duration
were applied via a 2-mm-diameter contact probe maintained at 53°C for
heat pain or 1°C for cold sensation. Subjects judged the magnitude of
heat pain and the magnitude of cold sensation using a visual analog
scale ranging from 0 (no pain) to 10 (most severe pain imaginable).
Heat and cold stimuli were each applied five times, and the mean
magnitude of pain and cold sensation was determined. Pricking pain was
evoked by a sharp probe (50-µm-diameter tip) attached to a nylon
monofilament with a bending force of 95 mN. This probe did not
penetrate the skin. The stimulus was applied 10 times, each for a
duration of 1-2 sec. The proportion of stimulus presentations that
evoked pain, as well as the magnitude of pain, was recorded. Tactile
threshold (in mN) was determined by the use of calibrated
Semmes-Weinstein monofilaments. Threshold was defined as the smallest
monofilament that could be perceived at least 50% of the time.
Individual monofilaments were applied 10 times beginning with a
suprathreshold stimulus. All sensory tests were performed at each test
site before and at various times after injection.
Skin biopsy and immunohistochemistry. Skin biopsies were
obtained from vehicle- and capsaicin-treated sites and occasionally from untreated skin. After the skin was anesthetized by intradermal injection of 1% xylocaine (Astra, Westborough, MA), the biopsy was
made with a 3 mm punch tool (Acupunch; Acuderm, Fort Lauderdale, FL)
and processed as described previously (Kennedy et al., 1996). Briefly,
biopsies were fixed in Zamboni's solution, cryoprotected, and
sectioned with a freezing sliding microtome (Leica, Nussloch, Germany).
Diluent and washing solutions comprised 1% normal donkey serum
(Jackson ImmunoResearch, West Grove, PA) in 0.1 M
PBS with 0.3% Triton X-100 (Sigma, St. Louis, MO). Floating
sections were blocked with 5% normal donkey serum in the diluent
solution. Nerve and tissue antigens were localized using primary
antibodies to protein gene product (PGP) 9.5 (1:800; Ultraclone, Isle
of Wight, England), substance P (SP) (1:1000; Incstar, Stillwater, MN), calcitonin gene-related peptide (CGRP) (1:1000; Amersham, Arlington Heights, IL) and type IV collagen (Chemicon, Temecula, CA), each diluted in PBS-Triton X-100-NGS. Nonimmune serum was used for negative controls. Secondary antibodies specific to the IgG species used as a primary antibody and labeled with cyanine dye fluorophores 3.18 and 5.18 (Jackson ImmunoResearch) were used to locate two antigens in each section. After immunohistochemical processing, sections were adhered to coverslips with agar, dehydrated via an
alcohol series, cleared with methyl salicylate, and mounted in
DPX (Fluka BioChemika, Ronkonkoma, NY).
Imaging and quantification of ENFs. Images of sections that
were double stained with PGP 9.5 and type IV collagen were
collected with a laser-scanning confocal microscope (Bio-Rad, Hercules, CA) with a Nikon 20× planapochromate objective (numerical aperture, 0.75) and appropriate filters. Each image set comprised a
z-series that was acquired in 2 µm increments throughout
the thickness of the section.
Quantitative analyses of ENFs were performed as described previously
(Kennedy et al., 1996). Briefly, z-series image stacks of
PGP 9.5-immunostained ENFs were acquired from the biopsy sections with
the confocal microscope, and the images were analyzed with Neurolucida
software (MicroBrightField, Colchester, VT) by tracing nerve fibers in
three dimensions. Individual ENFs are counted as they pass through the
basement membrane. Branching occurring within the epidermis did not
increase the number of ENFs counted. Epidermal nerve counts of PGP
9.5-immunoreactive fibers were standardized for section thickness (30 µm) and expressed as the number of fibers per millimeter of
epidermis.
The subepidermal neural plexus and SP- and CGRP-immunoreactive fibers
were examined qualitatively by visual inspection with the use of
fluorescence microscopy.
Data analyses. ENFs were counted, quantified, and compared
with the number of ENFs per millimeter length in normal epidermis. A
one-way ANOVA was used to compare the number of ENFs present 3 d after intradermal injection of vehicle and of 0.2, 2, and 20 µg doses of capsaicin. The innervation of epidermis before and
between 1 and 4 weeks after an intradermal injection of 20 µg was
assessed by repeated-measures ANOVA. Comparisons were made between the
number of ENFs in capsaicin-treated skin, vehicle-treated skin, and
normal untreated skin.
The effect of capsaicin on psychophysical measures of heat pain
sensation, cold sensation, and tactile sensation and on the proportion
of sharp stimuli perceived as painful was assessed using ANOVAs with
repeated measures. Separate analyses were used to examine the effect of
capsaicin dose on the various sensory modalities and to evaluate
changes in sensation over a 4 week time period after a single injection
of 20 µg of capsaicin.
Experimental design. To determine the effect of graded doses
of capsaicin on the sensation and morphology of ENFs, we gave each of
five subjects one set of four intradermal injections on each upper arm.
A set of injections consisted of capsaicin doses of 0.2, 2, and 20 µg
and the vehicle. Sensation was assessed and skin biopsy was performed
at each injection site after 24 hr for one set of injections and
after 72 hr for the other set.
