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Intraepidermal nerve fibres are not the exclusive tranducers of nociception
Accepted Manuscript Title: Intraepidermal nerve fibres are not the exclusive tranducers of nociception Authors: Matthieu Talagas, Nicolas Lebonvallet, Laurent Misery PII: DOI: Reference:
S0165-0270(18)30143-2 https://doi.org/10.1016/j.jneumeth.2018.05.013 NSM 8009
To appear in:
Journal of Neuroscience Methods
Received date: Revised date: Accepted date:
15-3-2018 18-5-2018 18-5-2018
Please cite this article as: Talagas M, Lebonvallet N, Misery L, Intraepidermal nerve fibres are not the exclusive tranducers of nociception, Journal of Neuroscience Methods (2018), https://doi.org/10.1016/j.jneumeth.2018.05.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Intraepidermal nerve fibres are not the exclusive tranducers of nociception Matthieu Talagas1,2, Nicolas Lebonvallet1, Laurent Misery1,3 1
Laboratory of Interactions Keratinocytes N (EA4685), University of Western Brittany, Brest,
France Department of Pathology, University Hospital of Brest, 29609 Brest cedex, France
3
Department of Dermatology, University Hospital of Brest, 29609 Brest cedex, France
IP T
2
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Highlights Bullet point 1: Intraepidermal nerve fibres are not the exclusive tranducers of nociception Bullet point 2: Keratinocytes can directly initiate nociceptive responses Bullet point 3: Intraepidermal nerve fibres and keratinocytes may act as a tworeceptor-site model
M
A
N
U
Abstract: This article is a commentary on a article entitled Micropatterned surface electrode for massive selective stimulation of intraepidermal nociceptive fibres and published last January in your journal (M. Leandri et al. 2018 Jan 1;293:17-26). The goal of this article is to provide an insight of the most recent datas on cutaneous nociception. Indeed recent studies have demonstrated that keratinocytes closely participate in sensory transduction, and therefore, intraepidermal free nerve endings are not exclusive transducers of pain. Therefore, the results presented by M. Leandri et al. should be interpreted in the light of this information.
TE D
Keywords: Free nerve endings; Keratinocytes; Pain; Electrodes; Stimulation In their article, Leandri et al. (Leandri et al., 2018) describe an interesting new micropatterned surface electrode device that allows the selective stimulation of cutaneous
EP
nociceptive afferents. The authors describe these afferents as A and C fibres that end in the epidermis to form sensory end organs called intraepidermal free nerve endings (FNE). FNE
CC
pass between the keratinocytes, the most abundant epidermal cells, and are present in the basal, spinous and granular layers of the epidermis and sometimes in the stratum corneum
A
(Kennedy et al., 1993). By using electric stimuli, the authors only activate FNE, while A fibres, associated to innocuous sensory end organs remain at rest. In a relevant way, the authors thereby highlight the specificity and the safety of their device. However, these results should be interpreted in light of the most recent datas on nociception. Indeed, the intraepidermal free nerve endings are classically described as the exclusive transducers of pain, temperature and itch. Yet, two recent studies, using
1
transgenic mouse models that enable selective keratinocyte activation without directly exciting associated A and C nerve fibres, now provide evidence that keratinocytes closely participate in sensory transduction, especially in noxious touch. In the first one, using TRPV1 (Transient Receptor Potential Vallinoid 1) global knockout mice, the selective expression of TRPV1 in epidermal keratinocytes was induced by the keratin 5 promoter. TRPV1 is one of the main transducer of painful heat, expressed by sensory neurons but also by keratinocytes
IP T
(Denda et al., 2001; Bodo et al., 2004, Ständer et al., 2004). It is activated by capsaicin, the active substance of spicy peppers (Caterina et al., 2001), resulting in calcium influx (Inoue et
al., 2002). Applications of capsaicin to the skin induced the expression of c-fos, a neuronal
SC R
activation marker, in the ipsilateral dorsal horn of the spinal cord, resulting in nocifensive behaviours. Considering TRPV1 is solely expressed in keratinocytes, these results demonstrate that selective acute chemical activation of keratinocytes is sufficient to activate
U
nociceptive sensory neurons (Pang et al., 2015). In the same way, in an optogenetic mouse
N
model expressing channelrhodopsin (ChR2) in epidermal keratinocytes, Baumbauer et al. showed that light stimulation is sufficient to activate cutaneous FNEs and generate the
A
withdrawal reflex (Baumbauer et al., 2015). Conversely, optogenetically silencing
M
keratinocytes through the expression of halorhodopsin reduces action potentials in these nerve fibres. Together, these experiments demonstrate that keratinocytes can directly
TE D
initiate nociceptive responses and modulate them, i.e. collaborate with nociceptive Aδ- and C-fibres.
