ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Chrysin, a Natural Kv7 Potassium Channel Opener, Alleviates Chronic Pain by Restoring M-current Activity in Sensory Neurons
Provisionally accepted
- 1Kocaeli Saglik ve Teknoloji Universitesi, Başiskele, Türkiye
- 2Yeditepe Universitesi, Istanbul, Türkiye
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Background: Pathological hyperexcitability of primary sensory neurons, driven in part by reduced activity of Kv7/M-type potassium channels, plays a central role in neuropathic, inflammatory, and osteoarthritic pain. Pharmacological activation of Kv7 channels is a promising non-opioid analgesic strategy, yet first-generation activators such as retigabine are limited by subtype non-selectivity and adverse effects. Chrysin, a naturally occurring flavonoid with known anti-inflammatory and neuroprotective actions, has not previously been evaluated for its effects on Kv7 channels or pain modulation. This study examined whether chrysin modulates Kv7-mediated neuronal excitability and alleviates chronic pain. Methods: Whole-cell patch-clamp recordings were performed in CHO cells expressing Kv7.1–Kv7.5 channels to determine chrysin’s subtype selectivity and biophysical actions. Native M-currents and action potential firing were assessed in dorsal root ganglion (DRG) neurons isolated from sham and spared nerve injury (SNI) mice. Kv7.2 mutagenesis and molecular docking were used to investigate potential interaction sites. Antinociceptive efficacy was tested in mouse models of SNI-induced neuropathic pain, complete Freund’s adjuvant (CFA)-induced inflammatory pain, and monoiodoacetate (MIA)-induced osteoarthritic pain. The Kv7 blocker XE991 was used to confirm channel dependence. Results: Chrysin selectively potentiated Kv7.2/7.3 currents (EC₅₀ = 8.7 ± 1.5 µM) and produced a ~24 mV hyperpolarising shift in activation V₁/₂ while minimally affecting Kv7.3, Kv7.4, and Kv7.5, and suppressing Kv7.1. In DRG neurons, chrysin restored suppressed M-currents and reduced repetitive firing, with more pronounced effects in neurons from SNI mice. Docking and mutagenesis suggested a distinct Kv7.2 interaction site conferring subtype preference. Systemic chrysin (1–20 mg·kg⁻¹) dose-dependently reduced mechanical allodynia and thermal hyperalgesia across SNI, CFA, and MIA models (EC₅₀ = 7.0 ± 0.9 mg·kg⁻¹). XE991 abolished all antinociceptive effects, confirming Kv7 involvement. Conclusion: Chrysin is a naturally occurring Kv7.2/7.3-preferential opener that restores M-currents, normalises sensory-neuron excitability, and produces broad analgesic efficacy in multiple chronic pain models. These findings highlight chrysin as a promising non-opioid therapeutic scaffold for selective Kv7-targeted pain relief.
Keywords: Chrysin, Kv7 potassium channels, M-current, Dorsal root ganglion, Chronic Pain
Received: 01 Nov 2025; Accepted: 09 Jan 2026.
Copyright: © 2026 Yusuf and Benkli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Muhammed Yusuf
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