Crosstalk between NFκB-dependent astrocytic CXCL1 and neuron CXCR2 plays a role in descending pain facilitation

Abstract

BackgroundDespite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation.MethodsIntramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing.ResultsBCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity.ConclusionThe NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1391-2) contains supplementary material, which is available to authorized users.

Liquiritin Alleviates Pain Through Inhibiting CXCL1/CXCR2 Signaling Pathway in Bone Cancer Pain Rat

“…The BCP model of intramedullary injection of walker 256 cells is successfully established and is widely used to explore the mechanism of analgesic drugs due to its stable and sustaining pain-related behaviors (Akoury et al, 2019). In our present study, the mechanical withdrawal threshold showed a significant decrease on day 6 and continued to decline at a certain speed until day 18, which was in line with the previous research results (Hu et al, 2013;Ni et al, 2019a). LQ is one of the major constituents of Glycyrrhiza radix that exerts antiinflammatory effect (Li et al, 2018), pro-apoptotic effect (Wei et al, 2017), neurotrophic effect (Chen et al, 2009), and anti-RA (Zhai et al, 2019).…”

“…Spinal CXCL1 is produced by astrocytes and mediates pain via CXCR2 receptors in various chronic pain models Cao et al, 2014;Chen et al, 2014;Xu et al, 2014). Our previous study also found that CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP (Ni et al, 2019a). In agreement with these reports, the astrocytic CXCL1 and neural CXCR2 expression were increased in the spinal cord on day 12 after surgery.…”

“…Recent findings strongly suggested that CXCL1 might act on CXCR2 via glial-neuronal interactions in the spinal cord in several pathological pain models (Cao et al, 2014;Chen et al, 2014). In addition to this, our recent study also demonstrated that CXCL1-CXCR2 signaling plays a critical role in glial-neuron interactions and in descending facilitation of BCP (Ni et al, 2019a).…”

Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

“…Moreover, NAT therapy was associated with an increased count of eosinophils and basophiles and a trend towards elevated monocytes. This effect has already been reported before [25,26], however Miller and collegues found that values returned to baseline by month 9 during treatment. This is surprising, since most of the patients receiving NAT in our study have been treated for longer than 9 months.…”

“…Our analyses were performed during the routine diagnostic work-up for which reason the treatment duration ranged between 16-36 months and could possibly have affected the treatment effects on B cell subsets. However, consistent treatment effects are mostly detectable after 3-6 months and longitudinal data on treatment durations with more than 12 months, which could address possible habituation effects, are hardly available yet [26,28,33,42,43]. Future studies are necessary to follow treatment effects over a period longer than 12 months.…”