By using electric stimuli to induce response of A and C fibres, Leandri et al. probably
EP
exclude the keratinocyte transduction and might underestimate the nociceptive response. But caloric or chemical stimulations, e.g.capsaicin, doesn’t represent a suitable alternative. It
CC
may represent a way of modulating nociception during selective electrical stimulation. The exact mechanism through which keratinocytes and sensory neurons communicate remains unknown. Several ultrastructural and functional arguments support the existence of
A
synaptic contacts (Talagas
et al., 2018). Keratinocytes could also communicate with
sensory neurons in a manner similar to the synapses of Merkel cells, other epidermal epithelial cells, with A fibres. They may also act as a two-receptor-site model, each conveying specific aspects of temperature, pain and itch, like Merkel cells and Aβ- nerve fibres do in the Merkel complexes (Ikeda et al., 2014).
2
References
-
Caterina, M.J., and Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517.
-
Baumbauer, K.M., DeBerry, J.J., Adelman, P.C., Miller, R.H., Hachisuka, J., Lee, K.H., Ross, S.E., Koerber, H.R., Davis, B.M., and Albers, K.M. (2015). Keratinocytes can modulate and
-
IP T
directly initiate nociceptive responses. eLife 4. Bodo, E., Kovacs, I., Telek, A., Varga, A., Paus, R., Kovacs, L., Biro, T. (2004). Vanilloid receptor-1 (VR1) is widely expressed on various epithelial and mesenchymal cell types of
-
SC R
human skin. J. Invest. Dermatol. 123, 410-413.
Denda, M., Fuziwara, S., Inoue, K., Denda, S., Akamatsu, H., Tomitaka, A., Matsunaga, K. (2001). Immunoreactivity of VR1 on epidermal keratinocyte of human skin. Biochem.
Ikeda, R., Cha, M., Ling, J., Jia, Z., Coyle, D., Gu, J.G. (2014). Merkel cells transduce and
N
-
U
Biophys. Res. Commun. 285(5), 1250-1252.
encode tactile stimuli to drive Aβ-afferent impulses. Cell 157, 664–675. Inoue, K., Koisumi, S., Fuziwara, S., Denda, S., Inoue, K., Denda, M. (2002). Functional
A
-
M
vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem. Biophys. Res. Commun. 291(1), 124-129.
Kennedy, W.R., and Wendelschafer-Crabb, G. (1993). The innervation of human
TE D
-
epidermis. J. Neurol. Sci. 115, 184–190. -
Leandri, M., Marinelli, L., Siri, A., Pellegrino, L. (2018). Micropatterned surface electrode
EP
for massive selective stimulation of intraepidermal nociceptive fibres. J. Neurosci. Methods. 293, 17-26.
Pang, Z., Sakamoto, T., Tiwari, V., Kim, Y.-S., Yang, F., Dong, X., Güler, A.D., Guan, Y., and
CC
-
Caterina, M.J. (2015). Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain 156, 656–665. Ständer, S., Moormann, C., Schumacher, M., Buddenkotte, J., Artuc, M., Shpacovitch, V.,
A
-
Brzoska, T., Lippert, U., Henz, BM., Luger, T.A., Metze, D., Steinhoff, M. (2004). Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp. Dermatol. 13(3), 129-139.
-
Talagas, M., Lebonvallet, N., Leschiera, R., Marcorelles, P., Misery, L. (2018). What about physicial contacts between epidermal keratinocytes and sensory neurons? Exp. 3
A
CC
EP
TE D
M
A
N
U
SC R
IP T
Dermatol. 27(1), 9-13.
