Aims: Chronic pain is a critical public health issue that severely impacts quality of life and poses significant treatment challenges, particularly due to the risk of adverse effects associated with pharmacological therapies. The search for effective non-invasive treatment alternatives has become increasingly relevant. Low-intensity focused ultrasound (LIFU) has been identified as an effective non-invasive strategy for pain management, although the underlying mechanism remains unclear. This study aimed to evaluate the analgesic effects and cellular mechanisms of LIFU-induced neuromodulation targeted on dorsal root ganglia (DRG) in both inflammatory and neuropathic pain models.
Materials and methods: The study adopted in vivo complete Freund's adjuvant-induced inflammatory pain and chronic constriction injury-induced neuropathic pain rat models, along with ex vivo DRG primary cultures.
Key findings: The application of LIFU resulted in a time-dependent analgesic response in both pain models. The neurophysiological analyses revealed that LIFU activated GABAergic neurons and deactivated CGRP-expressing neurons triggered by noxious stimuli. The analgesic effects of LIFU and the LIFU-deactivated CGRP-containing neurons were reversed by injecting GABA antagonist to the L5 DRG, confirming the mediation of these effects through the GABAergic pathways. Ex vivo LIFU stimulation of DRG resulted in increased GABA release and decreased capsaicin-triggered CGRP cascades, further supporting in vivo findings.
Significance: We demonstrate, for the first time, that LIFU modulates the GABA-CGRP pathways in the peripheral sensory neurons to alleviate pain, which underscores the importance of GABAergic systems in LIFU-induced analgesia. Our results reveal potential clinical applications of FUS for pain management through the peripheral nervous system.
Keywords: Analgesia; CGRP; Chronic pain; GABA; Low-intensity focused ultrasound; Neuromodulation; Non-invasive.
Copyright © 2024. Published by Elsevier Inc.