In a separate experiment, we determined the time course and extent of
reinnervation and whether reinnervation is accompanied by the return of
normal pain sensation. Five subjects were given four intradermal
injections of 20 µg of capsaicin into the upper arm. Evoked sensation
and cutaneous innervation were assessed at each injection site at 1, 2, 3, or 4 weeks after injection. Three subjects received one additional
injection of capsaicin, and measurements were also made at 6 weeks
after injection.
| |
RESULTS |
Effect of capsaicin on the number of ENFs and cutaneous sensation:
dose-response relationships
In vehicle-treated skin, like normal untreated skin, PGP
9.5-immunoreactive nerve fibers are abundant in the subepidermal neural
plexus, which lies just below the basement membrane (Fig. 1, Veh). The epidermis is
richly innervated by fibers that originate in the subepidermal plexus
and project up through the basement membrane and terminate in the
epidermis. It is likely that all nerve fibers have been visualized
because PGP 9.5-immunoreactive axons are greater in number and density
and the staining is stronger than that seen with antisera to other
neural markers (Karanth et al., 1991). It has been shown previously
that nerve fibers extending into the epidermis are unmyelinated (Ochoa,
1984; Wang et al., 1990; Kennedy and Wendelschafer-Crabb, 1993).
View larger version (81K):
[in this window]
[in a new window]
|
Figure 1.
Confocal images showing innervation of epidermis
and superficial dermis for one subject at 72 hr after a single
injection of vehicle (Veh) or capsaicin doses of 0.2, 2.0, or 20 µg. Nerve fibers (N) immunoreactive
for PGP 9.5 appear yellow-green; the basement membrane
(B) and vessels (V)
appear red. Scale bars, 100 µm.
|
|
Capsaicin produced a rapid, dose-dependent degeneration of
intracutaneous nerve fibers and a dramatic decrease in the sensation of
pain produced by heat and mechanical stimuli. All three doses of
capsaicin caused a significant reduction in the mean number of ENFs as
compared with that in vehicle-treated skin (p < 0.05). Although nerve degeneration was evident at 24 hr after
injection, the magnitude and spatial extent of fiber loss were more
pronounced at 72 hr after injection. An example of nerve degeneration
after capsaicin injection is provided in Figure 1, which shows confocal images of skin biopsies for one subject with typical neural
degeneration observed at 72 hr after injection. After the lowest dose
of capsaicin, loss of PGP 9.5-immunoreactive nerve fibers was
restricted primarily to fibers located in the epidermis, with little to
moderate disruption of nerve fibers in the subepidermal neural plexus.
Higher doses of capsaicin resulted in complete loss of PGP
9.5-immunoreactive ENFs plus various degrees of disruption or complete
loss of the subepidermal nerve plexus.
Nerve fibers immunoreactive for CGRP and SP are sparsely distributed
throughout the papillary dermis where they are typically associated
with capillary loops. CGRP-immunoreactive nerve fibers occasionally
penetrate the epidermis, whereas SP-immunoreactive fibers are sparse in
the subepidermal neural plexus and rarely enter the epidermis. Complete
loss of CGRP- immunoreactive fibers was also observed 72 hr after
capsaicin injection. The effect of capsaicin on SP-immunoreactive nerve
fibers was difficult to assess because very few fibers are normally
found in the superficial dermis, and after capsaicin a few
SP-immunoreactive nerve fibers were found in some subjects, whereas no
SP-immunoreactive fibers were found in other subjects.
The relationship between capsaicin dose, somatic sensation, and the
number of PGP 9.5-immunoreactive ENFs at 72 hr after injection is
summarized for all five subjects in Figure
2. The mean (± SEM) decrease in the
number of ENFs per length (in millimeters) of epidermis at 72 hr after
injection of 0.2, 2, and 20 µg of capsaicin was 43.5 ± 13.2, 98.7 ± 1.33, and 99.9 ± 0.99%, respectively, compared with
that in vehicle-treated skin. The decrease in the number of ENFs was
associated with diminished pain sensation. One-way ANOVAs revealed that
capsaicin decreased the magnitude of heat pain sensation
(p < 0.001) and the detection of sharp pain
sensation (p < 0.001). However, heat pain
sensation was more sensitive to capsaicin treatment than was mechanical
pain sensation. The magnitude of heat pain sensation decreased
significantly after injection of 2 and 20 µg of capsaicin
(p < 0.05), whereas the proportion of sharp
mechanical stimuli perceived as painful decreased significantly after
the 20 µg dose (p < 0.05). Tactile threshold was not altered significantly after capsaicin injection, but the effect
of capsaicin on this measure varied considerably between subjects.
Although the magnitude of cold sensation did not decrease significantly, the subjective magnitude of cold decreased >50% in two
of five subjects after the 2 µg dose and in three of five subjects
after the 20 µg dose. The remaining subjects experienced a lesser
decrement in cold sensation or no change at all. Injection of the
vehicle did not produce significant changes in any evoked sensations or
in innervation density as compared with that in normal untreated
skin.
View larger version (15K):
[in this window]
[in a new window]
|
Figure 2.
