MicroRNA-124 as a novel treatment for persistent hyperalgesia.
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.
Laboratory of Neuroimmunology and Developmental Origins of Disease-NIDOD, University Medical Center Utrecht, Utrecht, 3584 EA, The Netherlands.
Hanneke L D M
HL
Willemen
Xiao-Jiao
XJ
Huo
Qi-Liang
QL
Mao-Ying
Jitske
J
Zijlstra
Cobi J
CJ
Heijnen
Annemieke
A
Kavelaars
D000818:Animals; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency* / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D007278:Injections, Spinal; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2