rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels
Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate recepto...
| मुख्य लेखकों: | , , , , , , , , , , |
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| स्वरूप: | लेख |
| भाषा: | English |
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Frontiers Media S.A.
2024-05-01
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| श्रृंखला: | Frontiers in Molecular Neuroscience |
| विषय: | |
| ऑनलाइन पहुंच: | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1398839/full |
| _version_ | 1827256446848335872 |
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| author | Munal B. Kandel Gerald Z. Zhuang William F. Goins Marco Marzulli Mingdi Zhang Joseph C. Glorioso Yuan Kang Alexandra E. Levitt Wai-Meng Kwok Roy C. Levitt Roy C. Levitt Roy C. Levitt Roy C. Levitt Konstantinos D. Sarantopoulos Konstantinos D. Sarantopoulos |
| author_facet | Munal B. Kandel Gerald Z. Zhuang William F. Goins Marco Marzulli Mingdi Zhang Joseph C. Glorioso Yuan Kang Alexandra E. Levitt Wai-Meng Kwok Roy C. Levitt Roy C. Levitt Roy C. Levitt Roy C. Levitt Konstantinos D. Sarantopoulos Konstantinos D. Sarantopoulos |
| author_sort | Munal B. Kandel |
| collection | DOAJ |
| description | Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically. |
| first_indexed | 2025-03-22T01:39:02Z |
| format | Article |
| id | doaj.art-3621c8f032f6429ba118a169c8a8463e |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2025-03-22T01:39:02Z |
| publishDate | 2024-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-3621c8f032f6429ba118a169c8a8463e2024-05-09T05:13:50ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992024-05-011710.3389/fnmol.2024.13988391398839rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channelsMunal B. Kandel0Gerald Z. Zhuang1William F. Goins2Marco Marzulli3Mingdi Zhang4Joseph C. Glorioso5Yuan Kang6Alexandra E. Levitt7Wai-Meng Kwok8Roy C. Levitt9Roy C. Levitt10Roy C. Levitt11Roy C. Levitt12Konstantinos D. Sarantopoulos13Konstantinos D. Sarantopoulos14Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United StatesDepartment of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United StatesBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Anesthesiology and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, United StatesDepartment of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United StatesBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United StatesJohn T. MacDonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United StatesJohn P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United StatesDepartment of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United StatesBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United StatesChronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.https://www.frontiersin.org/articles/10.3389/fnmol.2024.1398839/fullnon-opioid analgesia from CA8 gene therapycarbonic anhydrase-8Kv7 voltage-gated potassium channelsneuronal excitabilityafterhyperpolarizationreplication defective herpes-1 virus |
| spellingShingle | Munal B. Kandel Gerald Z. Zhuang William F. Goins Marco Marzulli Mingdi Zhang Joseph C. Glorioso Yuan Kang Alexandra E. Levitt Wai-Meng Kwok Roy C. Levitt Roy C. Levitt Roy C. Levitt Roy C. Levitt Konstantinos D. Sarantopoulos Konstantinos D. Sarantopoulos rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels Frontiers in Molecular Neuroscience non-opioid analgesia from CA8 gene therapy carbonic anhydrase-8 Kv7 voltage-gated potassium channels neuronal excitability afterhyperpolarization replication defective herpes-1 virus |
| title | rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels |
| title_full | rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels |
| title_fullStr | rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels |
| title_full_unstemmed | rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels |
| title_short | rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels |
| title_sort | rdhsv ca8 non opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating kv7 voltage gated potassium channels |
| topic | non-opioid analgesia from CA8 gene therapy carbonic anhydrase-8 Kv7 voltage-gated potassium channels neuronal excitability afterhyperpolarization replication defective herpes-1 virus |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2024.1398839/full |
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