Article ; Online: Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance.
2023 Volume 165, Issue 4, Page(s) 893–907
Abstract: Abstract: Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and ... ...
| Abstract | Abstract: Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions. |
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| MeSH term(s) | Rats ; Mice ; Animals ; Humans ; Nociceptors ; Rats, Sprague-Dawley ; Cell Body ; Pain/metabolism ; Action Potentials/physiology ; Ion Channels/metabolism ; Ganglia, Spinal/metabolism ; TRPM Cation Channels/metabolism |
| Chemical Substances | Ion Channels ; TRPM4 protein, mouse ; TRPM Cation Channels ; TRPM4 protein, rat |
| Language | English |
| Publishing date | 2023-10-20 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 193153-2 |
| ISSN | 1872-6623 ; 0304-3959 |
| ISSN (online) | 1872-6623 |
| ISSN | 0304-3959 |
| DOI | 10.1097/j.pain.0000000000003091 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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