No abstract

Following various types of nerve injury, cyclooxygenase 2 and prostaglandin E2 (PGE2) are universally and chronically upregulated in injured nerves and contribute to the genesis of neuropathic pain. Persistent high levels of PGE2 likely exert chronic effects on nociceptive dorsal root ganglion (DRG) neurons. In the present study, we tested the hypothesis that injured nerve-derived PGE2 contributes to the up-regulation of the pro-inflammatory cytokine interleukin-6 (IL-6) in DRG neurons following partial sciatic nerve ligation. In naive adult rats, IL-6 was expressed in only a few small size DRG neurons which all co-expressed EP4 receptors. Partial sciatic nerve ligation increased and shifted IL-6 expression from small to medium and large size damaged DRG neurons. Perineural injection of a selective cyclooxygenase 2 inhibitor or a selective EP4 receptor antagonist significantly suppressed the up-regulation of IL-6 in DRG, suggesting that injured nerve derived PGE2 contributes to the de novo synthesis of IL-6 in DRG neurons through EP4 receptors. In cultured sensory ganglion explants, a stabilized PGE2 analog increased IL-6 mRNA and protein levels through the activation of EP4, protein kinase A, protein kinase C, extracelluar regulated protein kinase/MAPK, cAMP response element binding protein and NFjB signalling pathways. Taken together, these data indicate that facilitating the de novo synthesis of painrelated cytokines in injured medium and large size DRG neurons is a novel mechanism underlying the role of injured nerve derived PGE2 in the genesis of neuropathic pain. Keywords: cytokines, inflammatory mediator, neuropathic pain, prostaglandins, sciatic nerve, tract tracing. . We and others also showed that either perineural or intraplantar injection of a non-selective or selective COX2 inhibitor remarkably relieved neuropathic pain (Syriatowicz et al. 1999;Ma and Eisenach 2002, 2003a;Ma et al. 2010), suggesting that injured nerve derived COX2 and PGE2 contribute to the genesis of neuropathic pain. The mechanisms underlying the role of injured nerve derived COX2 and PGE2 in the genesis of neuropathic pain have recently been postulated (Ma and Quirion 2008). Persistent high levels of PGE2 likely exerts long-term effects on EP receptor bearing cells such as invading macrophages through autocrine or paracrine pathways and nociceptive DRG neurons (nociceptors) through stimulating en passant injured or spared axons in injured nerves. One of the chronic effects is to facilitate the synthesis of pain-related molecules including neuropeptides, growth factors, ion channels, cytokines and chemokines. Since the maintenance of neuropathic pain largely depends on the long-term up-regulation of these pain-related molecules (Scholz and Woolf 2007), persistently facilitating the synthesis of pain-related molecules in injured nerves and DRG might be one of the mechanisms underlying the contribution of injured nerve-derived COX2 and PGE2 to the genesis of neuropathic pain.After nerve injury, the pro-inflammatory cytokine ...

No abstract

Inflammatory pain severely affects the quality of life of millions of individuals worldwide. Prostaglandin E2 (PGE2), a pain mediator enriched in inflamed tissues, plays a pivotal role in nociceptor sensitization and in the genesis of inflammatory pain. Its EP4 receptor mainly mediates its role in inflammatory pain. However, the underlying mechanisms are poorly understood. Here we found that PGE2/EP4 signalling-induced EP4 externalization in dorsal root ganglion (DRG) neurons contributes to nociceptor sensitization and inflammatory pain. In cultured DRG neurons, PGE2 and the EP4 agonist concentration- and time-dependently stimulated EP4 externalization. The inhibitors of anterograde secretory pathway, protein synthesis, or recycling pathway suppressed PGE2-induced EP4 externalization, suggesting that EP4 retained in Golgi apparatus and in recycling endosomes, as well as newly synthesized, are mobilized in this event. Interestingly, the intracellular cAMP levels of cultured DRG explants following 2 sequential treatments with the EP4 agonist were significantly higher than a single treatment, suggesting that the first treatment of agonist likely induces EP4 export to sensitize DRG neurons. Intraplantar injection of complete Freud's adjuvant increases both total and cell-surface EP4 levels of L4-6 DRG neurons, an event suppressed by a cyclooxygenase-2 inhibitor or a selective EP4 antagonist, suggesting that PGE2/EP4 signalling in inflamed paw contributes to EP4 synthesis and export in DRG neurons, thus sensitizing nociceptors during inflammation. We conclude that PGE2/EP4 signalling-induced EP4 externalization in DRG neuron is a novel mechanism underlying nociceptor sensitization and inflammatory pain. Blocking EP4 externalization could open a novel therapeutic avenue to treat inflammatory pain.