CCL-1 in the spinal cord contributes to neuropathic pain induced by nerve injury

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.

Hydrogen-rich saline controls remifentanil-induced hypernociception and NMDA receptor NR1 subunit membrane trafficking through GSK-3β in the DRG in rats

“…Moreover, a recent paper by Li et al (2013) has reported that NMDAR activation induced maintenance of OIH is associated with NR1 and NR2B subunits expression, membrane trafficking and function in the spinal cord dorsal horn. The level of NMDA receptors, particularly NR1, in primary sensory neurons increases during inflammation, which contributes to peripheral inflammatory pain sensitization (Tan et al, 2010;Akimoto et al, 2013). Whether peripheral sensitization caused by NMDAR activation is implicated in OIH has been not well reported.…”

Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons

“…The SG was easily discernible with transmitted illumination as a relatively translucent band across the dorsal horn in the transverse slice preparations. Blind whole-cell voltage-clamp recordings were made from SG neurons, as previously described (36). The pipette solution contained 135 mM K-gluconate, 5 mM KCl, 0.5 mM CaCl 2 , 2 mM MgCl 2 , 5 mM EGTA, 5 mM Hepes, and 5 mM ATP-Mg, pH 7.20, with KOH.…”

The Study of Different Approaches of Parecoxib Sodium Pretreatment on the Behavior of Rats with Neuropathic Pain

“…Thus, neuropathic pain significantly lowers the life quality of patients [14][15][16][17][18]. Recent studies have shown that there is activation of peripheral and central gliocytes complicated with release of inflammatory cytokines in neuropathic pain.…”