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Fine morphological changes in the penicillate nerve endings of human hairy skin during prolonged itching.

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Fine Morphological Changes in the Penici late Nerve
Endings of Human Hairy Skin During
Prolonged Itching
NIKOLAJS CAUNA
Department of Anatomy and Cell Biology, Uni m i t u o f Pittsburoh
School of Medicine, Pittsburgh, Pennsylvania 15261- "
-
ABSTRACT
Morphological changes in cutaneous nerve endings were investigated electron microscopically in patients suffering from certain kinds of
urticaria with associated itching and in normal skin in which wheals and local
itching were induced either by application of nettle hairs or by intracutaneous
injections of a timothy pollen extract. Skin samples were obtained with a high
speed dermal punch without anesthesia from the wheal areas.
It was found that some subepidermal free nerve endings derived from nonmyelinated nerve fibers (penicillate endings) showed accumulations of extracytoplasmic glycogen which was localized in the distended spaces between the
axolemma, the Schwann cell membrane and the nerve basement membrane. In
some cases, the glycogen was found to be so abundant that it occupied most of
the cross sectional area of the ending. No morphological changes were observed
in the pappilary endings, in nerve endings of the hairs or in the autonomic
terminals. The conducting segments of all cutaneous nerve fibers showed normal
morphology .
The unusual morphological changes that occur i n some penicillate nerve endings during the wheal development indicate that these endings are involved in
the skin reaction and therefore they may be the specific end organs that are associated with itch. at least in urticaria.
The exact function or functions of each
form of sensory receptor organ encountered
in the skin is still a much debated issue.
Only mechanoreceptors have been identified with greater or lesser certainty on the
basis of electrophysiological experiments
or morphological characteristics of the
end organs. Warmth, cold and pain receptors are still escaping definite identification in most cases, and end organs associated with itch and tickle have so far
been subject of speculation (Sinclair, '67).
The present study is an attempt to identify
nerve endings that are associated with
itch.
MATERIAL A N D METHODS
Samples of the hairy skin from the deltoid region or the front of the thigh were
obtained from five patients suffering from
certain kinds of urticaria associated with
itching and from two individuals with
normal skin in which itching was induced
either by application of nettle hairs (UrtiANAT. REC., 188: 1-12.
caria dioica) or by intracutaneous injection
of ragweed pollen extract. The urticaria
cases included dermographism, pressure
urticaria, urticaria pigmentosa and diffuse cutaneous mastocytosis.
In the case of pressure urticaria, welts
and itching were induced by application of
a tourniquet for two to three minutes over
the arm or thigh. In the other urticaria
cases wheals were produced by stroking
the skin over the deltoid region or front
of the thigh with a smooth blunt stylus
exerting 400 g pressure (Ebken et al., '68).
Control samples were obtained from undisturbed skin areas of each urticaria patient
and from individuals with normal skin reaction.
All samples were obtained with a high
speed dermal punch, 3 mm in diameter,
without anestheiia. The tissue was immediately cut into strips oriented perpendicularly to the external surface of the
epidermis with the use of two stainlessReceived Aug. 19, '76. Accepted Nov. 17, '76.
1
2
NIKOLAJS CAUNA
epidermal endings. Figure 3 shows an axon
terminal entering the epidermis at the
far left. The distended space between the
axon and the related keratinocyte is occupied by the granular material (arrows).
Similar accumulations of granular material i n penicillate endings were observed
in urticaria pigmentosa (fig. 2) and in
experimentally induced itching (fig. 4).
Occasionally, the granular material was
found to be so abundant that it occupied
most of the cross sectional area of the ending. Figure 5 shows such a case in which
the Schwann sheath is compressed and
deformed. The basal lamina of the ending is probably distended but its continuity is not interrupted. However, some
of the granular material seems to have escaped through the basal lamina into the
interstitial space (on the left of the ending).
