Neuropathic pain remains a significant clinical challenge due to the limited efficacy and sustainability of existing pharmacological treatments, underscoring the urgent need for mechanism-based therapeutic strategies. In recent years, gene-targeted interventions have emerged as promising modalities capable of modulating key molecular pathways implicated in chronic pain. Approaches such as antisense oligonucleotides and RNA interference have demonstrated encouraging preclinical results by selectively downregulating pain-associated genes. Based on these developments, genome-editing technologies—particularly the clustered regularly interspaced short palindromic repeats (CRISPR) system—have enabled more precise and long-lasting modifications at both the DNA and RNA levels. This review highlights how CRISPR-based approaches in addressing the critical issues of specificity and long-term efficacy in pain gene therapy and exploring the functional roles of key gene targets and regulatory elements. Although challenges such as off-target activity and immunogenic responses remain, growing preclinical evidence supports the feasibility of CRISPR-based approaches in neuropathic pain. Collectively, these developments position CRISPR as a transformative tool to innovate the standard care for persistent pain syndromes and contribute to broader biomedical and pharmaceutical developments through continued refinement of targeting strategies and safety profiles.
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Objective The objective of this systematic review and meta-analysis was to assess the efficacy of exercise in neuropathic pain following traumatic spinal cord injuries.
Methods The search was conducted in MEDLINE, Embase, Scopus, and Web of Science by the end of 2022. Two independent researchers included the articles based on the inclusion and exclusion criteria. A standardized mean difference was calculated for each data and they were pooled to calculate an overall effect size. To assess the heterogeneity between studies, I2 and chi-square tests were utilized. In the case of heterogeneity, meta-regression was performed to identify the potential source.
Results Fifteen preclinical studies were included. Meta-analysis demonstrated that exercise significantly improves mechanical allodynia (standardized mean difference [SMD], -1.59; 95% confidence interval [CI], -2.16 to -1.02; p < 0.001; I2 = 90.37%), thermal hyperalgesia (SMD, 1.95; 95% CI, 0.96–2.94; p < 0.001), and cold allodynia (SMD, -2.92; 95% CI, -4.4 to -1.43; p < 0.001). The improvement in mechanical allodynia is significantly more in animals with a compression model of SCI (meta-regression coefficient, -1.33; 95% CI, -1.84 to -0.57; p < 0.001) and in mild SCI (p < 0.001). Additionally, the improvement was more prominent if the training was started 7 to 8 days postinjury (coefficient, -2.54; 95% CI, -3.85 to -1.23; p < 0.001) and was continued every day (coefficient, -1.99; 95% CI, -3.07 to -0.9; p < 0.001). Likewise, voluntary exercise demonstrated a significantly more effect size (coefficient, -1.45; 95% CI, -2.67 to -0.23; p = 0.02).
Conclusion Exercise is effective in the amelioration of neuropathic pain. This effect in mechanical allodynia is more prominent if voluntary, continuous training is initiated in the subacute phase of mild SCI.
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Objective Neuropathic pain is a common secondary complication of spinal cord injury (SCI). N-methyl-D-aspartate (NMDA) receptor activation is critical for hypersensitivity in neuropathic pain. This activation requires the binding of both glutamate and the D-serine co-agonist to the NMDA glycine site. We evaluated the effects of D-serine on neuropathic pain after SCI and explored the underlying molecular mechanisms.
Methods Anesthetized rats underwent T9 spinal cord contusion (130 kdyn). D-serine (500 and 1,000 mg/kg) and MK-801 hydrogen maleate (2.0 mg/kg) were injected daily for 2 weeks, starting the day after SCI. Functional outcomes were assessed according to the Basso, Beattie, and Bresnahan scale, while histological outcomes were evaluated based on lesion volume and spared tissue area. Mechanical allodynia and thermal hyperalgesia were evaluated by measuring the withdrawal threshold of a von Frey filament and hot/cold plate latency. Western blotting was performed to determine the expression levels of Trpv1, Nav1.9, calcitonin gene-related peptide (CGRP), and β-actin in damaged tissue.
Results The withdrawal threshold values and latency of the D-serine group were significantly lower than those of the noninjection group. The MK-801 group showed higher threshold values and latencies than the other groups. Western blotting showed increased Nav1.9 and Trpv1 levels and lower CGRP levels in the D-serine group, whereas the MK-801 group showed the opposite results.
Conclusion D-serine increases neuropathic pain after traumatic SCI by mediating the NMDA receptor. NMDA receptor antagonists alleviate neuropathic pain after traumatic SCI.
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Traumatic spinal cord injury (SCI) is the devastating neurological damage to the spinal cord that becomes more complicated in the secondary phase. The secondary injury comes with inevitable long-lasting complications, such as chronic neuropathic pain (CNP) and spasticity which interfere with day to day activities of SCI patients. Mechanisms underlying CNP post-SCI are complex and remain refractory to current medical treatment. Due to the damage, extensive inhibitory, excitatory tone dysregulation causes maladaptive synaptic transmissions, further altering the nociceptive and nonnociceptive pathways. Excitotoxicity mediated GABAergic cell loss, downregulation of glutamate acid decarboxylase enzyme, upregulation of gamma-aminobutyric acid (GABA) transporters, overactivation of glutamate receptors are some of the key evidence for hypoactive inhibitory tone contributing to CNP and spasticity post-SCI. Restoring the inhibitory GABAergic tone and preventing damage-induced excitotoxicity by employing various strategies provide neuroprotective and analgesic effects. The present article will discuss CNP and spasticity post-SCI, understanding their pathophysiological mechanisms, especially GABA-glutamate-related mechanisms, therapeutic interventions targeting them, and progress regarding how regulating the excitatory-inhibitory tone may lead to more targeted treatments for these distressing complications. Taking background knowledge of GABAergic analgesia and recent advancements, we aim to highlight how far we have reached in promoting inhibitory GABAergic tone for SCI-CNP and spasticity.
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