| Neuropathic pain(NP)is defined as pain arising from a lesion or disease affecting the somatosensory system either at peripheral or central level.There are many causes of neuropathic pain,including physical or chemical damage,metabolic neuropathy.Trauma,metabolic disorders,infection,poisoning,vascular disease,tumors,nerve compression and other causes can cause nerve damage,which further leads to neuropathic pain.The pathogenesis of neuropathic pain can be summarized as peripheral mechanisms and central mechanisms.Central sensitization of the spinal cord and above spinal cord level is an important factor in the generation and maintenance of neuropathic pain.Chemokine is a small molecule with cytokine activity that induces the migration and aggregation of leukocytes to the injured site after injury.In the central nervous system,microglia,astrocytes,neurons(including primary afferent neurons and secondary neurons in the dorsal horn of the spinal cord)can synthesize chemokines and receptors,suggesting that chemokines are also participate in the transmission of pain.In recent years,scholars have conducted a large number of studies on chemokines and pain.As a novel chemokine,the role of CXCL12 and its receptor CXCR4 in the central mechanism of pathological pain has received increasing attention.Methods:Neuropathic pain was induced and assessed in a SNL rat model.The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot.The effects of CXCL12 rat peptide,CXCL12 neutralizing antibody,CXCR4 antagonist,and astrocyte metabolic inhibitor fluorocitrate on pain hypersensitivity were explored by behavioral tests in naive rats or a SNL rat model.We measured the expression level of c-Fos and CGRP to evaluate the sensitization of neurons after SNL by RT-PCR.The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba-1 after SNL.The mRNA levels of the pro-inflammatory cytokines such as TNF-α,IL-1β,and IL-6 and Connexin 30,Connexin 43,EAAT 1,EAAT 2 were also detected by RT-PCR.Results:First,we found that the expression of CXCL12 and CXCR4 were upregulated after SNL.CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL.Moreover,intrathecal administration of rat peptide,CXCL12,induced hypersensitivity in naive rats,which was partly reversed by fluorocitrate.In addition,the CXCL12 rat peptide increased mRNA levels of c-Fos,GFAP and iba-1.A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model.Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain,and reduced the expression of GFAP and iba-1 in the spinal dorsal horn.Finally,repeated intrathecal administration of the CXCR4 antagonist,AMD3100,significantly suppressed the initiation and duration of neuropathic pain.The mRNA levels of c-Fos,CGRP,GFAP,iba-1 and pro-inflammatory cytokines,also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100,while EAAT 1 and EAAT 2 mRNAs were increased.Conclusion:We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms and neuron-astroglia interaction.Importantly,intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain. |
