SDF1-CXCR4 Signaling Maintains Central Post-Stroke Pain through Mediation of Glial-Neuronal Interactions

Abstract

Central post-stroke pain (CPSP) is an intractable central neuropathic pain that has been poorly studied mechanistically. Here we showed that stromal cell-derived factor 1 (SDF1 or CXCL12), a member of the CXC chemokine family, and its receptor CXCR4 played a key role in the development and maintenance of thalamic hemorrhagic CPSP through hypoxia inducible factor 1α (HIF-1α) mediated microglial-astrocytic-neuronal interactions. First, both intra-thalamic collagenase (ITC) and SDF1 injections could induce CPSP that was blockable and reversible by intra-thalamic administration of both AMD3100 (a selective CXCR4 antagonist) and inhibitors of microglial or astrocytic activation. Second, long-term increased-expression of SDF1 and CXCR4 that was accompanied by activations of both microglia and astrocytes following ITC could be blocked by both AMD-3100 and YC-1, a selective inhibitor of HIF-1α. AMD-3100 could also inhibit release of proinflammatory mediators (TNFα, IL1β and IL-6). Increased-expression of HIF-1α, SDF1, CXCR4, Iba1 and GFAP proteins could be induced by both ITC and intra-thalamic CoCl2, an inducer of HIF-1α that was blockable by both HIF-1α inhibition and CXCR4 antagonism. Finally, inhibition of HIF-1α was only effective in prevention, but not in treatment of ITC-induced CPSP. Taken together, the present study demonstrated that in the initial process of thalamic hemorrhagic state HIF-1α up-regulated SDF1-CXCR4 signaling, while in the late process SDF1-CXCR4 signaling-mediated positive feedback plays more important role in glial-glial and glial-neuronal interactions and might be a novel promising molecular target for treatment of CPSP in clinic.

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

“…Accumulating evidence indicated that immunemodulators play a key role in regulating synaptic plasticity and neuronal excitability, contributing to the persistence of various pain intensities (Jiang et al, 2017;Yang et al, 2017;Wu et al, 2019). The role of CXCL1, a member of the CXC family, depends on its primary receptor CXCR2 (Carreira et al, 2013).…”

Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

“…Considerable research has suggested that numerous extracellular signaling molecules and intracellular transduction pathways are involved in chronic pain. 21 – 24 The Janus family tyrosine kinase (JAK)/signal transducers and activators of transcription (STAT) pathway is one of the most important cell signaling pathways in chronic pain, which includes four types of JAK and seven types of STAT. 25 , 26 Our previous study has demonstrated that STAT1 contributes to CIBP by regulating MHC II expression in spinal microglia.…”

Intervertebral foramen injection of plerixafor attenuates CCD-induced low back pain in rats through down-regulation of Nav1.8 and Nav1.9

“…We speculated that the protracted analgesic effect was largely because of the plerixafor not only reduced the expression of Nav1.8 and Nav1.9, but also has the ability to relieve in ammation in compressed DRG which was also a pivotal mechanism for neuronal hyperexcitability and chronic pain. In supporting, recent studies have demonstrated that the pro-in ammatory cytokines dramatically up-regulated accompanying with several anti-in ammatory cytokines down-regulated in compressed DRG [22], while plerixafor has been proven to be able to reducing the expression of TNF-α, IL-1β, IL-6 and in ammatory cell in ltration in the nervous system [10,35]. Collectively, the above characteristics and advantages of plerixafor make it an effective and applicable therapeutic medicine for neuropathic pain.…”

“…In chronic constriction injury (CCI) and SNI model, elevation of CXCR4 immunoreactivity has also been demonstrated in the DRG neuronal soma [36,37]. The expression level of CXCR4 in the CNS could also be obviously enhanced under central neuropathic pain situations such as central post stroke pain [10], spinal cord ischemia-reperfusion [38], spinal cord contusion injury [39]. This inducible expression pattern of CXCR4 enable CXCR4 as an ideal analgesic target.…”

“…The chemokine CXC motif receptor 4 (CXCR4) belonging to the well-studied G protein-coupled receptor (GPCR) family is a primary cognate receptor for the chemokine CXC motif ligand 12 (CXCL12) which plays an important role in many biological functions, including embryogenesis, immune surveillance, in ammation response, tissue homeostasis, tumor growth and metastasis [6][7][8]. Much evidence has accumulated that CXCR4 chemokine signaling contributes to the development and maintenance of chronic pain [9][10][11]. A recent study have demonstrated that intraperitoneal injection of plerixafor (AMD3100), a selective antagonist for CXCR4, which has been approved for mobilization of hematopoietic stem cells clinically by the U.S. Food and Drug Administration in 2008, signi cantly ameliorated CCD-induced mechanical and thermal hyperalgesia, suggesting CXCR4 might be an adequate analgesic target [12][13][14].…”