Somatic sensation and the number of ENFs for all
five subjects at 72 hr after injection of capsaicin. Data are expressed
as the mean (± SEM) percent change from the data for vehicle-treated
skin. For heat pain and cold sensation, data represent the change in
the magnitude of sensation. Mechanical pain sensation is represented as
the change in the proportion of stimuli perceived as painful.
|
|
Reinnervation of the epidermis and restoration of
sensory function
To determine the extent to which ENFs regenerated after capsaicin
as well as the time course of epidermal reinnervation, we performed
skin biopsies and sensory tests at capsaicin injection sites 1-4
(n = 5) or 6 (n = 3) weeks after the
injection. A one-way ANOVA indicated a significant decrease in ENFs
after capsaicin (p < 0.001) compared with that
in normal skin. All subjects exhibited denervation in capsaicin-treated
skin during the first 2 weeks after injection, and ENFs were rarely
observed. Similarly, nerve fibers in the subepidermal neural plexus
were also sparse during this time period. Reinnervation of the
epidermis by ENFs began during the third and fourth weeks after the
capsaicin injection and was characterized by the return of an intact
subepidermal neural plexus and the reappearance of sparse nerve fibers
in the epidermis. However, the innervation of epidermis during this
time was still dramatically impaired, and the number of ENFs per length (in millimeters) of epidermis ranged from only 12 to 29% of that in
normal skin. Figure 3 shows confocal
images of biopsy sections stained for PGP 9.5 immunoreactivity in
normal untreated skin and in skin at 1, 2, and 4 weeks after capsaicin
treatment for one subject. For this subject, who exhibited the most
reinnervation of all subjects tested, innervation of the epidermis did
not improve further between 4 and 6 weeks (we did not examine at any
later time).
View larger version (102K):
[in this window]
[in a new window]
|
Figure 3.
Confocal images showing denervation and
reinnervation of epidermis and superficial dermis by PGP
9.5-immunoreactive nerve fibers for one subject. Biopsies were taken
from capsaicin-treated (20 µg) skin at 1, 2, and 4 weeks after
injection and from normal untreated skin. The appearance of nerve
fibers immunoreactive for PGP 9.5 is the same as that described in
Figure 1. Scale bars, 100 µm.
|
|
Nerve fibers immunoreactive for CGRP also reappeared 3-4 weeks after
capsaicin (Fig. 4). These
CGRP-immunoreactive nerve fibers were never observed in the epidermis
or superficial dermis 1 week after capsaicin. However, they were found
in the dermis, but not the epidermis, 4 weeks after injection of
capsaicin. Although quantitative measures of the number of
CGRP-immunoreactive fibers were not made, the number of fibers present
at 4 weeks after capsaicin appeared to be less than normal, as with PGP
9.5-immunoreactive fibers.
View larger version (131K):
[in this window]
[in a new window]
|
Figure 4.
Confocal images of skin biopsies from one subject
showing nerve fibers immunoreactive for CGRP and SP in normal skin and
skin at 1 and 4 weeks after capsaicin injection.
Right, CGRP-immunoreactive fibers were completely
absent 1 week after capsaicin injection and reappeared 4 weeks after
injection (arrows). Left, There was not a
complete loss of SP-immunoreactive fibers at 1 week after capsaicin
injection, and one fiber can be seen oriented
horizontally below the basement membrane
(arrow). At 4 weeks after capsaicin injection, fibers
were occasionally found deep in the dermis
(arrow) and oriented vertically
toward the basement membrane. Scale bars, 100 µm.
|
|
The extent of reinnervation of SP-immunoreactive nerve fibers was
difficult to assess because of the small number of fibers normally
observed in the superficial dermis and epidermis. A few nerve fibers
were found in at least some of the subjects at all times examined after
capsaicin. These fibers were observed only in the dermis, and the
number of these fibers found was similar to that in normal skin.
Gradual reinnervation of the epidermis coincided with the gradual
restoration of evoked pain sensation. This is illustrated in Figure
5 that shows the mean change in the
number of PGP 9.5-immunoreactive ENFs and the mean change in sensation
for all subjects. The magnitude of heat pain sensation and the percent
of mechanical stimuli perceived as painful decreased significantly
after capsaicin (p < 0.001). During the first 2 weeks after capsaicin injection, heat pain sensation was nearly
eliminated, and subjects exhibited an ~65% decrease in the
proportion of sharp mechanical stimuli perceived as painful. However,
the decrease in mechanically evoked pain sensation was variable
compared with the changes in heat pain sensation. For example, during
the first 2 weeks after capsaicin, three of the six subjects did not
perceive sharp pain, whereas the detection of sharp pain was not
altered in one subject. Although there were no significant alterations
in the sensation of cold during the first 2 weeks after capsaicin, all
but one subject exhibited at least a 16% decrease in the magnitude of
cold sensation. Similarly, there was no significant change in tactile
threshold during this time. Tactile thresholds were increased in three
of the six subjects and were unchanged in the remaining three
subjects.
View larger version (17K):
[in this window]
[in a new window]
|
Figure 5.
The mean (± SEM) change in sensation and in the
number of ENFs for all subjects through 1-6 weeks after injection of
20 µg of capsaicin. Data are presented as the percent change from
normal untreated skin.
|
|
At 3 and 4 weeks after capsaicin, detection of heat pain and of
pricking pain sensation had improved and was consistent with the onset
of reinnervation of the epidermis. There remained a 37 ± 19.9%
decrease in heat pain at 4 weeks after capsaicin as compared with that
in normal skin. Similarly, the sensation of pricking pain also improved
but was more variable than was the pain sensation evoked by heat.
Localization of capsaicin-evoked nerve degeneration
To determine the extent to which capsaicin diffused from the
injection site to cause degeneration of nerve fibers adjacent to the
injection site, we made one biopsy 72 hr after injection of 20 µg of
capsaicin that included part of the injection site (as defined by the
appearance of the bleb) and adjacent skin. A confocal image of this
biopsy is provided in Figure 6. It can be
seen that the left portion of the biopsied skin does not
contain ENFs, whereas ENFs are clearly seen in the right
portion. The right portion of the biopsy, which has a normal
appearance and number of ENFs, was ~1-2 mm from the edge of the
capsaicin injection. This demonstrates that capsaicin diffuses
minimally from the injection site and that nerve degeneration is
restricted to the capsaicin-treated area.
