rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels.

Autor:	Kandel MB; Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States., Zhuang GZ; Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States., Goins WF; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Marzulli M; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Zhang M; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Glorioso JC; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States., Kang Y; Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States., Levitt AE; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States., Kwok WM; Department of Anesthesiology and Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States., Levitt RC; Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States.; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States.; John T. MacDonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States.; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States., Sarantopoulos KD; Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, FL, United States.; Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular neuroscience [Front Mol Neurosci] 2024 May 09; Vol. 17, pp. 1398839. Date of Electronic Publication: 2024 May 09 (Print Publication: 2024).
DOI:	10.3389/fnmol.2024.1398839
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Kandel, Zhuang, Goins, Marzulli, Zhang, Glorioso, Kang, Levitt, Kwok, Levitt and Sarantopoulos.)
Databáze:	MEDLINE
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