In most cases, the layer of the deposit
extended from the axolemma to the basal
OBSERVATIONS
lamina. On occasions the granular maThe study revealed that a certain propor- terial was restricted within a space betion (of the free nerve endings of the itch- tween the axolemma and the plasmaleming human skin showed morphological ma Schwann sheath (arrow in the center
changes. The endings in question were of fig. 4). Isolated areas of deposit bederived from non-myelinated nerve fibers tween the external aspect of the Schwann
in a itypical manner (fig. 7) and have been sheath and the basal lamina were never
described as “penicillate” by the author encountered although the granular ma(Cauina, ’73, ’76). The changes were char- terial tended to spread around the Schwann
acterized by accumulation of extracyto- cell flaps, occasionally giving a n impresplasmic granular material between the sion of a n isolated pocket (fig. 5: arrows).
axon terminals and the Schwann sheath, These findings may signify that the granuusuallly extending as far as the nerve lar material first appears next to the axolembasal lamina. Figure 1 shows a penicillate
1 Penicillate nerve ending cut transversenerve ending from a patient suffering ly.Fig.
The Schwann sheath (Sch) enfolds three axon
from dermographism and itch. The axolem- terminals (ax). Two areas bounded by the plasmamata of all three axon terminals are ex- lemma of the Schwann cell, axolemmata of the
posed to the granular material that has terminals a n d the nerve basal lamina (bl) contain
granular material (arrows) which consists of paraccumulated i n two spaces within the ticles
that vary in size a n d staining intensity. In
ending (arrows i n fig. 1). Such spaces do the area at left, the two layers of the mesaxon have
not normally exist in nerve terminals. The been separated by the granular material and the
space on the left has apparently been axon terminal has been deformed. In the other
the Schwann cell flap has been dislocated
created by separation of the two layers of area,
away from t h e basal lamina and the axon terminthe mesaxon and by some compression of als. Wheal induced by stroking the skin over the
the respective axon terminal. The space on deltoid area. Male, 50 years old suffering from
the right has been produced by dislocation dermographism a n d itch. X 50,000.
2 Penicillate nerve ending cut transverseand compression of the Schwann sheath ly Fig.
located i n a groove on the deep aspect of the
flap that separates the two axon terminals epidermis (Ep). The basal lamina of the nerve
and possibly by distension of the basal ending 031) encloses three axon terminals (ax)
a n d their Schwann sheath (Sch) along with some
lamina in that area.
granular material (arrows).
Soime intraepidermul axon terminals de- extracytoplasmic
Wheal induced by stroking the skin over a macula
rived from the penicillate endings also re- at t h e front of the thigh. Male, 11 months old sufvealed features similar to those of the sub- fering from urticaria pigmentosa. X 50,000.
steel razor blades mounted parallel and
0.3-0.5 mm apart. The slices were fixed in
1 % osmic acid solution buffered a t pH
7.4 with phosphate buffer for two hours a t
4°C. During the dehydration stages through
the alcohol series the strips were divided
into blocks which were embedded in a n
Epon-Araldite mixture. Serial sections were
stained on grids with uranyl acetate and
lead citrate solutions.
For demonstration of glycogen electron
microscopically, osmium fixed sections were
mounted on uncoated gold grids and
stained with periodic acid-thiosemicarbazide-silver proteinate solutions (Anderson, ’72). Control sections were oxidized
with 5 % periodic acid solution for 20 minutes and treated with 0.1 % a-amylase solution in 0.1 M phosphate buffer at pH
7.0 for three hours and then stained for
glycogen.
CHANGES IN NERVE ENDINGS DURING ITCHING
3
4
NIKOLAJS CAUNA
Fig. 3 Intraepidermal axon terminal (ax) cut longitudinally enfolded by a basal keratinocyte (Ker). Some granular material (arrows) is situated between the axolemma of the ending
and the cell membrane of the keratinocyte. The basal lamina (bl) of the epidermis is continuous with that of the axon at the far left. Welt induced by application of a tourniquet,
front of the thigh. Female, 21 years old suffering from pressure urticaria. X 50,000.
ma and then progressively spreads towards
the basal lamina.
Not every axon terminal within a n ending wits similarly involved. Figure 2 shows
an ending with three axon terminals. The
one that is nearer to the top of the photographis completelyenfolded by the Schwann
sheath and has no relationship to the granular material. Similarly, two axon terminals
in figure 4 appear not to be involved. Furthermore, only a certain proportion of the
popula.tion of penicillate endings was subject to morphological changes in itching
skin. It was esimated that one in every
five to six endings showed the presence of
granular material. On occasions it was
possible to visualize all endings derived
from a single penicillus. This happened
frequently in blocks in which the plane of
sections was oriented perpendicularly to
the longitudinal distribution of the endings.
