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 naïve 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.

Efficacy of intravenous lidocaine on pain relief in patients undergoing laparoscopic cholecystectomy: A meta-analysis from randomized controlled trials.

OBJECTIVE: Whether intravenous lidocaine has a beneficial role in controlling acute pain after a laparoscopic cholecystectomy (LC) in currently unknown. We performed a meta-analysis from randomized controlled trials (RCTs) to determine the efficacy and safety of intravenous lidocaine for the treatment of acute postoperative pain after LC. METHODS: In November 2017, a systematic search was performed in PubMed, EMBASE, Web of Science, ScienceDirect, and the Cochrane Library. RCTs comparing lidocaine and placebo in patients undergoing LC were retrieved. The primary endpoint was the visual analogue scale (VAS) score and opioid requirements at 12 h, 24 h and 48 h. The secondary endpoint was the length of hospital stay and opioid-related adverse effect. Stata 12.0 was used for the data analysis. RESULTS: Finally, six RCTs were included in the meta-analysis. Results indicated that intravenous lidocaine was associated with reduced pain scores and cumulative opioid consumption at 12 h, 24 h, and 48 h following a LC. Similarly, lidocaine was associated with a reduction in the incidence of nausea and vomiting, ileus and pruritus. CONCLUSION: Intravenous use of lidocaine was able to reduce acute postoperative pain, total opioid requirements and opioid-related adverse effects following a LC. Further studies should determine whether lidocaine has a positive role in improving the postoperative function after a LC.

Spinal CXCL5 contributes to nerve injury-induced neuropathic pain via modulating GSK-3ß phosphorylation and activity in rats.

BACKGROUND: Neuroinflammation is identified to be crucial in the development of neuropathic pain, whereas definite molecular mechanisms remain obscure. Recently, chemokine CXCL5 is manifested to participate in the inflammatory process of central nervous system, however, little is known about the potential effect of spinal CXCL5 on pathogenesis of pain. This study investigated whether and how CXCL5 and its receptor CXCR2 regulated neuropathic pain in a rat model of chronic constriction injury (CCI) of the sciatic nerves. METHODS: Recombinant CXCL5, a neutralizing antibody against CXCL5, selective CXCR2 antagonist SB225002 and GSK-3ß inhibitor TDZD-8 were injected intrathecally. PWT and PWL were documented to assess mechanical allodynia and thermal hyperalgesia. Simultaneously, levels of CXCL5 and CXCR2 in spinal dorsal horn were measured by RT-qPCR after nociceptive testing. Western blot was utilized to evaluate spinal GSK-3ß expression and phosphorylation. RESULTS: We found that CCI engendered rapid and long-lasting mechanical allodynia and thermal hyperalgesia, which was accompanied by dramatical rise of spinal CXCL5 and CXCR2 expression. CCI also caused an increase of pGSK-3ß (Tyr216) and a decrease of pGSK-3ß (Ser9) without affecting total protein level of GSK-3ß. Moreover, spinal blockage of CXCL5/CXCR2 pathway attenuated neuropathic pain and inhibited the enhancement of GSK-3ß activity. Also, intrathecal delivery of exogenous CXCL5 dose-dependently induced nociceptive hypersensitivity in naïve rats, which was prevented by the supplemental addition of TDZD-8. CONCLUSION: These present findings indicate that up-regulation of spinal CXCL5 and CXCR2 is involved in neuropathic pain after nerve injury, through regulating GSK-3ß activity in rats.