Korean Journal of Pain最新文献

Background: There is converging evidence that indicates that the nucleus accumbens (NAc) plays a substantial role in pain modulation and analgesic drug responses. Here, the role of the NAc dopaminergic signaling in the development of morphine tolerance in a rat neuropathic pain model was explored.

Methods: Morphine tolerance was induced by twice daily administration of intrathecal morphine in spinal nerve-ligated animals. The extracellular dopamine level in the NAc was measured by microdialysis study and the effects of dopaminergic receptor agonists microinjected into the NAc on morphine analgesic tolerance were evaluated behaviorally. Using immunohistochemical techniques, dopaminergic fiber expression in the NAc was assessed. Additionally, the effects of microglial inhibitor minocycline on the extracellular dopamine level in the NAc and the development of morphine tolerance were investigated.

Results: Microdialysis study demonstrated that the extracellular level of dopamine in the NAc was decreased in morphine tolerant animals. A dopaminergic D1- or D2-like receptor agonist pretreated into the NAc improved analgesic response to morphine in the tolerant animals. By pretreating a microglial inhibitor minocycline with daily morphine administration, the level of extracellular dopamine in the NAc was partially recovered and the development of morphine tolerance was attenuated.

Conclusions: These observations indicate that the decreased dopaminergic neurotransmission in the NAc induced by microglial activation plays a significant role in the development of morphine tolerance. By delineating how alterations in dopamine transmission and related neuroadaptations within the NAc contribute to diminished opioid efficacy, future studies may identify novel molecular and cellular targets for therapeutic intervention.

Background: Pulsed radio frequency (PRF) is a novel therapeutic method for treating neuropathic pain (NP). This study aimed to elucidate the role of NF-E2-Related Factor 2 (Nrf2) in pain signal transduction associated with the mechanism of PRF analgesia action.

Methods: Establishing the spared nerve injury (SNI) rat model and PRF treated model (45 V5 minutes, 45 V15 minutes, 90 V15 minutes), the authors used behavioral testing, western blotting, and enzyme-linked immunosorbent assay methods to verify the analgesic effect of PRF. Secondly, behavioral testing and biomarker analyses were performed in SNI rats that received intrathecally injected calmodulin-dependent protein kinase type II (CaMKII) antagonist, calcitonin gene-related peptide (CGRP) antagonist, or Nrf2 activator.

Results: High-voltage, long-duration PRF significantly alleviated mechanical hypersensitivity in SNI rats. On the 9th day after PRF therapy, Nrf2 and heme oxygenase 1 (HO-1) expression were markedly upregulated, otherwise, CaMKII, phosphorylated level of CaMKII (p-CaMKII), NF-kappa B (NF-κB) p65, and CGRP content were downregulated. Otherwise, intrathecal CaMKII antagonist, CaMKII, p-CaMKII expression, and CGRP content were decreased. Intrathecal Nrf2 activator led to overexpression of Nrf2, while the expression of p-CaMKII, CaMKII, NF-κB p65, and CGRP content were significantly reduced. Additionally, administration of intrathecal CGRP antagonist decreased CGRP content. After the intrathecal injection of these three drugs, the SNI rats' mechanical hypersensitivity was ameliorated.

Conclusions: A novel therapeutic method employing high-voltage, long-duration PRF markedly ameliorated neuropathy, relieving central sensitization by activating the Nrf2 expression-regulated CaMKII/NF-κB signaling pathway blocking Ca²⁺ pain signal transmission.

Neuropathic pain (NP) is a chronic pain condition resulting from damage or disease in the nervous system. It is characterized by hyperalgesia, spontaneous pain, and mechanical allodynia. Due to limited treatment options, NP significantly impairs the quality of life of affected individuals. Recent research has highlighted the critical role of microglia in the initiation and maintenance of NP, however, the underlying mechanisms remain incompletely understood. Existing evidence suggests that signaling pathways, including NF-κB, PI3K/Akt/mTOR, p38MAPK, JAK2/STAT3, and Nrf2/HO-1, contribute to microglial activation and the modulation of NP. This review explores the key activation molecules in these pathways, the microglial phenotype, and associated inflammatory processes. Additionally, the authors summarize the latest literature and application prospects of certain drugs/compounds/ non-invasive treatments, aiming to provide a theoretical basis for the development of novel microglia-targeted therapies.

Background: The spinal nerve ligation (SNL) model induces neuropathic pain through peripheral nerve injury, leading to central sensitization and neuroinflammation. Recent evidence suggests that activation of Mincle (macrophage-inducible C-type lectin) in the spinal cord may also trigger pain hypersensitivity without peripheral nerve injury. This study compared the effects of SNL and spinal Mincle activation on pain behavior and neuroglial activation.

