Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2: Further Insights into Molecular, Synaptic, and Cellular Mechanisms

Abstract

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 was shown to enhance NMDA-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms of the CCL2 modulation of central sensitization are still unclear. Spinal injection of the CCR2 antagonist RS504393 attenuated CCL2 and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in vGluT2+ excitatory neurons. CCL2 increased NMDA-induced currents in CCR2+/vGluT2+ neurons in lamina IIo. CCL2 also enhanced evoked synaptic NMDA currents following dorsal root stimulation. Furthermore, CCL2 increased total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest a direct modulation of synaptic plasticity by CCL2 in CCR2-expressing excitatory neurons in the spinal cord lamina IIo underlying the generation of central sensitization in pathological pain.

Recent Progress in Understanding the Mechanisms of Pain and Itch: the Second Special Issue

“…Xie and co-authors report an active role of the chemokine CCL2 in promoting central sensitization, longterm potentiation, and inflammatory pain [31]. Little is known about the involvement of chemokines in pruritus.…”

Interleukin-17 regulates neuron-glial communications, inhibitory synaptic transmission and neuropathic pain after chemotherapy

“…SOM + neurons are excitatory interneurons and indispensable for mechanical pain (Duan et al, 2014a, Duan et al, 2018). These neurons also exhibit marked synaptic plasticity in pathological pain conditions (Xie et al, 2018, Xu et al, 2013). We first recorded spontaneous EPSCs (sEPSCs) in outer lamina II (II o ) SOM + neurons in isolated spinal cord slices of SOM-tdTomato mice (Fig.…”

“…The somatostatin-positive (SOM + ) neurons are a subset of interneurons in the dorsal horn. There neurons are predominantly excitatory and express the vesicular glutamate transporter VGLUT 2 , a marker for glutamatergic excitatory neurons (Duan et al, 2018, Xie et al, 2018). Recently, Duan et al demonstrate that SOM + neurons are required to sense mechanical pain (Duan et al, 2014b).…”

“…SOM + also receive input from inhibitory neurons (Duan et al, 2014b). Furthermore, these neurons exhibit remarkable plastic changes after inflammation and nerve injury and respond to inflammatory mediators (Park et al, 2011, Xie et al, 2018, Xu et al, 2010). Here, we investigated how IL-17 and IL-17R modulate excitatory and inhibitory synaptic transmission of SOM + excitatory neurons in the normal and pathological pain conditions and further tested the involvement of IL-17/IL-17R signaling in paclitaxel-induced neuropathic pain model.…”

Naringin provides neuroprotection in CCL2-induced cognition impairment by attenuating neuronal apoptosis in the hippocampus

“…The chemokine C-C motif ligand 2 (CCL2), also known as the monocyte chemoattractant protein-1(MCP-1) [1,2], belongs to the C-C chemokine family [3]. It has the potent ability to activate and recruit mononuclear phagocytes and activate T cells and B cells; functions that are well-characterised in the immune system [4,5].…”