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...

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Published in:Frontiers in molecular neuroscience 2024-05, Vol.17, p.1398839
Main Authors: Kandel, Munal B, Zhuang, Gerald Z, Goins, William F, Marzulli, Marco, Zhang, Mingdi, Glorioso, Joseph C, Kang, Yuan, Levitt, Alexandra E, Kwok, Wai-Meng, Levitt, Roy C, Sarantopoulos, Konstantinos D
Format: Article
Language:English
Subjects:
afterhyperpolarization
carbonic anhydrase-8
Kv7 voltage-gated potassium channels
Molecular Neuroscience
neuronal excitability
non-opioid analgesia from CA8 gene therapy
replication defective herpes-1 virus
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Summary: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 as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.
ISSN:1662-5099
1662-5099
DOI:10.3389/fnmol.2024.1398839