View larger version (30K):
[in this window]
[in a new window]
|
Figure 6.
The localization of degeneration of ENFs after an
intradermal injection of 20 µg of capsaicin as shown by confocal
images of skin biopsy from one subject. Top, Montage of
confocal images that span across the skin biopsy. Abundant ENFs are
seen only at the far right portion of the biopsy, which
was located outside the capsaicin injection site and presumably not
exposed to the neurotoxin. Bottom, The two opposite ends
of the skin biopsy, outlined by the
squares in the top image, shown at
greater magnification to illustrate differences in epidermal
innervation.
|
|
| |
DISCUSSION |
The present findings demonstrate that intradermal injection of
capsaicin produces rapid degeneration of nerve fibers in the epidermis
and superficial dermis. This phenomenon is local in that it occurred
only at the site of injection and presumably only to those nerve fibers
that came in contact with capsaicin. We used loss of immunoreactivity
for PGP 9.5 as evidence of degeneration. It could be argued that
capsaicin interferes with expression of PGP 9.5 without producing nerve
fiber destruction. However, we believe the initial loss and subsequent
reappearance of immunoreactivity for PGP 9.5 coincides with
degeneration and subsequent regeneration for the following reasons.
First, capsaicin produced a clear disruption of the subepidermal neural
plexus within 3 d after intradermal injection, followed by a
gradual loss within the next 2 weeks. Second, loss of immunoreactivity
also occurred for the neuropeptide CGRP, and there appeared to be a
decrease in the number of SP-immunoreactive fibers. Third, the
reappearance of immunoreactivity for PGP 9.5 was gradual and consistent
with the gradual regeneration of the subepidermal neural plexus and
reinnervation of the epidermis. Fourth, the number of PGP
9.5-immunoreactive fibers that reappeared was less than that in normal
skin, even at 4 and 6 weeks after capsaicin injection. Fifth, the loss
and subsequent reappearance of immunoreactivity for PGP 9.5 correlated
well with the loss and recovery of somatic sensation. The combined
disappearance of immunoreactivity for a cytoplasmic protein and two
neuropeptides and the associated decrement in sensation strongly
suggest that intracutaneous nerve fibers degenerated.
Degeneration of intradermal and epidermal nerve fibers by locally
applied capsaicin raises several important issues regarding (1) the
mechanisms of hypalgesia produced by capsaicin, (2) the mechanisms by
which capsaicin produces local degeneration of nerve fibers, and (3)
the function of epidermal nerve fibers in sensation, which are each
discussed below. It is noteworthy that capsaicin produced degeneration
of ENFs in the presence of local anesthesia. This suggests that
degeneration produced by capsaicin is not dependent on excitation and
generation of action potentials.
Hypalgesia and degeneration after capsaicin
Many studies have documented that application of capsaicin to the
skin initially produces pain and hyperalgesia followed by diminished
pain sensation, referred to as functional desensitization. The
peripheral neural mechanisms that contribute to the positive sensory
phenomena of pain and hyperalgesia produced by intradermal injection of
capsaicin include excitation and sensitization of C polymodal
nociceptors, whereas the neural mechanisms underlying functional
desensitization subsequent to capsaicin treatment are unclear. One
possibility is that capsaicin depletes C-fibers of neuropeptides, such
as SP and CGRP, resulting in desensitization of nociceptors. Capsaicin
has been shown to release these and other peptides from the peripheral
endings of primary afferent fibers (Holzer, 1988; Maggi and Meli, 1988;
Saria et al., 1988). Recent electrophysiological studies, however,
suggest that initial desensitization and hypalgesia are related to the
effects of capsaicin on neuronal ion channels. It has been found that
capsaicin initially excites nociceptors by interacting with a specific
receptor (Szallasi and Blumberg, 1990a,b; Caterina et al., 1997) to
decrease the input resistance (Heyman and Rang, 1985), to evoke an
inward current (Bevan and Docherty, 1993), and to open nonselective
cation channels (Wood et al., 1988; Bleakman et al., 1990; Docherty et
al., 1991). This is followed by the inactivation of voltage-gated ion
channels that prevents the generation of action potentials and may
account for short-lasting desensitization and hypalgesia. It is
therefore possible that capsaicin interferes with the generation of
action potentials by causing ultrastructural damage (e.g.,
mitochondrial swelling) to nociceptive endings as a result of prolonged
opening of cation channels. Although the mechanisms described above may account for initial desensitization and corresponding hypalgesia, it is
unlikely that they account for the long-lasting hypalgesia observed in
the present study. Rather, our findings demonstrate that hypalgesia
results from the loss of nerve fibers. This is the first study to
examine the morphology of intradermal and ENFs located at the site of
capsaicin injection. Our results are compatible with a previous study
in which repeated application of topical capsaicin to the rat hindpaw
produced no evidence of either nerve damage in the sciatic nerve
(proximal to capsaicin application) or neuron loss in the dorsal root
ganglion (DRG) (McMahon et al., 1991). Although topical capsaicin did
not produce remote degeneration of nerve fibers in the nerve trunk or
of sensory neurons in the DRG, it was not determined whether capsaicin
produced degeneration locally at the site of application. It has been
shown, however, that systemic administration of capsaicin caused some
degeneration of the subepidermal neural plexus (Chung et al., 1990),
demonstrating susceptibility of intracutaneous nerve fibers to the
neurotoxic actions of capsaicin. Also, local application of capsaicin
has been shown to cause degeneration of DRG neurons and axons
(Handwerker et al., 1984; Marsh et al., 1987; Pini et al., 1990). As
illustrated in the present study, degeneration occurred only at the
site of capsaicin application and in those fibers exposed to the
neurotoxin. Moreover, degeneration was progressive in that only ENFs
were affected at 24 hr after capsaicin, whereas degeneration included the subepidermal neural plexus within 1 week and the dermal CGRP- and
SP-immunoreactive nerve fibers. This was illustrated more clearly in a
parallel study (Nolano et al., 1996) in which repeated topical
application of capsaicin produced gradual degeneration of nerve fibers
in the epidermis. Recently, Reilly et al. (1997) confirmed the use of
the blister technique to show degeneration of ENFs by capsaicin. Thus,
capsaicin seems to produce a gradual but limited dying back of fibers
from the nerve endings in the epidermis. This pattern of degeneration
is common with various types of clinical neuropathies, such as diabetic
neuropathy (Kennedy et al., 1996) and neuropathy associated with human
immunodeficiency virus injection (McCarthy et al., 1995).
