Circular RNA-GRIN2B Suppresses Neuropathic Pain by Targeting the NF-κB/SLICK Pathway.

The role of circular RNAs (circRNAs) in neuropathic pain is linked to the fundamental physiological mechanisms involved. However, the exact function of circRNAs in the context of neuropathic pain is still not fully understood. The functional impact of circGRIN2B on the excitability of dorsal root ganglion (DRG) neurons was investigated using siRNA or overexpression technology in conjunction with fluorescence in situ hybridization and whole-cell patch-clamp technology. The therapeutic efficacy of circGRIN2B in treating neuropathic pain was confirmed by assessing the pain threshold in a chronic constrictive injury (CCI) model. The interaction between circGRIN2B and NF-κB was examined through RNA pulldown, RIP, and mass spectrometry assays. CircGRIN2B knockdown significantly affected the action potential discharge frequency and the sodium-dependent potassium current flux (SLICK) in DRG neurons. Furthermore, knockdown of circGRIN2B dramatically reduced the SLICK channel protein and mRNA expression in vivo and in vitro. Our research confirmed the interaction between circGRIN2B and NF-κB. These findings demonstrated that circGRIN2B promotes the transcription of the SLICK gene by binding to NF-κB. In CCI rat models, the overexpression of circGRIN2B has been shown to hinder the progression of neuropathic pain, particularly by reducing mechanical and thermal hyperalgesia. Additionally, this upregulation significantly diminished the levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α in the DRG. Upon reviewing these findings, it was determined that circGRIN2B may mitigate the onset of neuropathic pain by modulating the NF-κB/SLICK pathway.

Compounded Pain Formulations: What is the Evidence?

Pain syndromes are among the most widespread, costly, and debilitating of all neurological disorders. The number of patients living with chronic pain is expected to increase with the aging population and with the rise in obesity and diabetes across the nation. This type of pain is often insensitive to the traditional pain pharmacopeia or surgical intervention. Over the last 10 years the number of prescriptions that have been compounded by pharmacists has increased dramatically. There are a number of drugs in the area of pain management that have been formulated and compounded by pharmacists to treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic neuralgia, joint pain, arthritis, and a variety of other conditions. A significant portion of these compounded analgesic preparations is made up of topical/transdermal dosage forms such as gels and creams. While the efficacy and doses of these drugs in systemic dosage forms have been widely established, little is known about the permeation and efficacy of these compounds from topical/transdermal gels. This review will provide an overview of chronic pain as a disease, the mechanisms of chronic pain, current treatment approaches to chronic pain, and a discussion of the drugs that are typically compounded into these topical formulations and studied in clinical trials.

[Interventional effect and inflammatory regulation mechanism of dihydroartemisinin combined with pregabalin on neuropathic pain mice].