Sections cut through the penicillus immediately distal to the terminal Schwann
cell made it possible to examine all its
components before they had splayed out
over their distribution areas (fig. 7 cf. with
CHANGES IN NERVE ENDINGS DURING ITCHING
5
Fig. 4 Penicillate nerve ending cut transversely showing four axon terminals, (ax), their
Schwann sheath (Sch) and extracytoplasmic granular material (arrows). Itching induced by
touching normal skin of the deltoid area with nettle hairs. Male, 24 years old. x 50,000.
fig. 6). In such cases it was evident that
only one or two endings of the whole penicillus were involved (arrow in fig. 7).
The changes described in the penicillate endings were not observed in the
preterminal nerve fibers from which the
endings were derived. Nor did the changes
occur in the papillary endings which were
derived from myelinated nerve fibers, or
in the nerve terminals associated with the
shafts of the fine hairs. The autonomic
nerve terminals related to blood vessels,
arrectores pilorum muscles or sweat glands
also showed normal morphology. Nochanges
in any nerve endings were observed in the
20 urticaria cases in which itching was
absent or minimal.
Morphologically, the granular material
resembled glycogen particles. When stained
histochemically,
the
extracytoplasmic
granular material encountered in the
penicillate nerve endings gave a strong
positive reaction for glycogen. Figure 8 (arrows) shows the heavily stained particles
in the intercellular space. These can be
compared with a cluster of glycogen particles that are present in the axoplasm
of one of the terminals (ax: right bottom
in fig. 8). Following treatment of the
osmium fixed sections with a-amylase, the
glycogen stain gave a negative reaction in
the tissues of the skin in general and
also in the spaces previously occupied by
the granular material (arrows in fig. 9).
Although extracytoplasmic location of
glycogen particles in nerve endings is an
6
NIKOLAJS C A U N A
Fig. 5 Penicillate nerve ending cut transversely situated next t o the deep aspect of the
epidermis (Ep). The ending contains two axon terminals (ax) and a greatly deformed
Schwann sheath (Sch). Most of the cross sectional area of the ending i s filled with granular
material. The basal lamina of the nerve ending (bl) is not disrupted. Wheal induced by
stroking the skin of the deltoid region. Male, 9 years old suffering from d i f h s e cutaneous
mastocytosis. X 50,000.
CHANGES IN NERVE ENDINGS DURING ITCHING
7
Fig, 6 Diagram showing the manner of origin of the penicillate nerve endings from a
sensory non-myelinated nerve fiber. The perikaryon of the terminal Schwann cell (T Sch)
marks the origin of the penicillus, and it provides each ending and its branches with cytoplasmic sheaths throughout their subepidermal course. Arrows indicate the approximate
plane of figure 7.
intense itching, only some endings derived from a penicillus underwent changes
while the majority of the same kind and
all other kinds of nerve endings, both sensory and autonomic, as well as the conducting segments of nerve fibers remained unDISCUSSION
affected. This may be an indication that
The fine reversible changes that occur those penicillate nerve endings that undergo
in a sensory end organ during its stimula- changes are associated with itch. It does not
tion are not accessible to morphological follow that itch is the only function of
observations. Therefore, the transient ac- these endings, nor that other nerve endings
cumulation of glycogen in certain penicillate could not be associated with itch under difnerve endings during prolonged itching ferent conditions.
While the morphological changes that
is an unexpected finding, and to evaluate
its significance requires careful considera- occur in certain penicillate nerve endings
serve as a marker by which their association.
It is fairly evident that the phenomenon tion with itch can be identified, the cytorepresents a byproduct of a rather com- chemical process itself is obscure, and the
plex skin reaction of which itching is a source of the glycogen is not evident. Scatpart. In all cases represented in this study tered particles and occasional larger clusters
itching was accompanied by wheal or welt of glycogen are normally present in the
formation (Cauna and Levine, '70). How- axoplasm as well as in the cytoplasm of
ever, wheal induced without itch did not the Schwann sheath of the endings. Thereproduce changes in nerve endings. Fur- fore, i t might be argued that the extracythermore, when wheal was accompanied by toplasmic glycogen had escaped from its
unusual finding, extracytoplasmic glycogen
occurs naturally in certain areas of the
epidermis. In particular, the epithelial root
sheath of the fine hairs is rich in intraand extracytoplasmic glycogen (fig. 10).
8
NIKOLAJS CAUNA
Fig. 7 Penicillus cut transversely immediately distal to the terminal Schwann cell (arrows i n fig. 6). It consists of seven nerve endings of various sizes. Only one ending reveals
extracytoplasmic granular material (arrow). The other endings show normal morphology.
