Abstract
Cytokines such as interleukins are known to be involved in the development of neuropathic pain through activation of neuroglia. However, the role of chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, in the nociceptive transmission remains unclear. We found that CCL-1 was upregulated in the spinal dorsal horn after partial sciatic nerve ligation. Therefore, we examined actions of recombinant CCL-1 on behavioural pain score, synaptic transmission, glial cell function and cytokine production in the spinal dorsal horn. Here we show that CCL-1 is one of the key mediators involved in the development of neuropathic pain. Expression of CCL-1 mRNA was mainly detected in the ipsilateral dorsal root ganglion, and the expression of specific CCL-1 receptor CCR-8 was upregulated in the superficial dorsal horn. Increased expression of CCR-8 was observed not only in neurons but also in microglia and astrocytes in the ipsilateral side. Recombinant CCL-1 injected intrathecally (i.t.) to naive mice induced allodynia, which was prevented by the supplemental addition of N-methyl-𝒟-aspartate (NMDA) receptor antagonist, MK-801. Patch-clamp recordings from spinal cord slices revealed that application of CCL-1 transiently enhanced excitatory synaptic transmission in the substantia gelatinosa (lamina II). In the long term, i.t. injection of CCL-1 induced phosphorylation of NMDA receptor subunit, NR1 and NR2B, in the spinal cord. Injection of CCL-1 also upregulated mRNA level of glial cell markers and proinflammatory cytokines (IL-1β, TNF-α and IL-6). The tactile allodynia induced by nerve ligation was attenuated by prophylactic and chronic administration of neutralizing antibody against CCL-1 and by knocking down of CCR-8. Our results indicate that CCL-1 is one of the key molecules in pathogenesis, and CCL-1/CCR-8 signaling system can be a potential target for drug development in the treatment for neuropathic pain.
Highlights
Glutamate, the major excitatory neurotransmitter in the brain and spinal cord, exerts its postsynaptic effects via a diverse set of ionotropic and metabotropic membrane receptors
The present study, for the first time, demonstrates that expression of CCL-1 in the spinal cord and dorsal root ganglion (DRG) at the mRNA and protein levels is increased after nerve ligation, and the nerve ligation-induced tactile allodynia is attenuated by treatment with neutralizing antibody against CCL-1 and in CCR-8 knockdown mice
We further show that CCL-1 has an excitatory action on the glutamatergic synaptic transmission and phosphorylation of N-methyl-D-aspartate receptors (NMDARs) subunits, NR1 and NR2B, in the spinal dorsal horn and increase expression of glial cells activation markers (Iba[1], CD11b and GFAP) and cytokines (IL-1b, tumour necrosis factor-a (TNF-a) and IL-6)
Summary
The major excitatory neurotransmitter in the brain and spinal cord, exerts its postsynaptic effects via a diverse set of ionotropic and metabotropic membrane receptors. There are many reports that nerve injury triggers reactive changes in peripheral immune system and in neuroglial cells in both peripheral and central nervous systems.[4,11,12] In the periphery, activation of Schwann cells and resident macrophages recruit hematogenous immune cells, which subsequently invade the injured nerves.[12,13,14] In the spinal dorsal horn receiving the injured sensory afferents, activation of microglia is commonly associated with early establishment stages of neuropathic pain.[2,15,16] Cytokines such as interleukin-1b (IL-1b), tumour necrosis factor-a (TNF-a) and IL-6, which originate from the peripheral injured area or from activated neuroglial cells in the spinal cord, are known to alter synaptic transmission in the dorsal horn.[13,14].
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