This study aims to clarify the effects of dihydroartemisinin(DHA) combined with pregabalin(PGB) on neuropathic pain(NP) in mice and explore the neuroinflammatory regulatory mechanism. NP mice model was established using spinal nerve ligation, whereas the sham group exposed the spinal nerve without ligation. The mice were randomly divided into sham group, model group, PGB groups of low, medium, and high doses(PGB-L, PGB-M, and PGB-H, with 22, 45, and 91 mg·kg~(-1)), DHA group(16 mg·kg~(-1)), and DHA combined with PGB groups of low, medium, and high doses(DHA + PGB-L, DHA + PGB-M, and DHA + PGB-H). Administration by gavage 18 days after modeling. Von Frey and cold plate were used to detect mechanical pain threshold and cold pain sensitivity in mice. The tail suspension test and forced swimming test were used to investigate depressive behavior, and the open field test was used to estimate anxiety behavior. The Morris water maze was used to evaluate cognitive function. Liquid suspension chip technology was used to quantitatively analyze immune inflammation-related factors. Immunofluorescence was used to detect the expression of CC chemokine ligand 3(CCL3) and transmembrane protein 119(TMEM119). The results showed that compared with the sham group, the mechanical pain and cold pain sensitivity thresholds of the model group were significantly reduced, and the struggle time was significantly increased in the tail suspension test and forced swimming test. The activity time in the central area was significantly reduced in the open field test. The residence time in the second/fourth quadrant was significantly longer than that in other quadrants, and the latency time of platform climbing significantly increased after platform withdrawal in the Morris water maze experiment. The expression of CCL3 was significantly increased; the number of TMEM119 positive cells and the cell body area were significantly increased. Compared with the model group, the DHA + PGB-M group showed a significant increase in mechanical pain and cold pain sensitivity thresholds, as well as a significant increase in struggle time in the tail suspension test and forced swimming test. The activity time in the central area of the open field test was significantly reduced. The residence time in the second/fourth quadrant was significantly shorter than that in other quadrants, and the latency time of platform climbing after platform withdrawal was significantly reduced. Compared with the PGB-M group, the mechanical pain threshold of D14-17 in the DHA + PGB-M group was significantly increased, and the struggle time during forced swimming was significantly increased. The residence time in the second/fourth quadrant of the Morris water maze was significantly shorter than that in other quadrants. Compared with the model group, the expression of CCL3, the number of TMEM119 positive cells, and the cell body area in the DHA + PGB-M group were significantly decreased. This study indicates that DHA + PGB can enhance the analgesic effect of PGB on NP mice, break through the limitations of PGB tolerance, and make up for the shortcomings of PGB in antidepressant and cognitive improvement. Its mechanism may be related to regulating neuroinflammation by inhibiting the activation of microglial cells and expression of CCL3.

[Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury].

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 µL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 µm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) µg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) µg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of "automatic blood collection-microdialysis/PK-PD" in the research on neuropathic pain.

Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. METHODS: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. RESULTS: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. CONCLUSIONS: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. CLINICAL TRIAL REGISTRY NUMBER: NCT02560545.

Pregabalin-induced delayed cutaneous hypersensitivity reaction occurring after 40 days of use: a case report.

Pregabalin is the first-line treatment for neuropathic pain. Cases of cutaneous hypersensitivity reactions caused by pregabalin generally occur within 2 weeks of initiating medication. We report a rare case of a delayed cutaneous hypersensitivity reaction caused by pregabalin, which was confirmed by a drug provocation test. A 72-year-old man with severe herpes zoster neuralgia developed maculopapular drug eruption covering 80% to 90% of his total body surface area after 40 days of combined multidrug analgesia. A drug provocation test for pregabalin was positive. The time interval between initiating medication and the onset of the patient's rash was the longest and he also had the largest area of skin affected compared with patients with a similar condition in previous related reports. Remaining vigilant for possible adverse cutaneous hypersensitivity reactions during treatment is important because of the long-term course of pregabalin treatment for neuropathic pain.

Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Serotonin norepinephrine reuptake inhibitors in managing neuropathic pain following spinal and non-spinal surgery: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: While serotonin norepinephrine reuptake inhibitors (SNRIs) offer promise in managing Post-surgical neuropathic pain (PSNP), uncertainties remain. This study aims to evaluate the effectiveness and adverse events of SNRIs in managing PSNP. METHODS: Systematic searches of PubMed, Embase, and Cochrane databases up to January 1st 2023 identified randomized controlled trials (RCTs) comparing SNRIs to placebo for PSNP. The primary outcome measures were pain at rest and adverse events post-surgery. Subgroup analyses were conducted based on surgical type and specific SNRIs. RESULTS: A total of 19 RCTs, encompassing 1440 participants (719 in the SNRI group vs 721 in the placebo group), met the inclusion criteria and were included. The pooled results demonstrated that pain scores were significantly lower in patients treated with SNRIs at 2 hours (MD:-0.26; 95%CI: -0.47 to -0.04; p=0.02), 6 hours (MD:-0.68; 95%CI: -1.01 to -0.34; p<0.0001), 24 hours (MD:-0.54; 95%CI: -0.99 to -0.09; p=0.02), and 48 hours (MD:-0.66; 95%CI: -1.23 to -0.10; p=0.02) post-surgery. In terms of adverse events, dizziness (OR:2.53; 95%CI: 1.34-4.78; p=0.004) and dry mouth (OR:2.21; 95%CI: 1.25-3.92; p=0.007) were significantly higher in the SNRIs group. Subgroup analysis showed that SNRI was found to significantly lower the 24-hour pain score after spinal surgery (MD:-0.45; 95%CI: -0.84 to -0.05; p=0.03). Duloxetine (MD:-0.63; 95%CI: -1.15 to -0.11; p=0.02) had a significant effect in lowering the 24-hour pain score at rest compared to placebo, whereas venlafaxine did not. CONCLUSIONS: SNRIs yielded considerable pain score reductions across multiple post-surgical intervals, although accompanied by an increased incidence of dizziness and dry mouth.