Functions of epidermal nerve fibers
The present findings provide new information about the function of
ENFs. Because loss of ENFs correlated primarily with diminished pain
sensation, we believe that many of the ENFs are nociceptors. Furthermore, many are likely to be polymodal nociceptors because pain
evoked by heat and mechanical stimuli was depressed. However, an
interesting paradox is that cold and tactile sensitivities were not
altered significantly, although virtually all fibers in the superficial
skin were absent. Although the probe used for cold sensation was small
and maintained at very low temperature, it evoked cold sensation
without pain. This suggests that cold-specific receptors normally
sensitive to innocuous cold temperatures were excited. The finding that
cold and tactile sensations were not altered by capsaicin is in
agreement with electrophysiological studies showing that evoked
responses of low threshold receptors were not altered after intradermal
injection of capsaicin (Baumann et al., 1991). It is likely that those
sensations arose from activation of receptors located deep in the
dermis or just adjacent to the capsaicin injection where innervation is
normal. Similarly, deep nociceptors or activated proximal segments of
ENFs are likely to account for the residual pricking pain sensation
that persisted after capsaicin treatment.
There seemed to be a mismatch in the relationship between the number of
regenerated ENFs and evoked sensation. During reinnervation when there
were relatively few fibers in the epidermis, there was a striking
return of heat and sharp pain sensation. For example, at 3 weeks after
capsaicin injection, the mean magnitude of heat pain and sharp pain
sensation was 61 and 77%, respectively, of that obtained in normal
skin. At this time, however, epidermal reinnervation was only ~17%
of normal. Two possibilities might account for the apparent mismatch
between the magnitude of sensation and the number of epidermal nerve
fibers. One is that relatively few epidermal nerve fibers are needed
for pain detection. This is supported by microneurography studies in
humans that suggest activation of a small number of nociceptive primary
afferent fibers evoke clear pain sensation (Ochoa and Torebjörk,
1989). If this is true, sensory testing by conventional methods may not
be sensitive enough to detect neuropathy in the early stages of
degeneration. A second possibility is that the subepidermal neural
plexus and receptors located on these fibers contribute to evoked
sensation. Indeed at 3 weeks or less after capsaicin treatment, the
subepidermal neural plexus appeared to have returned to normal, on
visual inspection, with respect to its density and continuity.
Conclusions
The present study demonstrates that the hypalgesia after
application of capsaicin to the skin results from degeneration of ENFs.
This finding has important clinical implications because topical
capsaicin has been used for a variety of painful syndromes, including
diabetic neuropathy. Because we have shown that degeneration of ENFs
also occurs after topical capsaicin, although the degeneration has a
slower onset and is not as severe as that produced by intradermal injection (Nolano et al., 1996), it is debatable whether capsaicin should be used in syndromes in which there is ongoing nerve pathology and nerve regeneration is necessary to preserve or restore detection of
noxious stimuli. In this regard, the capsaicin model may be useful to
study mechanisms of regeneration of intracutaneous nerve fibers and to
assess the effects of neurotrophins and other pharmacological agents in
correlative morphological and psychophysical studies.
| |
FOOTNOTES |
Received May 13, 1998; revised Aug. 12, 1998; accepted Aug. 13, 1998.
This work was supported in part by National Institutes of Health Grants
NS31223 (D.A.S.) and NS31397 (W.R.K.) and by a grant from Toray
Industries Inc. (W.R.K.). We thank Dr. Paul Thuras for assistance with
statistical analyses.
Correspondence should be addressed to Dr. Donald A. Simone, Department
of Psychiatry, University of Minnesota, 420 Delaware Street SE, Box
392, Minneapolis, MN 55455.
| |
REFERENCES |
-
Baumann TK,
Simone DA,
Shain CN,
LaMotte RH
(1991)
Neurogenic hyperalgesia: the search for the primary afferent nerve fibers that contribute to capsaicin-induced pain and hyperalgesia.
J Neurophysiol
66:212-227[Abstract/Free Full Text].
-
Bevan SJ,
Docherty RJ
(1993)
Cellular mechanisms of the action of capsaicin.
