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JOURNAL CLUB REPORT / JOURNAL CLUB REPORT
Nociception in the Skin: nociceptors are no longer the only actors*
La nociception cutanée par les cellules de Schwann
M. Cherpi · A. Delage · T. Paul · M. Renard
© Lavoisier SAS 2020
Résumé Les nocicepteurs à terminaisons libres ont long-
temps été considérés comme les seuls senseurs nociceptifs
dans la peau. Abdo et al. réévaluent le rôle des cellules de
Schwann (CSs), cellules gliales de soutien du système ner-
veux périphérique, dans la perception de la douleur chez la
souris. Après observation de la morphologie et de la locali-
sation des CSs et des fibres nociceptives dans la peau, les
chercheurs s’intéressent à leur relation fonctionnelle. Ils gén-
èrent des souris exprimant des canaux ioniques photosensi-
bles à la surface des CSs. Cela leur permet de les stimuler
spécifiquement (par optogénétique) tout en mesurant la
réponse électrique du nerf palmaire. En combinant l’excita-
tion ou l’inhibition des CSs avec des tests comportementaux,
ils mesurent la capacité des CSs à sensibiliser les souris à la
douleur thermique et mécanique. Enfin, des CSs sont isolées
pour évaluer leur capacité à répondre à un stimulus mécani-
que. Les observations par microscopie électronique et à fluo-
rescence révèlent que les nocicepteurs se trouvent entourés
par le cytoplasme des CSs dans le derme et accolés à ces
dernières dans l’épiderme. Ce complexe glioneural se rami-
fie au niveau subépidermal. Les chercheurs décident ainsi
d’appeler ces cellules gliales « cellules de Schwann nocicep-
tives » (CSn). Leur stimulation par optogénétique révèle une
augmentation de l’activité électrique des fibres nocicep-
tives, des comportements « de douleur » chez la souris, et
augmente la sensibilité des souris aux stimuli douloureux
mécaniques et thermiques. L’inhibition via optogénétique
des CSn diminue leur sensibilité aux stimuli mécaniques
mais ne modifie pas leur sensibilité aux stimuli thermiques.
L’enregistrement unicellulaire des CSn révèle qu’elles sont
hautement sensibles aux stimuli mécaniques. Les auteurs de
cette étude ont découvert un nouveau type de cellule de
Schwann nociceptive jouant un rôle important dans la gen-
èse et modulation de la nociception cutanée.
Mots clés Nociception · Douleur · Peau · Schwann ·
Nocicepteurs · Souris
Introduction
Nociceptors are specialized high-threshold sensory neurons
that allow living organisms to recognize and react to poten-
tially or currently damaging stimuli for the body. Unmyelin-
ated nociceptive fibers (also called C fibers) transduce and
conduct noxious stimuli from the periphery to the central
nervous system. An intensely unpleasant or painful sensa-
tion and a behavioral response are then triggered by the cen-
tral nervous system to preserve the body’s integrity [1].
Cutaneous nociceptors are sensitive to mechanical, ther-
mal, and chemical stimuli [2]. In the dermis, unmyelinated
nociceptors’axons are ensheathed by a specialized type of
glial cells called Remak Schwann cells in a Remak bundle of
axons [3].
So far, nociceptive fibers were thought to lose their
Remak Schwann cell ensheathment in the dermis, reaching
the epidermis as “free nerve endings”[4]. Therefore, few
studies have analyzed the involvement of non-myelinating
Schwann cells in nociception.
M. Cherpi
BSc in Molecular and Cellular Biology,
University of Nantes, France
A. Delage (*)
BSc in Physiology, University of Lyon, France
e-mail : adelage@etu.unistra.fr
T. Paul
BSc in Biochemistry, University of Rennes, France
M. Renard
BSc in Molecular and Cellular Biology,
University of Bretagne Sud, France
M. Cherpi · A. Delage · T. Paul · M. Renard
École universitaire de recherche interdisciplinaire sur la douleur
(EURIDOL Graduate School of Pain), Joint Master in
Neuroscience,
université de Strasbourg, faculté des sciences de la vie,
28, rue Goethe, F-67000 Strasbourg, France
* JC report written from Abdo et al., Science (2019) 365:695–99.