The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain.

Refractory peripheral neuropathy can occur as a side effect in 60-70% of patients receiving Paclitaxel (PTX). Yokukansan (YKS) is a Japanese herbal medicine reported to have analgesic properties for entrapment nerve injuries. Therefore, we investigated the anti-allodynic effect of Yokukansan on Paclitaxel-induced neuropathic pain. All experiments used 6-week-old male Sprague Dawley rats. Mechanical allodynia was evaluated using a dynamic plantar aesthesiometer. A mobile touch-stimulator unit applied progressively increasing force to the mid-plantar region of the hind paw in a vertical direction until the animal withdrew its paw. This was carried out before the Paclitaxel administration and during the first, second, third, and fourth weeks. Using a rat model of PTX-induced neuropathic pain (PTX rat), we injected PTX (intraperitoneally, 2 mg/kg) five times every 2 days. Using the dynamic plantar test, we evaluated the anti-allodynic effect of YKS (orally administered, 1 g/kg). YKS administration on a daily basis significantly enhanced the withdrawal threshold in PTX rats and reduced the expression level of activated microglia immunostaining with Iba1, a specific marker for microglia. The intrathecal administration of WAY-100635 (5-hydroxytryptamine [5-HT]1A receptor antagonist) and Ketanserin (5-HT2A/2C receptor antagonist) inhibited the protective effects of YKS. YKS exhibited an anti-allodynic effect in a rodent model of PTX-induced neuropathic pain by reducing the sensitivity to pain stimuli. These results suggest that Yokukansan may activate 5-HT receptors in the spinal cord, mediating Paclitaxel-induced neuropathic pain.

Cannabidiol and it fluorinate analog PECS-101 reduces hyperalgesia and allodynia in trigeminal neuralgia via TRPV1 receptors.

Trigeminal neuralgia (TN) is an intense and debilitating orofacial pain. The gold standard treatment for TN is carbamazepine. This antiepileptic drug provides pain relief with limited efficacy and side effects. To study the antinociceptive potential of cannabidiol (CBD) and its fluorinated analog PECS-101 (former HUF-101), we induced unilateral chronic constriction injury of the infraorbital nerve (IoN-CCI) in male Wistar rats. Seven days of treatment with CBD (30 mg/kg), PECS-101 (3, 10, and 30 mg/kg), or carbamazepine (10 and 30 mg/kg) reduced allodynia and hyperalgesia responses. Unlike carbamazepine, CBD and PECS-101 did not impair motor activity. The relief of the hypersensitive reactions has been associated with transient receptor potential vanilloid type 1 (TRPV1) modulation in the trigeminal spinal nucleus. CBD (30 mg/kg) and PECS-101 (10 and 30 mg/kg) reversed the increased expression of TRPV1 induced by IoN-CCI in this nucleus. Using a pharmacological strategy, the combination of the selective TRPV1 antagonist (capsazepine-CPZ - 5 mg/kg) with sub-effective doses of CBD (3 and 10 mg/kg) is also able to reverse the IoN-CCI-induced allodynia and hyperalgesia responses. This effect was accompanied by reduced TRPV1 protein expression in the trigeminal spinal nucleus. Our results suggest that CBD and PECS-101 may benefit trigeminal neuralgia without motor coordination impairments. PECS-101 is more potent against the hypernociceptive and motor impairment induced by TN compared to CBD and carbamazepine. The antinociceptive effect of these cannabinoids is partially mediated by TRPV1 receptors in the caudal part of the trigeminal spinal nucleus, the first central station of orofacial pain processing.