In: Capsaicin in the study of pain (Wood J,
ed), pp 27-44. London: Academic.
-
Bleakman D,
Brorson JR,
Miller RJ
(1990)
The effect of capsaicin on voltage-gated calcium currents and calcium signals in cultured dorsal root ganglion cells.
Br J Pharmacol
101:423-431[Web of Science][Medline].
-
Buck SH,
Burks TF
(1986)
The neuropharmacology of capsaicin: review of some recent observations.
Pharmacol Rev
38:179-226[Web of Science][Medline].
-
Capsaicin Study Group
(1991)
Arch Intern Med
151:2225-2229[Abstract/Free Full Text].
-
Carpenter SE,
Lynn B
(1981)
Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin.
Br J Pharmacol
73:755-759[Web of Science][Medline].
-
Caterina MJ,
Schumacher MA,
Tominaga M,
Rosen TA,
Levine JD,
Julius D
(1997)
The capsaicin receptor: a heat-activated ion channel in the pain pathway.
Nature
389:816-824[Web of Science][Medline].
-
Chung K,
Klein CM,
Coggeshall RE
(1990)
The receptive part of the primary afferent axon is most vulnerable to systemic capsaicin in adult rats.
Brain Res
511:222-226[Web of Science][Medline].
-
Culp WJ,
Ochoa JL,
Cline M,
Dotson R
(1989)
Heat and mechanical hyperalgesia induced by capsaicin. Cross modality threshold modulation in human C nociceptors.
Brain
112:1317-1331[Abstract/Free Full Text].
-
Docherty RJ,
Robertson B,
Bevan S
(1991)
Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture.
Neuroscience
40:513-521[Web of Science][Medline].
-
Fitzgerald M
(1983)
Capsaicin and sensory neurones
 a review.
Pain
15:109-130[Web of Science][Medline]. -
Fusco BM,
Giacovazzo M
(1997)
Peppers and pain. The promise of capsaicin.
Drugs
53:909-914[Web of Science][Medline].
-
Handwerker HO,
Holzer-Petsche U,
Heym C,
Welk E
(1984)
C-fibre functions after topical application of capsaicin to a peripheral nerve and after neonatal capsaicin treatment.
In: Antidromic vasodilatation and neurogenic inflammation (Chahl LA,
Szolcsányi J,
Lembeck F,
eds), pp 57-78. Budapest: Akadémiai Kiadó.
-
Heyman I,
Rang HP
(1985)
Depolarizing responses to capsaicin in a subpopulation of dorsal root ganglion cells.
Neurosci Lett
56:69-75[Web of Science][Medline].
-
Holzer P
(1988)
Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides.
Neuroscience
24:739-768[Web of Science][Medline].
-
Holzer P
(1991)
Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons.
Pharmacol Rev
43:143-201[Web of Science][Medline].
-
Karanth SS,
Pringall DR,
Kuhn DM,
Levene MM,
Polak M
(1991)
An immunocytochemical study of cutaneous innervation and the distribution of neuropeptides and protein gene product 9.5 in man and commonly employed laboratory animals.
Am J Anat
191:369-383[Web of Science][Medline].
-
Kennedy WR,
Wendelschafer-Crabb G
(1993)
The innervation of the human epidermis.
J Neurol Sci
115:184-190[Web of Science][Medline].
-
Kennedy WR,
Wendelschafer-Crabb G,
Johnson T
(1996)
Quantitation of epidermal nerves in diabetic neuropathy.
Neurology
47:1042-1048[Abstract/Free Full Text].
-
LaMotte RH,
Shain CN,
Simone DA,
Tsai E-F
(1991)
Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms.
J Neurophysiol
66:190-211[Abstract/Free Full Text].
-
LaMotte RH,
Lundberg LER,
Torebjörk HE
(1992)
Pain, hyperalgesia and activity in nociceptive C units after intradermal injection of capsaicin.
J Physiol (Lond)
448:749-764[Abstract/Free Full Text].
-
Maggi CA,
Meli A
(1988)
The sensory-efferent function of capsaicin-sensitive sensory neurons.
Gen Pharmacol
19:1-43[Web of Science][Medline].
-
Marsh SJ,
Stansfeld CE,
Brown DA,
Davey R,
McCarthy D
(1987)
The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro.
Neuroscience
23:275-290[Web of Science][Medline].
-
McCarthy BG,
Hsieh S-T,
Stocks A,
Hauer P,
Macko C,
Cornblath DR,
Griffin JW,
McArthur JC
(1995)
Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy.
Neurology
45:1848-1855[Abstract/Free Full Text].
-
McMahon SB,
Lewin G,
Bloom SR
(1991)
The consequences of long-term topical capsaicin application in the rat.
Pain
44:301-310[Web of Science][Medline].
-
Nagy JI
(1982)
Capsaicin: a chemical probe for sensory neuron mechanisms.
In: Handbook of psychopharmacology, Vol 15 (Iversen LL,
Iversen SD,
Snyder SH,
eds), pp 185-235. New York: Plenum.
-
Nolano M,
Simone DA,
Wendelschafer-Crabb G,
Kennedy WR
(1996)
Decreased sensation and loss of epidermal nerve fibers following repeated topical application of capsaicin in humans.
Soc Neurosci Abstr
22:1802.
-
Ochoa JL
(1984)
Peripheral unmyelinated units in man: structure, function, disorder, and role in sensation.
In: Advances in pain research and therapy, Vol 6 (Kruger L,
Liebeskind JC,
eds), pp 53-68. New York: Raven.
