MicroRNA-124 as a novel treatment for persistent hyperalgesia
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Updated: May 21, 2026
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Published on: June 13, 2025
Hanneke L D M Willemen1, Xiao-Jiao Huo, Qi-Liang Mao-Ying
1Laboratory of Neuroimmunology and Developmental Origins of Disease-NIDOD, University Medical Center Utrecht, Utrecht, 3584 EA, The Netherlands.
Background:
Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein-coupled receptor kinase (GRK)2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/- mice) develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT) mice.
Methods:
Hyperalgesia was induced by intraplantar IL-1β in WT and LysM-GRK2+/- mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro-inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1β-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed.
Results:
Transition from acute to persistent hyperalgesia in LysM-GRK2+/- mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/- mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1β in LysM-GRK2+/- mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM-GRK2+/- mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of mechanical allodynia in the spared nerve injury model of chronic neuropathic pain in WT mice.
Conclusions:
We present the first evidence that intrathecal miR-124 treatment can be used to prevent and treat persistent inflammatory and neuropathic pain. In addition, we show for the first time that persistent hyperalgesia in GRK2-deficient mice is associated with an increased ratio of M1/M2 type markers in spinal cord microglia/macrophages, which is restored by miR-124 treatment. We propose that intrathecal miR-124 treatment might be a powerful novel treatment for pathological chronic pain with persistent microglia activation.
Insights
MicroRNA miR-124 prevents and treats chronic pain by reducing spinal microglia activation. This study shows miR-124 normalizes M1/M2 markers, offering a novel therapeutic approach for persistent pain.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Chronic pain is linked to spinal microglia activation.
- Reduced G protein-coupled receptor kinase 2 (GRK2) in microglia exacerbates chronic pain.
- MicroRNA miR-124 is crucial for maintaining microglial quiescence.
Purpose of the Study:
- To investigate miR-124's role in hyperalgesia and microglia activation in GRK2-deficient mice.
- To evaluate miR-124's therapeutic potential for chronic inflammatory and neuropathic pain in wild-type mice.
Main Methods:
- Induced hyperalgesia using IL-1β in wild-type (WT) and LysM-GRK2+/- mice.
- Assessed spinal cord miR-124 expression and M1/M2 activation markers.
- Administered intrathecal miR-124 to evaluate its effects on pain and microglial phenotype.
Main Results:
- Reduced miR-124 levels correlated with persistent hyperalgesia and M1 phenotype in LysM-GRK2+/- mice.
- Intrathecal miR-124 prevented persistent pain and normalized M1/M2 markers in GRK2-deficient mice.
- miR-124 treatment reversed carrageenan-induced pain and prevented allodynia in spared nerve injury models.
Conclusions:
- Intrathecal miR-124 effectively prevents and treats persistent inflammatory and neuropathic pain.
- miR-124 restores the M1/M2 balance in spinal microglia/macrophages.
- miR-124 represents a promising novel therapeutic strategy for chronic pain associated with microglia activation.