Methods: Pain hypersensitivity was evaluated following a single intrathecal (i.t.) injection of the Mincle ligand, trehalose-6,6'-dibehenate (TDB) at doses of 0.1 μg, 1 μg, or 10 μg (single injection, S-TDB). In a separate group, rats received repeated i.t. TDB injection (10 μg/day for 2 days, R-TDB) or surgery for SNL. Pain behaviors were assessed for 28 days. Spinal expression of microglia (Iba1) and astrocytes (GFAP) was analyzed via immunofluorescence in R-TDB and SNL groups.

Results: I.t. TDB administration at all tested doses produced significant pain hypersensitivity from day 1 to day 28, with no clear dose-dependent effects. Repeated i.t. TDB administration led to greater mechanical allodynia than S-TDB, but thermal responses were similar. Compared to SNL, the R-TDB group produced a comparable pain hypersensitivity to SNL but exhibited faster activation of microglia and astrocytes.

Conclusions: Spinal Mincle receptor activation via i.t. TDB induces persistent pain hypersensitivity in the absence of peripheral nerve injury, accompanied by a more rapid neuroinflammatory response than that observed in the SNL model. These findings support Mincle activation as a potential experimental model for neuroinflammationassociated neuropathic pain.

Background: Neuropathic pain (NP) is a complex and intractable chronic pain condition. This study aims to clarify the functional role of lncRNA HOTTIP in NP.

Methods: A chronic constriction injury (CCI) surgery was used to establish a NP rat model. Lipopolysaccharide (LPS) stimulation was employed to activate BV2 cells. Intrathecal administration of HOTTIP-targeting lentiviral vectors and antagomiR-216a-5p was performed to lower HOTTIP and miR-216a-5p expression. RT-qPCR analyzed HOTTIP, miR-216a-5p, and inflammatory markers (cyclooxygenase-2 [COX-2], inducible nitric oxide synthase [INOS], toll-like receptor 4 [TLR4]) in rat dorsal root ganglion and BV2 cells to evaluate their roles in NP, while also tracking pain behavior changes in CCI rats to correlate molecular targets with pain perception. ELISA measured anti-inflammatory (interleukin [IL]-4) and pro-inflammatory (IL-6, tumor necrosis factor [TNF]-α) factor levels to quantify inflammation and evaluate inflammatory response severity. A specific binding relationship between HOTTIP and miR-216a-5p was evaluated using bioinformatics prediction, dual-luciferase reporter assays, and RNA pull-down techniques.

Results: In a rat model of CCI, inhibition of HOTTIP attenuated NP, decreased pro-inflammatory mediators (TNF-α, IL-6, COX-2, INOS, TLR4), and increased IL-4. In LPS-induced BV2 cells, inhibition of HOTTIP also exhibited antiinflammatory effects. HOTTIP targeted binding to miR-216a-5p. Inhibition of miR-216a-5p significantly counteracted the inhibitory effects of silencing HOTTIP on NP and neuroinflammatory responses. In addition, Janus kinase 2 (JAK2) was found to be a direct target of miR-216a-5p.

Conclusions: HOTTIP contributes to the worsening of NP and neuroinflammation by modulating the miR-216a-5p/JAK2 pathway, exerting analgesic protective effects, indicating its potential as a therapeutic target for NP.

Neuropathic pain remains a major challenge in pain management because of its complex mechanisms and suboptimal response to conventional treatments, which often provide incomplete relief and carry the risk of adverse effects. Injections of 5% glucose in water (D5W) delivered via intradermal, subcutaneous, fascial, or perineural glucopuncture have emerged as a minimally invasive and safe therapeutic option. Although the exact mechanism has not been fully elucidated, the proposed pathways include transient receptor potential vanilloid 1 modulation, suppression of neurogenic inflammation, and stabilization of C-fiber excitability. Clinical studies, ranging from case reports to randomized controlled trials, have suggested the efficacy of this approach in postherpetic neuralgia, entrapment neuropathies, chronic tendinopathies, and fascial pain, with minimal complications. Unlike prolotherapy, glucopuncture uses isotonic glucose (D5W), and primarily exerts neuromodulatory rather than regenerative effects. Current evidence, while limited, indicates meaningful and sustained pain relief in selected neuropathic conditions with a favorable safety profile and low procedural complexity. This review outlines key mechanisms, clinical outcomes, differences between related interventions, and clinical considerations.