Chemokine contribution to neuropathic pain: Respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons

Abstract

Recent studies have indicated an important role of chemokines such as CCL2 in the development of chronic pain. However, the distinct roles of different chemokines in the development and maintenance of neuropathic pain and in their interactions with neurons have not been clearly elucidated. We found that spinal nerve ligation (SNL) not only induced persistent neuropathic pain symptoms including mechanical allodynia and heat hyperalgesia but also produced sustained CXCL1 upregulation in the spinal cord. Double staining of immunofluorescence and in situ hybridization revealed that CXCL1 was primarily induced in spinal astrocytes. In cultured astrocytes, TNF-α induced robust CXCL1 expression, via the activation of the c-jun N-terminal kinase (JNK). Intrathecal administration of CXCL1 neutralizing antibody transiently reduced SNL-induced pain hypersensitivity, suggesting an essential role of CXCL1 in neuropathic pain sensitization. In particular, intraspinal delivery of CXCL1 shRNA lentiviral vectors, either before or after SNL, persistently attenuated SNL-induced pain hypersensitivity. Spinal application of CXCL1 not only elicited pain hypersensitivity but also induced rapid neuronal activation, as indicated by the expression of phosphorylated ERK and CREB (pERK and pCREB) and c-Fos in spinal cord neurons. Interestingly, CXCR2, the primary receptor of CXCL1, was upregulated in dorsal horn neurons after SNL, and the CXCR2 antagonist SB225002 completely blocked the CXCL1-induced heat hyperalgesia. SB225002 also attenuated SNL-induced pain hypersensitivity. Collectively, our results have demonstrated a novel form of chemokine-mediated glial-neuronal interaction in the spinal cord that can drive neuropathic pain. Inhibition of the CXCL1-CXCR2 signaling may offer a new therapy for neuropathic pain management.

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

“…Role of TNF-a in Upregulation of CXCL12 in the Lumbar DRG and Spinal Cord During the Development of Neuropathic Pain Following SNI Recent studies have shown that TNF-a regulates CXCL1 release in the spinal cord following SNL at L5 [19]. Here, we found that SNI induced an increase in the expression of TNFa in the DRG and spinal cord compared to the sham group.…”

“…The prevailing evidence shows that TNF-a stimulates IL-1b and IL-6 release from DRGs and the spinal cord following nerve injury [38,39]. Further, the spinal nerve ligation-induced increase in the expression of CXCL1 in the L5 spinal cord is regulated by TNF-a [19] and i.t. administration of TNF-a induces the expression of monocyte chemoattractant protein-1 by spinal astrocytes [39].…”

“…It is known that cytokines such as tumor necrosis factor-alpha (TNF-a) regulate chemokine release from glial cells in the spinal cord following lumbar 5 spinal nerve ligation (L5 SNL) [19] and that chemokines such as CXCL12 promote TNF-a secretion from cultured astrocytes [9]. Thus, in the present study, the time-course of CXCL12/CXCR4 expression, its cellular localization in the DRG and spinal cord, and the role of TNF-a in the regulation of CXCL12 expression were examined following spared nerve injury (SNI) in rats.…”

Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α

“…It is reported that IL-1␤ induces CXCL1 and neutrophil infiltration and TNF-␣ induces CCL2 and monocyte infiltration (Campbell et al, 2005) and that these pathways do not significantly cross over (Schnell et al, 1999;Blond et al, 2002) cord CXCL1 (Zhang et al, 2013) but demonstrations of this in the brain are lacking. Here both IL-1␤ and TNF-␣ robustly induced both CXCL1 and CCL2 in astrocytes of the degenerating brain.…”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…По данным экспериментальных иссле-дований, наряду с индукцией остеокластогенеза АЦБ об-ладают способностью вызывать болевые ощущения (меха-ническая и термальная гиперчувствительность) в отсутст-вие признаков воспаления [78]. Развитие боли также опо-средуется ИЛ8-зависимым механизмом, а именно -свя-зыванием ИЛ8 (или CXCL1) с CXC хемокиновыми рецеп-торами 1-го и 2-го типа, что приводит к сенситизации и активации сенсорных нейронов [88]. Блокада хемокинов с использованием рецепторных антагонистов отменяет как АЦБ-индуцированную потерю костной ткани, так и болевые ощущения [78].…”