gsk-j4 and Pain--Postoperative

C-C motif chemokine ligand 17 (CCL17), an important chemokine, plays a vital role in regulating immune balance in the central nervous system. In this study, we explored the potential roles of CCL17 in a rat postoperative pain model and that of blocking CCL17 in the prevention of postoperative pain in rats. A right plantar incision in rat was used as a model of postoperative pain. A behavioral change was measured preoperatively and postoperatively using mechanical withdrawal thresholds and thermal withdrawal latency. CCL17 and its upstream Jmjd-3 mRNA levels in the spinal cord were detected using real-time PCR, CCL17 levels in the serum were measured using enzyme-linked immunosorbent assay (ELISA), and the expression of interferon regulatory factor 4 (IRF4), which interacts with Jmjd-3, was detected by immunohistochemistry staining. After that, rats were intraperitoneally injected with either anti-CCL17 monoclonal antibody (mAb) or GSK-J4 (the Jmjd3 inhibitor) to evaluate the protective effects of blocking CCL17 on postoperative pain. We found that CCL17 and Jmjd-3 were significantly increased in the spinal cords of the postoperative pain rat, consistent with changes in hyperalgesia. In addition, our results showed that the mechanical and thermal allodynia was significantly ameliorated using anti-CCL17mAb or GSK-J4. Moreover, we found that anti-CCL17mAb or GSK-J4 treatment decreased c-fos expression in response to peripheral stimulation. Finally, our preliminary exploration found that anti-CCL17mAb or GSK-J4 had a protective effect on tissue damage. These findings indicated that high expression of CCL17 played a critical role in postoperative pain induced by plantar incision and that CCL17 blockade may serve as an effective approach to managing postoperative pain.

Topics: Animals; Chemokines; Hyperalgesia; Ligands; Pain, Postoperative; Rats

Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification.

Topics: Animals; Annexins; Benzazepines; Cornified Envelope Proline-Rich Proteins; Disease Models, Animal; Electrocoagulation; Female; Foot Injuries; Gene Expression Regulation; Gene Knock-In Techniques; Genes, fos; Genes, Reporter; Histone Code; Histones; Hyperalgesia; Jumonji Domain-Containing Histone Demethylases; Lysine; Male; Methylation; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuralgia; Neurons; Pain, Postoperative; Pyrimidines; RNA, Messenger; Spinal Cord; Tamoxifen