Douleur analg. (2019) 32:217-220
DOI 10.3166/dea-2020-0081
Abdo et al. [5] in their recent report has focused on the
morphology of non-myelinating Schwann cells at the der-
mis–epidermis border, and on their role in cutaneous noci-
ception in the mouse.
Morphological characterization of a new glial
cell type in the skin: the nociceptive Schwann
cell
The authors first studied the morphology and localization of
non-myelinating Schwann cells (SCs) in mice skin sections.
Genetically modified mice producing fluorescent proteins in
non-myelinating SCs and nociceptive fibers were used.
Immunohistochemistry, electron microscopy, and immuno-
electron microscopy studies were performed on mice hind
paw and back skin sections. Unmyelinated nociceptors and
glial cell markers were used to study the localization of these
cells at the dermis/epidermis border.
With these visualization techniques, the authors found
SCs ensheathing nociceptive fibers in the dermis. This
glio-neural complex resembles that of the Remak bundle of
axons [3]. At the epidermal boundary, Abdo et al. has also
observed SCs penetrating into the epidermis, abutting the
long-thought “free”nerve endings of nociceptive fibers [4],
in both hairy and glabrous skin (Fig. 1A). A layer of fibrillar
collagen was seen to be structurally oriented in the glio-
neural complex direction: it may act by supporting and insu-
lating the complex.
Thus, a morphologically distinct type of SCs has
been discovered by Abdo et al. As these SCs are in close
relationship with nociceptive fiber terminals in the dermis
and epidermis, the authors decided to name them nocicep-
tive Schwann cells.
Fig. 1 Specialized Schwann cells form a sensory organ in the skin A. Specific Schwann (nSCs) cells engulf free nerve endings and form
a mesh-like network. B. Genetically modified nSCs expressing rhodopsin (ChR2) or archaerhodopsin (ArchT) channels. Specific wave-
length modulates the cells activity. C. nSCs optogenetic stimulation elicits nociceptive fibers compound action potential (Palmar nerve
recording). D
1
. nSCs subthreshold optogenetic: stimulation results in potentiation of mechanical and thermal stimuli. D
2
. Control: mice
behavioral response to thermal or mechanical stimulation without optogenetics. D
3
. nSCs optogenetics: inhibition results in lower
response to mechanical stimuli
218 Douleur analg. (2019) 32:217-220
Stimulation of nociceptive Schwann cells
triggers an electrical response in nociceptive
fibers and nocifensive behaviors
As nociceptive Schwann cells (nSCs) seem to form a struc-
tural complex with nociceptors, Abdo et al. then studied the
role they could play in nociception. They decided to use an
optogenetic strategy to stimulate them in mice palmar skin of
the hind paw. Using a virus to infect the cells of this region,
they made nSCs produce a specific light-sensitive ion chan-
nel called Channelrhodopsin 2 (ChR2) at their membrane
surface. By this way, they were able to specifically activate
nSCs using blue light (Fig. 1B).
During optogenetic activation of nSCs, they measured the
extracellular electrical response of the palmar nerve. They
showed a dose-dependent increase in nociceptive fibers fir-
ing activity following nSCs stimulation with blue-light trains
(Fig. 1C). They also observed an increase in pain-like beha-
viors after specific stimulations of nSC: paw withdrawal,
licking, shaking, and guarding (Fig. 1D
1
).
Hence, this study provides direct evidence that nSCs
induce pain-like behaviors by stimulating the nerve endings,
which then convey the information to the central nervous
system to trigger behavioral responses.
Nociceptive Schwann cells contribute to skin
mechanosensitivity and potentiate skin
thermosensitivity
Abdo et al. went further and studied the specific sensory
modalities that nociceptive Schwann cells could modulate.
They measured if the stimulation of nSCs could elicit a sen-
sitization of mice to mechanical or thermal noxious stimuli.
