Resolvin D1 Inhibits Mechanical Hypersensitivity in Sciatica by Modulating the Expression of Nuclear Factor-κB, Phospho-extracellular Signal–regulated Kinase, and Pro- and Antiinflammatory Cytokines in the Spinal Cord and Dorsal Root Ganglion

Abstract

Background Accumulating evidence indicates that spinal inflammatory and immune responses play an important role in the process of radicular pain caused by intervertebral disk herniation. Resolvin D1 (RvD1) has been shown to have potent antiinflammatory and antinociceptive effects. The current study was undertaken to investigate the analgesic effect of RvD1 and its underlying mechanism in rat models of noncompressive lumbar disk herniation. Methods Rat models of noncompressive lumber disk herniation were established, and mechanical thresholds were evaluated using the von Frey test during an observation period of 21 days (n = 8/group). Intrathecal injection of vehicle or RvD1 (10 or 100 ng) was performed for three successive postoperative days. On day 7, the ipsilateral spinal dorsal horns and L5 dorsal root ganglions (DRGs) were removed to assess the expressions of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-10, and transforming growth factor-β1 (TGF-β1) and the activation of nuclear factor-κB (NF-κB)/p65 and phospho-extracellular signal–regulated kinase (p-ERK) signaling (n = 30/group). Results The application of nucleus pulposus to L5 DRG induced prolonged mechanical allodynia, inhibited the production of IL-10 and TGF-β1, and up-regulated the expression of TNF-α, IL-1β, NF-κB/p65, and p-ERK in the spinal dorsal horns and DRGs. Intrathecal injection of RvD1 showed a potent analgesic effect, inhibited the up-regulation of TNF-α and IL-1β, increased the release of IL-10 and TGF-β1, and attenuated the expression of NF-κB/p65 and p-ERK in a dose-dependent manner. Conclusions The current study showed that RvD1 might alleviate neuropathic pain via regulating inflammatory mediators and NF-κB/p65 and p-ERK pathways. Its antiinflammatory and proresolution properties may offer novel therapeutic approaches for the management of neuropathic pain.

CXCL12/CXCR4 signaling-mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats

“…Previous studies have shown that peripheral nerve injury or inflammation also lead to significant increased activations of CXCL12/CXCR4, ERK, and NF-kB signaling in DRG. 9,34,35 Because the dural membrane in rats extends onto the capsule of the DRG, the proximal face of the DRG is in direct continuity with the subarachnoid space. 30 Therefore, the effects of intrathecal injection of AMD3100 or CXCL12 neutralizing antibody may partially work in DRG in our present study.…”

Palmitoylation of δ-catenin promotes kinesin-mediated membrane trafficking of Na v 1.6 in sensory neurons to promote neuropathic pain

“…Considering the potential that the drugs dispersed to both the DRG and spinal cord after intrathecal injection, the present study cannot exclude the possibility that the anti-allodynia effect of intrathecal delivery of the -catenin shRNA or the PAT inhibitor 2-BP might partially result from drug action in the spinal dorsal horn, but we, nonetheless, demonstrated their effect to modulate Na v 1.6 membrane trafficking and current density in DRG neurons. TNF-, a proinflammatory cytokine critically involved in the pathogenesis of neuropathic pain (26,33), was an inducing signal, enhanced by oxaliplatin, to promote increased abundance of the palmitoylase DHHC3 and its interaction/colocalization with -catenin in DRG sensory neurons and mechanical allodynia in rats. Hence, these results established that palmitoylation of -catenin, potentially by DHHC3, prompted the membrane-directed trafficking of Na v 1.6 in sensory neurons and contributed to the development of neuropathic pain.…”

Prevention of Chronic Post-Thoracotomy Pain in Rats By Intrathecal Resolvin D1 and D2: Effectiveness of Perioperative and Delayed Drug Delivery

“…29,37,38,47,49,51 Resolvins have direct actions on the recruitment and migration of neutrophils and macrophages, underlying the resolution phase of inflammation 48,51–53 , and they also alter peripheral and central nervous system responses to inflammation and injury, through direct actions on neurons and glia. 65 Since the drugs that are traditionally used to treat inflammatory and post-operative pain, namely opiates and cyclo-oxygenase-2 (COX-2) inhibitors, have unwanted side effects, there is a need to find new approaches and compounds that will be more selective in their actions and have fewer adverse actions.…”