4
S0165-0270(18)30143-2 https://doi.org/10.1016/j.jneumeth.2018.05.013 NSM 8009
To appear in:
Journal of Neuroscience Methods
Received date: Revised date: Accepted date:
15-3-2018 18-5-2018 18-5-2018
Please cite this article as: Talagas M, Lebonvallet N, Misery L, Intraepidermal nerve fibres are not the exclusive tranducers of nociception, Journal of Neuroscience Methods (2018), https://doi.org/10.1016/j.jneumeth.2018.05.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Intraepidermal nerve fibres are not the exclusive tranducers of nociception Matthieu Talagas1,2, Nicolas Lebonvallet1, Laurent Misery1,3 1
Laboratory of Interactions Keratinocytes N (EA4685), University of Western Brittany, Brest,
France Department of Pathology, University Hospital of Brest, 29609 Brest cedex, France
3
Department of Dermatology, University Hospital of Brest, 29609 Brest cedex, France
IP T
2
SC R
Highlights Bullet point 1: Intraepidermal nerve fibres are not the exclusive tranducers of nociception Bullet point 2: Keratinocytes can directly initiate nociceptive responses Bullet point 3: Intraepidermal nerve fibres and keratinocytes may act as a tworeceptor-site model
M
A
N
U
Abstract: This article is a commentary on a article entitled Micropatterned surface electrode for massive selective stimulation of intraepidermal nociceptive fibres and published last January in your journal (M. Leandri et al. 2018 Jan 1;293:17-26). The goal of this article is to provide an insight of the most recent datas on cutaneous nociception. Indeed recent studies have demonstrated that keratinocytes closely participate in sensory transduction, and therefore, intraepidermal free nerve endings are not exclusive transducers of pain. Therefore, the results presented by M. Leandri et al. should be interpreted in the light of this information.
TE D
Keywords: Free nerve endings; Keratinocytes; Pain; Electrodes; Stimulation In their article, Leandri et al. (Leandri et al., 2018) describe an interesting new micropatterned surface electrode device that allows the selective stimulation of cutaneous
EP
nociceptive afferents. The authors describe these afferents as A and C fibres that end in the epidermis to form sensory end organs called intraepidermal free nerve endings (FNE). FNE
CC
pass between the keratinocytes, the most abundant epidermal cells, and are present in the basal, spinous and granular layers of the epidermis and sometimes in the stratum corneum
A
(Kennedy et al., 1993). By using electric stimuli, the authors only activate FNE, while A fibres, associated to innocuous sensory end organs remain at rest. In a relevant way, the authors thereby highlight the specificity and the safety of their device. However, these results should be interpreted in light of the most recent datas on nociception. Indeed, the intraepidermal free nerve endings are classically described as the exclusive transducers of pain, temperature and itch. Yet, two recent studies, using
1
transgenic mouse models that enable selective keratinocyte activation without directly exciting associated A and C nerve fibres, now provide evidence that keratinocytes closely participate in sensory transduction, especially in noxious touch. In the first one, using TRPV1 (Transient Receptor Potential Vallinoid 1) global knockout mice, the selective expression of TRPV1 in epidermal keratinocytes was induced by the keratin 5 promoter. TRPV1 is one of the main transducer of painful heat, expressed by sensory neurons but also by keratinocytes
IP T
(Denda et al., 2001; Bodo et al., 2004, Ständer et al., 2004). It is activated by capsaicin, the active substance of spicy peppers (Caterina et al., 2001), resulting in calcium influx (Inoue et
al., 2002). Applications of capsaicin to the skin induced the expression of c-fos, a neuronal
SC R
activation marker, in the ipsilateral dorsal horn of the spinal cord, resulting in nocifensive behaviours. Considering TRPV1 is solely expressed in keratinocytes, these results demonstrate that selective acute chemical activation of keratinocytes is sufficient to activate
U
nociceptive sensory neurons (Pang et al., 2015). In the same way, in an optogenetic mouse
N
model expressing channelrhodopsin (ChR2) in epidermal keratinocytes, Baumbauer et al. showed that light stimulation is sufficient to activate cutaneous FNEs and generate the
A
withdrawal reflex (Baumbauer et al., 2015). Conversely, optogenetically silencing
M
keratinocytes through the expression of halorhodopsin reduces action potentials in these nerve fibres. Together, these experiments demonstrate that keratinocytes can directly
TE D
initiate nociceptive responses and modulate them, i.e. collaborate with nociceptive Aδ- and C-fibres.