A novel microglia-targeting strategy based on nanoparticle-mediated delivery of miR-26a-5p for long-lasting analgesia in chronic pain.

Accumulating evidence supports the notion that microglia play versatile roles in different chronic pain conditions. However, therapeutic strategies of chronic pain by targeting microglia remain largely overlooked. This study seeks to develop a miRNA-loaded nano-delivery system by targeting microglia, which could provide a decent and long-lasting analgesia for chronic pain. Surface aminated mesoporous silica nanoparticles were adopted to load miR-26a-5p, a potent analgesic miRNA, by electrostatic adsorption, which can avoid miR-26a-5p is rapidly released and degraded. Then, targeting peptide MG1 was modified on the surface of aminated mesoporous silica particles for microglia targeting. In peripheral nerve injury induced neuropathic pain model, a satisfactory anti-allodynia effect with about 6 weeks pain-relief duration were achieved through targeting microglia strategy, which decreased microglia activation and inflammation by Wnt5a, a non-canonical Wnt pathway. In inflammatory pain and chemotherapy induced peripheral neuropathic pain, microglia targeting strategy also exhibited more efficient analgesia and longer pain-relief duration than others. Overall, we developed a microglia-targeting nano-delivery system, which facilitates precisely miR-26a-5p delivery to enhance analgesic effect and duration for several chronic pain conditions.

Subcutaneous sodium valproate in palliative care: A systematic review.

BACKGROUND: Seizures are an important palliative symptom, the management of which can be complicated by patients' capacity to swallow oral medications. In this setting, and the wish to avoid intravenous access, subcutaneous infusions may be employed. Options for antiseizure medications that can be provided subcutaneously may be limited. Subcutaneous sodium valproate may be an additional management strategy. AIM: To evaluate the published experience of subcutaneous valproate use in palliative care, namely with respect to effectiveness and tolerability. DESIGN: A systematic review was registered (PROSPERO CRD42023453427), conducted and reported according to PRISMA reporting guidelines. DATA SOURCES: The databases PubMed, EMBASE and Scopus were searched for publications until August 11, 2023. RESULTS: The searches returned 429 results, of which six fulfilled inclusion criteria. Case series were the most common study design, and most studies included <10 individuals who received subcutaneous sodium valproate. There were three studies that presented results on the utility of subcutaneous sodium valproate for seizure control, which described it to be an effective strategy. One study also described it as an effective treatment for neuropathic pain. The doses were often based on presumed 1:1 oral to subcutaneous conversion ratios. Only one study described a local site adverse reaction, which resolved with a change of administration site. CONCLUSIONS: There are limited data on the use of subcutaneous sodium valproate in palliative care. However, palliative symptoms for which subcutaneous sodium valproate have been used successfully are seizures and neuropathic pain. The available data have described few adverse effects, supporting its use with an appropriate degree of caution.

Targeting TRP channels for pain relief: A review of current evidence from bench to bedside.

Several decades of research support the involvement of transient receptor potential (TRP) channels in nociception. Despite the disappointments of early TRPV1 antagonist programs, the TRP family remains a promising therapeutic target in pain disorders. High-dose capsaicin patches are already in clinical use to relieve neuropathic pain. At present, localized injections of the side-directed TRPV1 agonist capsaicin and resiniferatoxin are undergoing clinical trials in patients with osteoarthritis and bone cancer pain. TRPA1, TRPM3, and TRPC5 channels are also of significant interest. This review discusses the role of TRP channels in human pain conditions.