-
Ochoa JL,
Torebjörk H
(1989)
Sensations evoked by intraneural microstimulation of C nociceptor fibres in human skin nerves.
J Physiol (Lond)
415:583-599[Abstract/Free Full Text].
-
Pini A,
Baranowski R,
Lynn B
(1990)
Long-term reduction in the number of C-fibre nociceptors following capsaicin treatment of a cutaneous nerve in adult rats.
Eur J Neurosci
2:89-97[Web of Science][Medline].
-
Reilly DM,
Ferdinando D,
Johnston C,
Shaw C,
Buchanan KD,
Green MR
(1997)
The epidermal nerve fibre network: characterization of nerve fibres in human skin by confocal microscopy and assessment of racial variations.
Br J Dermatol
137:163-170[Web of Science][Medline].
-
Russell LC,
Burchiel KJ
(1984)
Neurophysiological effects of capsaicin.
Brain Res Rev
8:165-176.
-
Saria A,
Martling CR,
Yan Z,
Theodorsson-Norheim E,
Gamse R,
Lundberg JM
(1988)
Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium, and vagal nerve stimulation.
Am Rev Respir Dis
137:1330-1335[Web of Science][Medline].
-
Simone DA,
Ochoa JL
(1991)
Early and late effects of prolonged topical capsaicin on cutaneous sensibility and neurogenic vasodilatation in humans.
Pain
47:285-293[Web of Science][Medline].
-
Simone DA,
Ngeow JYF,
Putterman GJ,
LaMotte RH
(1987)
Hyperalgesia to heat after intradermal injection of capsaicin.
Brain Res
418:201-203[Web of Science][Medline].
-
Simone DA,
Baumann TK,
LaMotte RH
(1989)
Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin.
Pain
38:99-107[Web of Science][Medline].
-
Simone DA,
Nolano M,
Wendelschafer-Crabb G,
Kennedy WR
(1996)
Intradermal injection of capsaicin in humans: diminished pain sensation associated with rapid degeneration of intracutaneous nerve fibers.
Soc Neurosci Abstr
22:1802.
-
Szallasi A,
Blumberg PM
(1990a)
Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes.
Brain Res
524:106-111[Web of Science][Medline].
-
Szallasi A,
Blumberg PM
(1990b)
Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor.
Life Sci
47:1399-1408[Web of Science][Medline].
-
Szolcsányi J
(1977)
A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain.
J Physiol (Paris)
73:251-259[Medline].
-
Szolcsányi J
(1993)
Actions of capsaicin on sensory receptors.
In: Capsaicin in the study of pain (Wood J,
ed), pp 1-26. London: Academic.
-
Szolcsányi J,
Janscó-Gábor A,
Joó F
(1975)
Functional and fine structural characteristics of the sensory neuron blocking effect of capsaicin.
Naunyn Schmiedebergs Arch Pharmacol
287:157-169[Web of Science][Medline].
-
Wang L,
Hilliges M,
Jernberg T,
Wiegleb-Edström D,
Johansson O
(1990)
Protein gene product 9.5-immunoreactive nerve fibres and cells in human skin.
Cell Tissue Res
261:25-33[Web of Science][Medline].
-
Wood JN,
Winter J,
James IF,
Rang HP,
Yeats J,
Bevan S
(1988)
Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture.
J Neurosci
8:3208-3220[Abstract].
Copyright © 1998 Society for Neuroscience 0270-6474/98/18218947-13$05.00/0
This article has been cited by other articles:
|
|
|
|
 
I. G. Panoutsopoulou, G. Wendelschafer-Crabb, J. S. Hodges, and W. R. Kennedy
Skin blister and skin biopsy to quantify epidermal nerves: A comparative study
Neurology,
April 7, 2009;
72(14):
1205 - 1210.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-F. Wang, P. Gerner, B. Schmidt, Z. Z. Xu, C. Nau, S.-Y. Wang, R.-R. Ji, and G. K. Wang
Use of Bulleyaconitine A as an Adjuvant for Prolonged Cutaneous Analgesia in the Rat
Anesth. Analg.,
October 1, 2008;
107(4):
1397 - 1405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Devigili, V. Tugnoli, P. Penza, F. Camozzi, R. Lombardi, G. Melli, L. Broglio, E. Granieri, and G. Lauria
The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology
Brain,
July 1, 2008;
131(7):
1912 - 1925.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Kissin
Vanilloid-Induced Conduction Analgesia: Selective, Dose-Dependent, Long-Lasting, with a Low Level of Potential Neurotoxicity
Anesth. Analg.,
July 1, 2008;
107(1):
271 - 281.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Siegel, J. W. Lee, and A. L. Oaklander
Needlestick Distal Nerve Injury in Rats Models Symptoms of Complex Regional Pain Syndrome
Anesth. Analg.,
December 1, 2007;
105(6):
1820 - 1829.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Kissin, C. F. Freitas, H. L. Mulhern, and U. DeGirolami
Sciatic Nerve Block with Resiniferatoxin: An Electron Microscopic Study of Unmyelinated Fibers in the Rat
Anesth. Analg.,
September 1, 2007;
105(3):
825 - 831.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Lauria and R. Lombardi
Skin biopsy: a new tool for diagnosing peripheral neuropathy
BMJ,
June 2, 2007;
334(7604):
1159 - 1162.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Takahashi, J. P. Tasto, M. Ritter, N. Ochiai, S. Ohtori, H. Moriya, and D. Amiel
Pain Relief Through an Antinociceptive Effect After Radiofrequency Application
Am. J. Sports Med.,
May 1, 2007;
35(5):
805 - 810.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hahn, A. Triolo, P. Hauer, J. C. McArthur, and M. Polydefkis
Impaired reinnervation in HIV infection following experimental denervation
Neurology,
April 17, 2007;
68(16):
1251 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Final Report on the Safety Assessment of Capsicum Annuum Extract, Capsicum Annuum Fruit Extract, Capsicum Annuum Resin, Capsicum Annuum Fruit Powder, Capsicum Frutescens Fruit, Capsicum Frutescens Fruit Extract, Capsicum Frutescens Resin, and Capsaicin
International Journal of Toxicology,
January 1, 2007;
26(1_suppl):
3 - 106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Caterina
Transient receptor potential ion channels as participants in thermosensation and thermoregulation
Am J Physiol Regulatory Integrative Comp Physiol,
January 1, 2007;
292(1):
R64 - R76.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Roosterman, T. Goerge, S. W. Schneider, N. W. Bunnett, and M. Steinhoff
Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.
