Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord
Abstract Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it ori...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-38605-9 |
| _version_ | 1827895317201158144 |
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| author | Olivia C. Davis Allen C. Dickie Marami B. Mustapa Kieran A. Boyle Tyler J. Browne Mark A. Gradwell Kelly M. Smith Erika Polgár Andrew M. Bell Éva Kókai Masahiko Watanabe Hendrik Wildner Hanns Ulrich Zeilhofer David D. Ginty Robert J. Callister Brett A. Graham Andrew J. Todd David I. Hughes |
| author_facet | Olivia C. Davis Allen C. Dickie Marami B. Mustapa Kieran A. Boyle Tyler J. Browne Mark A. Gradwell Kelly M. Smith Erika Polgár Andrew M. Bell Éva Kókai Masahiko Watanabe Hendrik Wildner Hanns Ulrich Zeilhofer David D. Ginty Robert J. Callister Brett A. Graham Andrew J. Todd David I. Hughes |
| author_sort | Olivia C. Davis |
| collection | DOAJ |
| description | Abstract Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch. |
| first_indexed | 2024-03-12T22:19:17Z |
| format | Article |
| id | doaj.art-e1e8b47c69cd415985186a348e491925 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-12T22:19:17Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e1e8b47c69cd415985186a348e4919252023-07-23T11:11:00ZengNature PortfolioScientific Reports2045-23222023-07-0113112210.1038/s41598-023-38605-9Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cordOlivia C. Davis0Allen C. Dickie1Marami B. Mustapa2Kieran A. Boyle3Tyler J. Browne4Mark A. Gradwell5Kelly M. Smith6Erika Polgár7Andrew M. Bell8Éva Kókai9Masahiko Watanabe10Hendrik Wildner11Hanns Ulrich Zeilhofer12David D. Ginty13Robert J. Callister14Brett A. Graham15Andrew J. Todd16David I. Hughes17School of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of NewcastleSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of NewcastleSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of NewcastleSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowDepartment of Anatomy, Hokkaido University School of MedicineInstitute of Pharmacology and Toxicology, University of ZurichInstitute of Pharmacology and Toxicology, University of ZurichDepartment of Neurobiology, Howard Hughes Medical Institute, Harvard Medical SchoolSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of NewcastleSchool of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of NewcastleSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowSchool of Psychology and Neuroscience, College of Medical, Veterinary and Life Sciences, University of GlasgowAbstract Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1–3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.https://doi.org/10.1038/s41598-023-38605-9 |
| spellingShingle | Olivia C. Davis Allen C. Dickie Marami B. Mustapa Kieran A. Boyle Tyler J. Browne Mark A. Gradwell Kelly M. Smith Erika Polgár Andrew M. Bell Éva Kókai Masahiko Watanabe Hendrik Wildner Hanns Ulrich Zeilhofer David D. Ginty Robert J. Callister Brett A. Graham Andrew J. Todd David I. Hughes Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord Scientific Reports |
| title | Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord |
| title_full | Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord |
| title_fullStr | Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord |
| title_full_unstemmed | Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord |
| title_short | Calretinin-expressing islet cells are a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord |
| title_sort | calretinin expressing islet cells are a source of pre and post synaptic inhibition of non peptidergic nociceptor input to the mouse spinal cord |
| url | https://doi.org/10.1038/s41598-023-38605-9 |
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