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MicroRNA-124 as a novel treatment for persistent hyperalgesia
Abstract
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.
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Inflammatory hyperalgesia can be caused by activated microglia in the spinal cord; miR-124 reduction in spinal cord microglia is associated with increase in M1 and upregulation of pro-inflammatory factors; intrathecal administration of miR-124 mimics suppresses neuropathic pain, inflammation, and M1 microglia.
“They confirmed that inflammatory hyperalgesia can be caused by activated microglia in the spinal cord. They showed that miR-124 reduction in spinal cord microglia is associated with increase in M1 and upregulation of pro-inflammatory factors. Intrathecal administration of miR-124 mimics suppresses neuropathic pain, inflammation, and M1 microglia (Willemen et al. 2012).”
From MiR-124 and MiR-155 as Therapeutic Targets in Microglia-Mediated Inflammation in Multiple Sclerosis (2025) · cites this paper as Willemen et al. 2012
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“As a functional correlate of the M1 and M2 phenotype, we quantified mRNA encoding the pro-inflammatory (M1) cytokine IL-1β, the M1-related enzyme iNOS, and the anti-inflammatory (M2) cytokine TGF-β [23-26].”
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Andersen, H. H., Duroux, M., & Gazerani, P. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.003 · Cited by 175
miR-124: A Promising Therapeutic Target for Central Nervous System Injuries and Diseases
Xu, J., Zheng, Y., Wang, L., Liu, Y., Wang, X., Li, Y., & Chi, G. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01091-6 · Cited by 55
MiR-124 and MiR-155 as Therapeutic Targets in Microglia-Mediated Inflammation in Multiple Sclerosis
Asl, E. R., Hosseini, S. E., Tahmasebi, F., Bolandi, N., & Barati, S. (2025) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01578-6 · Cited by 19
Metadata
- Authors
- Willemen, H. L., Huo, X.-J., Mao-Ying, Q.-L., Zijlstra, J., Heijnen, C. J., & Kavelaars, A.
- Venue
- Journal of Neuroinflammation
- Published
- 2012-06-25
- Volume
- 9
- Issue
- 1
- ISSN
- 1742-2094
- PMC
- PMC3418202
- Cited by
- 137
- References
- 4
- Language
- en
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