Wheal induced by stroking the skin over a macula, front of the thigh. Male, 21 months old
suffering from urticaria pigmentosa. X 40,000.
CHANGES IN NERVE ENDINGS DURING ITCHING
9
Fig. 8 Penicillate nerve ending stained for glycogen using the Periodic acid-ThiosemicarbazideSilver proteinate method. The Schwann sheath (Sch) enfolds three axon terminals (ax) one of which
(right bottom) contains glycogen particles i n its axoplasm. Extracytoplasmic glycogen is present i n
three areas (arrows). Wheal induced by stroking the skin over the deltoid region. Male, 9 years old suffering from diffuse cutaneous mastocytosis. X 50,000.
Fig. 9 Penicillate nerve ending treated with a-Amylase (after oxidizing the osmium fixed section
with Periodic acid) a n d stained for glycogen (as i n fig. 8). The Schwann sheath (Sch) enfolds three axon
terminals (ax). Two empty extracytoplasmic areas (between arrows) bounded by the plasmalemma of
the Schwann sheath, axolemmata of the terminals a n d the nerve basal lamina (bl) mark the position
previously occupied by glycogen. Wheal induced by stroking the skin over a macula, front of the thigh.
Male, 11 months old suffering from urticaria pigmentosa. X 50.000.
10
NIKOLAJS CAUNA
Fig. 10 Part of the epithelial root sheath of a small hair follicle cut transversely showing
two keratinocytes (Ker) connected by a dermosome (d). The space between the two cells
which is separated from the surrounding corium by the basal lamina (bl) contains accumulatiasn of glycogen particles (unlabelled arrows). Skin from the deltoid region. Male, 49 years
old. X 50,000
naturallocation. However, the small amount
of int racellular glycogen is insufficient to
account for the large extracytoplasmic accumul.ations.
From a neurophysiological point of view
the present findings are of particular interest. This is the first indication that itch
may be linked with a particular end organ.
Since each penicillus gives origin to a
numbler of endings and only some of these
undergo changes during itching the findings also tend to support a n earlier suggestio:n that penicillate endings are multimodal receptor organs (Cauna, '73, '76).
The set ofsensory non-myelinated axons that
gives origin to the penicillate endings
(fig. 6) originates from several nerve cell
bodies in the sensory ganglion, each of
which may be associated with a different
modality of sensation. Therefore the penicillus seems to represent a package of receptor
organs subserving several sensory modalities
rather than a single sensation. This suggestioin appears to be confirmed by recent
electrophysiological studies of sensory nonmyelinated nerve fibers (Pearl et al., '76).
ACKNOWLEDGMENTS
The author wishes to thank Macy I.
Levine, M.D., Department of Medicine,
University of Pittsburgh, for the supply of
biopsy material along with the clinical
data, and to Ms. Gloria DeLuiso for her
technical assistance and the aid with the
photographic work.
This study was supported by U. S. Public
Health Service Grant NB 04147.
LITERATURE CITED
Anderson, W. A. 1972 Methods for electron
microscopic localization of glycogen. In: Techniques of Biochemical and Biophysical Morphology. Vol. 1. D. Glick and R. M. Rosenbaum,
eds. Wiley-Interscience, a division of John
Wiley & Sons, Inc., New York, pp. 1-23.
Cauna, N. 1973 The free penicillate nerve endings of the h u m a n hairy skin. J. Anat., 1 1 5 :
277-288.
Cauna, N. 1976 Morphological basis of sensation in hairy skin. Progress i n Brain Res., 43:
3545.
CHANGES IN NERVE ENDINGS DURING ITCHING
Cauna, N., and M . I. Levine 1970 The fine
morphology of the human skin in dermographism. J. Allergy, 45: 266-285.
Ebken, R. K., F. A. Bauschard and M. I. Levine
1968 Dermographism: Its definition, demonstration and prevalence. J. Allergy, 41: 338343.
11
Pearl, E. R., T. Kumazawa, B. Lynn and P.
Kenins 1976 Sensitization of high threshold
receptors with unmyelinated ( C ) afferent fibers.
Progress i n Brain Res., 43: 263-277.
Sinclair, D. 1967 Cutaneous sensation. Oxford
University Press, London, pp. 104, 110-113,
142-144.
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