Blocking Pannexin 1 Channels Alleviates Peripheral Inflammatory Pain but not Paclitaxel-Induced Neuropathy.

BACKGROUND: Pannexin1 (Panx1) is a membrane channel expressed in different cells of the nervous system and is involved in several pathological conditions, including pain and inflammation. At the central nervous system, the role of Panx1 is already well-established. However, in the periphery, there is a lack of information regarding the participation of Panx1 in neuronal sensitization. The dorsal root ganglion (DRG) is a critical structure for pain processing and modulation. For this reason, understanding the molecular mechanism in the DRG associated with neuronal hypersensitivity has become highly relevant to discovering new possibilities for pain treatment. Here, we aimed to investigate the role of Panx1 in acute nociception and peripheral inflammatory and neuropathic pain by using two different approaches. METHODS: Rats were treated with a selective Panx1 blocker peptide (10Panx) into L5-DRG, followed by ipsilateral intraplantar injection of carrageenan, formalin, or capsaicin. DRG neuronal cells were pre-treated with 10Panx and stimulated by capsaicin to evaluate calcium influx. Panx1 knockout mice (Panx1-KO) received carrageenan or capsaicin into the paw and paclitaxel intraperitoneally. The von Frey test was performed to measure the mechanical threshold of rats' and mice's paws before and after each treatment. RESULTS: Pharmacological blockade of Panx1 in the DRG of rats resulted in a dose-dependent decrease of mechanical allodynia triggered by carrageenan, and nociception decreased in the second phase of formalin. Nociceptive behavior response induced by capsaicin was significantly lower in rats treated with Panx1 blockade into DRG. Neuronal cells with Panx1 blockage showed lower intracellular calcium response than untreated cells after capsaicin administration. Accordingly, Panx1-KO mice showed a robust reduction in mechanical allodynia after carrageenan and a lower nociceptive response to capsaicin. A single dose of paclitaxel promoted acute mechanical pain in wildtype (WT) but not in Panx1-KO mice. Four doses of chemotherapy promoted chronic mechanical allodynia in both genotypes, although Panx1-KO mice had significant ablation in the first eight days. CONCLUSION: Our findings suggest that Panx1 is critical for developing peripheral inflammatory pain and acute nociception involving transient receptor potential vanilloid subtype 1 (TRPV1) but is not essential for neuropathic pain chronicity.

Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.6, Nav1.7, and Nav1.8. In this study, we screened in virtual hits from dihydrobenzofuran and 3-hydroxyoxindole hybrid molecules against Navs via a veratridine (VTD)-based calcium imaging method. The results showed that one of the molecules, 3g, could inhibit VTD-induced neuronal activity significantly. Voltage clamp recordings demonstrated that 3g inhibited the total Na+ currents of DRG neurons in a concentration-dependent manner. Biophysical analysis revealed that 3g slowed the activation, meanwhile enhancing the inactivation of the Navs. Additionally, 3g use-dependently blocked Na+ currents. By combining with selective Nav inhibitors and a heterozygous expression system, we demonstrated that 3g preferentially inhibited the TTX-S Na+ currents, specifically the Nav1.7 current, other than the TTX-R Na+ currents. Molecular docking experiments implicated that 3g binds to a known allosteric site at the voltage-sensing domain IV(VSDIV) of Nav1.7. Finally, intrathecal injection of 3g significantly relieved mechanical pain behavior in the spared nerve injury (SNI) rat model, suggesting that 3g is a promising candidate for treating chronic pain.

Effects of Nutraceutical Compositions Containing Rhizoma Gastrodiae or Lipoic Acid in an In Vitro Induced Neuropathic Pain Model.

BACKGROUND: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine). METHOD: To assess the combination's absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy. RESULTS: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site. CONCLUSION: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways.

