MicroRNA-124 as a novel treatment for persistent hyperalgesia

Abstract

BackgroundChronic 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.MethodsHyperalgesia 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.ResultsTransition 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.ConclusionsWe 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.

MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia

“…Recently, it was demonstrated that a sufficient miR-124 concentration is crucial for its effectiveness [42]. Earlier experiments using either repetitive injection of the miR-124 mimic every 2e3 days after disease onset [10] or intracranial miR-124 expression through viral vector injection [14] prolonged the protective effects over weeks.…”

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain

“…We identified nociceptor GPCR kinase 2 (GRK2) as a novel regulator of the duration of inflammatory hyperalgesia (21)(22)(23)(24)(25)(26)(27). GRK2 restrains signaling by promoting desensitization of GPCRs (28) and/or by interacting with multiple components of intracellular signaling pathways (22,29,30).…”

Practical Considerations of Convection Enhanced Delivery for Novel Therapies Treating Spinal Cord Injury Related Neuropathic Pain

“…They have proposed that intrathecal miR-124 treatment might be a powerful novel treatment for pathological chronic pain with persistent microglia activation. A decreased level of microglia miR-124 observed in LysM-GRK2 +/-mice when hyperalgesia became chronic [84]. Administration of miR-124 prevented persistent pain the mice.…”