The involvement of iron responsive element (-) divalent metal transporter 1-mediated the spinal iron overload via CXCL10/CXCR3 pathway in neuropathic pain in rats

Background Iron is pivotal for life, but it is toxic if in excess. Iron overload mediated by divalent metal transporter 1 (DMT1) in the central nervous system has participated in various neuroinflammatory diseases. Chemokine-induced neuroinflammation involves the development of pathological pain. Recently, chemokine CXCL10 is implicated in the pathogenesis of chronic pain, however, little is known about the potential link between iron accumulation and CXCL10 in pain condition. Here, we examined whether iron accumulation regulated neuropathic pain via CXCL10. Methods: Pain behavior was assessed in a rat model of chronic constriction injury (CCI) of the sciatic nerve. Spinal expressions of CXCL10 and its receptor CXCR3 were measured using RT-qPCR. Western blot and atomic absorption spectrophotometer were employed to measure spinal DMT1 with/without iron responsive element [IRE ( + ) DMT1 and IRE (-) DMT1] and iron concentration. Iron chelator, recombinant CXCL10, and a selective CXCR3 antagonist NBI-74330 were injected to verify the mechanisms. Results: We found that CCI induced long-lasting increase of spinal iron concentration, IRE (-) DMT1 expression, CXCL10 and CXCR3 levels. Moreover, iron chelator attenuated neuropathic pain and inhibited the over-expression of CXCL10 and CXCR3 in a dose dependent manner. CCI-induced mechanical allodynia and thermal hyperalgesia were also prevented by the delivery of NBI-74330. Exogenous CXCL10 elicited behavioral hypernociceptive state and CXCR3 over-expression in naive rats, which was reversed by the co-administration of iron chelator. Conclusion: Our findings demonstrated the contribution of spinal abnormal iron accumulation in regulating CXCL10 pathway in the pathogenesis of neuropathic pain.