By using electric stimuli to induce response of A and C fibres, Leandri et al. probably
EP
exclude the keratinocyte transduction and might underestimate the nociceptive response. But caloric or chemical stimulations, e.g.capsaicin, doesn’t represent a suitable alternative. It
CC
may represent a way of modulating nociception during selective electrical stimulation. The exact mechanism through which keratinocytes and sensory neurons communicate remains unknown. Several ultrastructural and functional arguments support the existence of
A
synaptic contacts (Talagas
et al., 2018). Keratinocytes could also communicate with
sensory neurons in a manner similar to the synapses of Merkel cells, other epidermal epithelial cells, with A fibres. They may also act as a two-receptor-site model, each conveying specific aspects of temperature, pain and itch, like Merkel cells and Aβ- nerve fibres do in the Merkel complexes (Ikeda et al., 2014).
2
References
-
Caterina, M.J., and Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517.
-
Baumbauer, K.M., DeBerry, J.J., Adelman, P.C., Miller, R.H., Hachisuka, J., Lee, K.H., Ross, S.E., Koerber, H.R., Davis, B.M., and Albers, K.M. (2015). Keratinocytes can modulate and
-
IP T
directly initiate nociceptive responses. eLife 4. Bodo, E., Kovacs, I., Telek, A., Varga, A., Paus, R., Kovacs, L., Biro, T. (2004). Vanilloid receptor-1 (VR1) is widely expressed on various epithelial and mesenchymal cell types of
-
SC R
human skin. J. Invest. Dermatol. 123, 410-413.
Denda, M., Fuziwara, S., Inoue, K., Denda, S., Akamatsu, H., Tomitaka, A., Matsunaga, K. (2001). Immunoreactivity of VR1 on epidermal keratinocyte of human skin. Biochem.
Ikeda, R., Cha, M., Ling, J., Jia, Z., Coyle, D., Gu, J.G. (2014). Merkel cells transduce and
N
-
U
Biophys. Res. Commun. 285(5), 1250-1252.
encode tactile stimuli to drive Aβ-afferent impulses. Cell 157, 664–675. Inoue, K., Koisumi, S., Fuziwara, S., Denda, S., Inoue, K., Denda, M. (2002). Functional
A
-
M
vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem. Biophys. Res. Commun. 291(1), 124-129.
Kennedy, W.R., and Wendelschafer-Crabb, G. (1993). The innervation of human
TE D
-
epidermis. J. Neurol. Sci. 115, 184–190. -
Leandri, M., Marinelli, L., Siri, A., Pellegrino, L. (2018). Micropatterned surface electrode
EP
for massive selective stimulation of intraepidermal nociceptive fibres. J. Neurosci. Methods. 293, 17-26.
Pang, Z., Sakamoto, T., Tiwari, V., Kim, Y.-S., Yang, F., Dong, X., Güler, A.D., Guan, Y., and
CC
-
Caterina, M.J. (2015). Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain 156, 656–665. Ständer, S., Moormann, C., Schumacher, M., Buddenkotte, J., Artuc, M., Shpacovitch, V.,
A
-
Brzoska, T., Lippert, U., Henz, BM., Luger, T.A., Metze, D., Steinhoff, M. (2004). Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp. Dermatol. 13(3), 129-139.
-
Talagas, M., Lebonvallet, N., Leschiera, R., Marcorelles, P., Misery, L. (2018). What about physicial contacts between epidermal keratinocytes and sensory neurons? Exp. 3
A
CC
EP
TE D
M
A
N
U
SC R
IP T
Dermatol. 27(1), 9-13.
4