Peripheral signaling pathways contributing to non-histaminergic itch in humans
Abstract Background Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods He...
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| Language: | English |
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BMC
2023-12-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04698-z |
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| author | Andrea Fiebig Victoria Leibl David Oostendorf Saskia Lukaschek Jens Frömbgen Maral Masoudi Andreas E. Kremer Marion Strupf Peter Reeh Miriam Düll Barbara Namer |
| author_facet | Andrea Fiebig Victoria Leibl David Oostendorf Saskia Lukaschek Jens Frömbgen Maral Masoudi Andreas E. Kremer Marion Strupf Peter Reeh Miriam Düll Barbara Namer |
| author_sort | Andrea Fiebig |
| collection | DOAJ |
| description | Abstract Background Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. Results The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A “slow bursting discharge pattern” was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Conclusion Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade. |
| format | Article |
| id | doaj-art-c20ec1f4f53649f2acacc3d1eb12ec4d |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-c20ec1f4f53649f2acacc3d1eb12ec4d2025-01-19T12:37:04ZengBMCJournal of Translational Medicine1479-58762023-12-0121112410.1186/s12967-023-04698-zPeripheral signaling pathways contributing to non-histaminergic itch in humansAndrea Fiebig0Victoria Leibl1David Oostendorf2Saskia Lukaschek3Jens Frömbgen4Maral Masoudi5Andreas E. Kremer6Marion Strupf7Peter Reeh8Miriam Düll9Barbara Namer10Research Group Neuroscience, Interdisciplinary Centre for Clinical Research, Faculty of Medicine, RWTH Aachen UniversityInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergResearch Group Neuroscience, Interdisciplinary Centre for Clinical Research, Faculty of Medicine, RWTH Aachen UniversityResearch Group Neuroscience, Interdisciplinary Centre for Clinical Research, Faculty of Medicine, RWTH Aachen UniversityInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergDepartment of Gastroenterology and Hepatology, University Hospital Zürich, University of ZürichInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergInstitute of Physiology and Pathophysiology, University of Erlangen-NürnbergAbstract Background Chronic itch (chronic pruritus) is a major therapeutic challenge that remains poorly understood despite the extensive recent analysis of human pruriceptors. It is unclear how the peripheral nervous system differentiates the signaling of non-histaminergic itch and pain. Methods Here we used psychophysical analysis and microneurography (single nerve fiber recordings) in healthy human volunteers to explore the distinct signaling mechanisms of itch, using the pruritogens β-alanine, BAM 8-22 and cowhage extract. Results The mode of application (injection or focal application using inactivated cowhage spicules) influenced the itch/pain ratio in sensations induced by BAM 8-22 and cowhage but not β-alanine. We found that sensitizing pre-injections of prostaglandin E2 increased the pain component of BAM 8-22 but not the other pruritogens. A-fibers contributed only to itch induced by β-alanine. TRPV1 and TRPA1 were necessary for itch signaling induced by all three pruritogens. In single-fiber recordings, we found that BAM 8-22 and β-alanine injection activated nearly all CM-fibers (to different extents) but not CMi-fibers, whereas cowhage extract injection activated only 56% of CM-fibers but also 25% of CMi-fibers. A “slow bursting discharge pattern” was evoked in 25% of CM-fibers by β-alanine, in 35% by BAM 8-22, but in only 10% by cowhage extract. Conclusion Our results indicate that no labeled line exists for these pruritogens in humans. A combination of different mechanisms, specific for each pruritogen, leads to itching sensations rather than pain. Notably, non-receptor-based mechanisms such as spatial contrast or discharge pattern coding seem to be important processes. These findings will facilitate the discovery of therapeutic targets for chronic pruritus, which are unlikely to be treated effectively by single receptor blockade.https://doi.org/10.1186/s12967-023-04698-zMicroneurographyβ-AlanineBAM 8-22CowhageDischarge patternsSpatial contrast |
| spellingShingle | Andrea Fiebig Victoria Leibl David Oostendorf Saskia Lukaschek Jens Frömbgen Maral Masoudi Andreas E. Kremer Marion Strupf Peter Reeh Miriam Düll Barbara Namer Peripheral signaling pathways contributing to non-histaminergic itch in humans Journal of Translational Medicine Microneurography β-Alanine BAM 8-22 Cowhage Discharge patterns Spatial contrast |
| title | Peripheral signaling pathways contributing to non-histaminergic itch in humans |
| title_full | Peripheral signaling pathways contributing to non-histaminergic itch in humans |
| title_fullStr | Peripheral signaling pathways contributing to non-histaminergic itch in humans |
| title_full_unstemmed | Peripheral signaling pathways contributing to non-histaminergic itch in humans |
| title_short | Peripheral signaling pathways contributing to non-histaminergic itch in humans |
| title_sort | peripheral signaling pathways contributing to non histaminergic itch in humans |
| topic | Microneurography β-Alanine BAM 8-22 Cowhage Discharge patterns Spatial contrast |
| url | https://doi.org/10.1186/s12967-023-04698-z |
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