TY - JOUR
T1 - Sex-dependent reduction in mechanical allodynia in the sural-sparing nerve injury model in mice lacking merkel cells
AU - Jeon, Sang Min
AU - Chang, Dennis
AU - Geske, Aleksander
AU - Ginty, David D.
AU - Caterina, Michael J.
N1 - Funding Information:
This work was supported by National Institute of Dental and Craniofacial Research R01DE022750 to M.J.C. and D.D.G.; and the Neurosurgery Pain Research Institute at Johns Hopkins School of Medicine. D.D.G. is an Investigator of the Howard Hughes Medical Institute. We thank Ling Bai for helpful suggestions regarding TrkCtdtomato mice and for discussing unpublished findings; Daniel Bennett, Neil Bolduc, Luke Davis, John Robinson, Ian Reucroft, Julie Gokhale, and Gabriella Muwanga for assistance with genotyping and immunostaining experiments; Xiaobu Ye for assistance with statistical analysis; Jeremy Nathans for providing K14Cre mice; Lintao Qu, Zhiyong Chen, Yun Guan, and members of the M.J.C., Qu, Latremoliere, and Alexandre laboratories for helpful suggestions; and Yun Guan, Lintao Qu, and LaTasha Crawford for critically reading the manuscript. pS.-M.J. and D.C. contributed equally to this work. The authors declare no competing financial interests. Correspondence should be addressed to Michael J. Caterina at caterina@jhmi.edu. https://doi.org/10.1523/JNEUROSCI.1668-20.2021 Copyright © 2021 the authors
Funding Information:
This work was supported by National Institute of Dental and Craniofacial Research R01DE022750 to M.J.C. and D.D.G.; and the Neurosurgery Pain Research Institute at Johns Hopkins School of Medicine. D.D.G. is an Investigator of the Howard Hughes Medical Institute. We thank Ling Bai for helpful suggestions regarding TrkCtdtomato mice and for discussing unpublished findings; Daniel Bennett, Neil Bolduc, Luke Davis, John Robinson, Ian Reucroft, Julie Gokhale, and Gabriella Muwanga for assistance with genotyping and immunostaining experiments; Xiaobu Ye for assistance with statistical analysis; Jeremy Nathans for providing K14Cre mice; Lintao Qu, Zhiyong Chen, Yun Guan, and members of the M.J.C., Qu, Latremoliere, and Alexandre laboratories for helpful suggestions; and Yun Guan, Lintao Qu, and LaTasha Crawford for critically reading the manuscript.
Publisher Copyright:
© 2021 the authors
PY - 2021/6/30
Y1 - 2021/6/30
N2 - Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Ab slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Ab SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Using a genetic Merkel cell KO mouse model, we subsequently examined the importance of intact Merkel cell-Ab complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that, in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Ab afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex-dependent manner.
AB - Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Ab slowly adapting type I (SAI) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Ab SAI LTMR action potentials that are transmitted to the CNS, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Using a genetic Merkel cell KO mouse model, we subsequently examined the importance of intact Merkel cell-Ab complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that, in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Ab afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex-dependent manner.
KW - Allodynia
KW - Mechanoreceptor
KW - Merkel cell
KW - Neuropathic
KW - Pain
UR - http://www.scopus.com/inward/record.url?scp=85110975861&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110975861&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1668-20.2021
DO - 10.1523/JNEUROSCI.1668-20.2021
M3 - Article
C2 - 34031166
AN - SCOPUS:85110975861
SN - 0270-6474
VL - 41
SP - 5595
EP - 5619
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 26
ER -