Physiol Rev,
October 1, 2006;
86(4):
1309 - 1379.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Fink and A. L. Oaklander
Small-fiber neuropathy: answering the burning questions.
Sci. Aging Knowl. Environ.,
February 15, 2006;
2006(6):
pe7 - pe7.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. Y. Kissin, C. F. Freitas, and I. Kissin
The Effects of Intraarticular Resiniferatoxin in Experimental Knee-Joint Arthritis
Anesth. Analg.,
November 1, 2005;
101(5):
1433 - 1439.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Shimizu, T. Iida, N. Horiuchi, and M. J. Caterina
5-Iodoresiniferatoxin Evokes Hypothermia in Mice and Is a Partial Transient Receptor Potential Vanilloid 1 Agonist in Vitro
J. Pharmacol. Exp. Ther.,
September 1, 2005;
314(3):
1378 - 1385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-Y. Zhuang, H. Xu, D. E. Clapham, and R.-R. Ji
Phosphatidylinositol 3-Kinase Activates ERK in Primary Sensory Neurons and Mediates Inflammatory Heat Hyperalgesia through TRPV1 Sensitization
J. Neurosci.,
September 22, 2004;
24(38):
8300 - 8309.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Polydefkis, P. Hauer, S. Sheth, M. Sirdofsky, J. W. Griffin, and J. C. McArthur
The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy
Brain,
July 1, 2004;
127(7):
1606 - 1615.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Amato and A. L. Oaklander
Case 16-2004 - A 76-Year-Old Woman with Numbness and Pain in the Feet and Legs
N. Engl. J. Med.,
May 20, 2004;
350(21):
2181 - 2189.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Mason, R A. Moore, S. Derry, J. E Edwards, and H. J McQuay
Systematic review of topical capsaicin for the treatment of chronic pain
BMJ,
April 24, 2004;
328(7446):
991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
M. Dux, P. Santha, and G. Jancso
Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat
J. Physiol.,
November 1, 2003;
552(3):
859 - 867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Polydefkis, J. W. Griffin, and J. McArthur
New Insights Into Diabetic Polyneuropathy
JAMA,
September 10, 2003;
290(10):
1371 - 1376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P Anand
Capsaicin and menthol in the treatment of itch and pain: recently cloned receptors provide the key
Gut,
September 1, 2003;
52(9):
1233 - 1235.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Kissin, C. A. Bright, and E. L. Bradley Jr.
Selective and Long-Lasting Neural Blockade with Resiniferatoxin Prevents Inflammatory Pain Hypersensitivity
Anesth. Analg.,
May 1, 2002;
94(5):
1253 - 1258.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Cain, P. W. Wacnik, M. Turner, G. Wendelschafer-Crabb, W. R. Kennedy, G. L. Wilcox, and D. A. Simone
Functional Interactions between Tumor and Peripheral Nerve: Changes in Excitability and Morphology of Primary Afferent Fibers in a Murine Model of Cancer Pain
J. Neurosci.,
December 1, 2001;
21(23):
9367 - 9376.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Koike, K. Mori, K. Misu, N. Hattori, H. Ito, M. Hirayama, and G. Sobue
Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status
Neurology,
June 26, 2001;
56(12):
1727 - 1732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. T. Simons, J.-M. Dessirier, S. L. Jinks, and E. Carstens
An Animal Model to Assess Aversion to Intra-oral Capsaicin: Increased Threshold in Mice Lacking Substance P
Chem Senses,
June 1, 2001;
26(5):
491 - 497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-M. Dessirier, M. O'Mahony, M. Iodi-Carstens, and E. Carstens
Sensory Properties of Citric Acid: Psychophysical Evidence for Sensitization, Self-desensitization, Cross-desensitization and Cross-stimulus-induced Recovery Following Capsaicin
Chem Senses,
December 1, 2000;
25(6):
769 - 780.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-M. Dessirier, C. T. Simons, M. Sudo, S. Sudo, and E. Carstens
Sensitization, Desensitization and Stimulus-Induced Recovery of Trigeminal Neuronal Responses to Oral Capsaicin and Nicotine
J Neurophysiol,
October 1, 2000;
84(4):
1851 - 1862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Szallasi and P. M. Blumberg
Vanilloid (Capsaicin) Receptors and Mechanisms
Pharmacol. Rev.,
June 1, 1999;
51(2):
159 - 212.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Introduction
