Role of prostaglandin E2 in the synthesis of the pro‐inflammatory cytokine interleukin‐6 in primary sensory neurons: an in vivo and in vitro study

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 ...

Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation

“…10,17 Indeed, peripheral nerve injury induces the increase in IL-6 in both the DRG and spinal cord, which is in agreement with our results. The increase in IL-6 may be linked to various pathways including the activation of EP4 receptors by prostaglandin 2 18 and signaling pathways involving the TNF-α receptor and nuclear factor κB. 19 It is plausible that SCS modulates the activation of these pathways and reduces the expression of IL-6 in the DRG.…”

Targeting cytokines for treatment of neuropathic pain

“…Early animal studies have shown that there is a local increase in IL-6 mRNA and protein levels following peripheral nerve injury [60–63]. Further studies have suggested that the upregulation of IL-6 may be through a prostaglandin E2-stimulated pathway [64,65]. However, in a rat nerve compression experiment, onset of allodynia immediately followed the compressing injury, whereas IL-6 elevation was delayed [66].…”

Relieving idiopathic dental pain without drugs

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