For doing this process, they stimulated nSCs with blue light,
exposing mice to a stimulation not sufficient enough to
induce pain-like behaviors and simultaneously conducted a
stimuli on skin. They also created mice-expressing Archae-
rhodopsin receptors, called ArchT receptors, at the nSCs
membrane. These light-sensitive proteins, instead of activat-
ing Schwann cells, inhibit them when exposed to yellow
light. They looked at the effect of nSCs inhibition in mice
pain sensitivity.
Mice sensitivity to mechanical stimuli was increased
by nSCs activation in a dose-dependent manner: a longer
stimulation of nSCs resulted in an increased sensitivity
to mechanical stimulation (Fig. 1D
1
) compared to control
(Fig. 1D
2
). Conversely, the mechanical sensitivity was sig-
nificantly decreased when nSCs were inhibited (Fig. 1D
3
).
Researchers carried on the study by figuring out on what
extent these nSCs were affected by mechanical stimuli.
They measured their electrical response to mechanical sti-
muli performing electrophysiological recordings of single
nociceptive Schwann cells ex vivo. Abdo et al. showed
that a mechanical stimulation elicits a fast-electrical
response. From these experiments, they concluded that noci-
ceptive Schwann-cells are inherently mechanosensitive and
contribute to the sensation of mechanical stimuli in the skin.
Both heat and cold sensitivity was increased by the nSCs
blue light stimulation (Fig. 1D
1
). However, thermal sensitiv-
ity was not significantly reduced in mice expressing the
ArchT receptors compared to the control mice. This means
that, contrary to mechanical sensitivity, activation of nSCs
only potentiates thermal sensitivity. Indeed, the contribution
of nociceptive Schwann cells is not required for this modal-
ity: nociceptors could be sufficient for the detection of ther-
mal stimuli in mice skin.
Conclusion
Abdo et al. characterized a new type of glial cells present
into mice skin’s dermis and epidermis. In the dermis, these
non-myelinating Schwann cells resemble the previously
described Remak Schwann cells, as they ensheath nocicep-
tive fibers [3]. Contrary to Remak Schwann cells, they were
shown to penetrate the epidermis abutting the long-thought
“free”nerve endings of nociceptors [4]. Hence, they named
them nociceptive Schwann cells (nSCs). Their stimulation
generates an electrical response characteristic of the activity
of nociceptive fibers and nocifensive behaviors. A lighter
stimulation of nSCs increases mice sensitivity to mechanical
stimuli while their inhibition lowers mice mechanosensitiv-
ity. Abdo et al. also showed that nSCs are inherently
mechanosensitive and hypothesized that they could detect
noxious mechanical stimuli and stimulate nociceptive fibers
in return, directly contributing to mechanical nociception.
Activation of nSCs also sensitized mice to noxious thermal
stimuli, but their activity is not required for this modality.
Nociceptors could be sufficient for thermal nociception,
and nSCs activation could only potentiate thermal nocicep-
tion in mice skin. More research is needed to clarify the role
of nSCs in thermoception.
This article challenges the perspective we had of skin
nociception. Nociceptive Schwann cells have a singular
morphological and functional relationship with nerve fiber
terminals. These glial cells are able to activate nociceptors
and trigger pain-like behavior. They are inherently mechan-
osensitive and potentiate thermoception. The contribution of
nSCs suggests a broader response profile of nociceptors: the
sensory modality that they encode is not only dependent on
their molecular profile [6,7] but also on their glio-neural
complex. Further research is needed to characterize nocicep-
tive Schwann cells more precisely and maybe to evaluate
their involvement and therapeutic potential in some neuro-
pathologies such as chronic pain.
Douleur analg. (2019) 32:217-220 219
Acknowledgments This journal club report has been written
in the course of the Joint Master in Neuroscience training
program (teaching unit: fundamental in neuroscience) with
the support of the French National Research Agency (ANR)
through the Programme d’Investissement d’Avenir (contract
ANR-17-EURE-0022, EURIDOL graduate school of pain)
Conflicts of interests: The authors declare that they have no
conflict of interest
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