Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol
Abstract Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion channels. We assessed CBN effects on voltag...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-05781-x |
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| author | Mohammad-Reza Ghovanloo Philip R. Effraim Sidharth Tyagi Peng Zhao Sulayman D. Dib-Hajj Stephen G. Waxman |
| author_facet | Mohammad-Reza Ghovanloo Philip R. Effraim Sidharth Tyagi Peng Zhao Sulayman D. Dib-Hajj Stephen G. Waxman |
| author_sort | Mohammad-Reza Ghovanloo |
| collection | DOAJ |
| description | Abstract Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion channels. We assessed CBN effects on voltage-dependent sodium (Nav) channels expressed heterologously and in native dorsal root ganglion (DRG) neurons. Our results indicate that CBN is a functionally-selective, but structurally-non-selective Nav current inhibitor. CBN’s main effect is on slow inactivation. CBN slows recovery from slow-inactivated states, and hyperpolarizes steady-state inactivation, as channels enter deeper and slower inactivated states. Multielectrode array recordings indicate that CBN attenuates DRG neuron excitability. Voltage- and current-clamp analysis of freshly isolated DRG neurons via our automated patch-clamp platform confirmed these findings. The inhibitory effects of CBN on Nav currents and on DRG neuron excitability add a new dimension to its actions and suggest that this cannabinoid may be useful for neuropathic pain. |
| format | Article |
| id | doaj-art-60407da0abdb4b1b9e5d0e2499727ac9 |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-60407da0abdb4b1b9e5d0e2499727ac92025-08-20T02:07:45ZengNature PortfolioCommunications Biology2399-36422024-01-017111710.1038/s42003-024-05781-xFunctionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinolMohammad-Reza Ghovanloo0Philip R. Effraim1Sidharth Tyagi2Peng Zhao3Sulayman D. Dib-Hajj4Stephen G. Waxman5Department of Neurology, Yale University School of MedicineCenter for Neuroscience & Regeneration Research, Yale UniversityDepartment of Neurology, Yale University School of MedicineDepartment of Neurology, Yale University School of MedicineDepartment of Neurology, Yale University School of MedicineDepartment of Neurology, Yale University School of MedicineAbstract Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion channels. We assessed CBN effects on voltage-dependent sodium (Nav) channels expressed heterologously and in native dorsal root ganglion (DRG) neurons. Our results indicate that CBN is a functionally-selective, but structurally-non-selective Nav current inhibitor. CBN’s main effect is on slow inactivation. CBN slows recovery from slow-inactivated states, and hyperpolarizes steady-state inactivation, as channels enter deeper and slower inactivated states. Multielectrode array recordings indicate that CBN attenuates DRG neuron excitability. Voltage- and current-clamp analysis of freshly isolated DRG neurons via our automated patch-clamp platform confirmed these findings. The inhibitory effects of CBN on Nav currents and on DRG neuron excitability add a new dimension to its actions and suggest that this cannabinoid may be useful for neuropathic pain.https://doi.org/10.1038/s42003-024-05781-x |
| spellingShingle | Mohammad-Reza Ghovanloo Philip R. Effraim Sidharth Tyagi Peng Zhao Sulayman D. Dib-Hajj Stephen G. Waxman Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol Communications Biology |
| title | Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| title_full | Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| title_fullStr | Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| title_full_unstemmed | Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| title_short | Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| title_sort | functionally selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol |
| url | https://doi.org/10.1038/s42003-024-05781-x |
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