High-Frequency Terahertz Stimulation Alleviates Neuropathic Pain by Modulating Pyramidal Neuron Activity in the Anterior Cingulate Cortex of Mice

Core Concepts

High-frequency terahertz stimulation alleviates neuropathic pain in mice by enhancing voltage-gated potassium channel conductance, which decreases the excitability of pyramidal neurons in the anterior cingulate cortex.

Abstract

This study investigates the use of high-frequency terahertz (HFTS) stimulation as a novel optical intervention for the treatment of neuropathic pain (NP). The key findings are:

Molecular dynamics simulations revealed that HFTS at around 36 THz preferentially interacts with and enhances the conductance of voltage-gated potassium (Kv) channels, particularly Kv1.2, without significantly affecting voltage-gated sodium channels.

In vitro patch-clamp recordings showed that HFTS increased the amplitude and slope of Kv currents in pyramidal neurons of the anterior cingulate cortex (ACC) in mice with spared nerve injury (SNI), a model of NP. This led to a reduction in the excitability of these neurons.

In vivo multi-channel recordings in the ACC of awake SNI mice confirmed that HFTS decreased the firing rate of pyramidal neurons, while having a lesser effect on interneurons.

Behavioral tests demonstrated that HFTS application in the ACC significantly alleviated mechanical allodynia and improved gait abnormalities in SNI mice, indicating an analgesic effect.

The proposed mechanism is that the specific frequency of HFTS resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating potassium ion translocation and reducing the hyperexcitability of ACC pyramidal neurons, which is a key pathological feature of neuropathic pain. This study presents a novel optical intervention strategy using terahertz waves for the treatment of NP.

Stats

The application of HFTS induced a significant increase in the amplitude of K+ currents and an increased slope of the current-voltage characteristic (I-V) curve in pyramidal neurons of the ACC in SNI mice.
HFTS significantly decreased the mean firing rate of ACC neurons in both sham and SNI groups.
HFTS significantly increased the paw withdrawal mechanical thresholds in SNI mice, indicating an analgesic effect.
HFTS increased the stand time, stand index, max contact area, mean print area, and mean intensity of the left hind paw in SNI mice, suggesting improved gait function.

Quotes

"HFTS reduces the spike firing of ACC neurons, whereas BLS does not have the same effect."
"HFTS alleviates neuropathic pain symptoms in mice with spared nerve injury."
"HFTS increases voltage-gated potassium ion conductance through resonance with the carbonyl group in the potassium channel filter region."

Key Insights Distilled From

High Frequency Terahertz Stimulation Alleviates Neuropathic Pain by Inhibiting the Pyramidal Neuron Activity in the Anterior Cingulate Cortex of mice

by Peng,W., Wan... at www.biorxiv.org 03-11-2024

https://www.biorxiv.org/content/10.1101/2024.03.06.583763v1

Deeper Inquiries

How could the non-invasive delivery of terahertz waves be achieved for potential clinical applications?

Non-invasive delivery of terahertz waves for potential clinical applications could be achieved through advancements in technology and innovative approaches. One possible method is the development of terahertz emitters that can penetrate biological tissues without causing harm. This could involve the use of specialized materials or structures that allow for safe and efficient transmission of terahertz waves through the skin and into deeper tissues. Additionally, techniques such as focused ultrasound or magnetic resonance imaging (MRI)-guided delivery systems could be utilized to target specific areas of the body with precision, minimizing potential side effects.

What other ion channels or cellular mechanisms might be affected by HFTS, and how could these off-target effects be mitigated?

While the focus of the study is on the effects of high-frequency terahertz stimulation (HFTS) on voltage-gated potassium (Kv) channels, it is possible that other ion channels or cellular mechanisms could be affected by HFTS. For example, HFTS may influence calcium channels, sodium channels, or even non-ion channel proteins involved in neuronal excitability. To mitigate off-target effects, thorough preclinical studies should be conducted to assess the impact of HFTS on various ion channels and cellular processes. This can help identify potential off-target effects and guide the development of strategies to minimize or counteract these effects. Additionally, the use of specific frequencies or intensities of terahertz waves that target Kv channels more selectively could help reduce off-target effects on other ion channels.

Could HFTS be combined with other pain management strategies, such as pharmacological interventions or neuromodulation, to achieve synergistic effects in treating neuropathic pain?

Combining high-frequency terahertz stimulation (HFTS) with other pain management strategies, such as pharmacological interventions or neuromodulation, could potentially lead to synergistic effects in treating neuropathic pain. For example, HFTS could be used in conjunction with existing pain medications to enhance their efficacy or reduce the required dosage, thereby minimizing side effects. Additionally, combining HFTS with neuromodulation techniques like transcranial magnetic stimulation (TMS) or spinal cord stimulation could target different aspects of pain processing pathways, providing a more comprehensive and effective treatment approach. However, careful consideration of the safety and efficacy of combined therapies is essential, and further research is needed to explore the potential synergies and interactions between HFTS and other pain management strategies.