Sodium aescinate ameliorates chronic neuropathic pain in male mice via suppressing JNK/p38-mediated microglia activation.

OBJECTIVE: A study confirmed that sodium aescinate (SA) can effectively relieve bone cancer pain, but its role in neuropathic pain (NP) remains confused. METHODS: Eighty male mice were randomly divided into four groups: sham+vehicle, sham+SA (40 µg/L, intrathecal injection), chronic contraction injury (CCI)+vehicle, CCI+SA. Behavioral assessments were used to evaluate the locomotor activity and paw withdrawal threshold (PWT) of mice. At the end of the study, spinal cord tissues were collected for histopathological analysis. The JNK/p38 signaling activation, Iba-1 expression, pro-inflammatory cytokines levels, and microglia subtype were assessed by western blotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and flow cytometry with CD86/CD206, respectively. RESULTS: Early treatment with SA delayed the development of mechanical allodynia in CCI mice. Repeated SA treatment could prominently increase the reduction of PWT induced by CCI, and improve the locomotor activity of CCI mice. Mechanically, CCI surgery induced significant up-regulation of p-JNK and p-p38 protein levels, increased number and M1/M2 ratio of microglia, as well as pro-inflammatory factors in the spinal cords of mice, which could be blocked after SA administration. CONCLUSIONS: SA might suppress the activation of microglia and neuroinflammation by selectively inhibiting the JNK/p38 signaling pathway, thereby alleviating CCI-induced NP in male mice.

Synthesis and Antiallodynic Activity of Cannabidiol Analogue on Peripheral Neuropathy in Mice.

Cannabidiol (CBD) is a substance that exerts several therapeutic actions, including analgesia. CBD is generally administered orally, but its poor water solubility and metabolism impair its bioavailability. Thus, the development of molecules with better pharmacokinetic profile from cannabidiol becomes an interesting strategy for the design of novel analgesic drugs for the relief of painful conditions that are difficult to manage clinically, such as neuropathic pain. In the present study, an unprecedented analogue of CBD (1) was synthesized and some of its physicochemical properties were evaluated in silico as well as its stability in an acid medium. Additionally, its effect was investigated in a model of neuropathic pain induced by the chemotherapy drug paclitaxel in mice, in comparison with cannabidiol itself. Cannabidiol (20 mg/kg), pregabalin (30 mg/kg), or analogue 1 (5, 10, and 20 mg/kg), administered on the 14th day after the first administration of paclitaxel, attenuated the mechanical allodynia of the sensitized animals. The antinociceptive activity of analogue 1 was attenuated by previous administration of a cannabinoid CB1 receptor antagonist, AM 251, which indicates that its mechanism of action is related to the activation of CB1 receptors. In conclusion, the CBD analogue 1 developed in this study shows great potential to be used in the treatment of neuropathic pain.

Pharmacological and Non-pharmacological Approaches for the Management of Neuropathic Pain in Multiple Sclerosis.

Multiple sclerosis is a chronic inflammatory disease that affects the central nervous system and can cause various types of pain including ongoing extremity pain, Lhermitte's phenomenon, trigeminal neuralgia, and mixed pain. Neuropathic pain is a major concern for individuals with multiple sclerosis as it is directly linked to myelin damage in the central nervous system and the management of neuropathic pain in multiple sclerosis is challenging as the options available have limited efficacy and can cause unpleasant side effects. The literature search was conducted across two databases, PubMed, and Google Scholar. Eligible studies included clinical trials, observational studies, meta-analyses, systematic reviews, and narrative reviews. The objective of this article is to provide an overview of literature on pharmacological and non-pharmacological strategies employed in the management of neuropathic pain in multiple sclerosis. Pharmacological options include cannabinoids, muscle relaxants (tizanidine, baclofen, dantrolene), anticonvulsants (benzodiazepines, gabapentin, phenytoin, carbamazepine, lamotrigine), antidepressants (duloxetine, venlafaxine, tricyclic antidepressants), opioids (naltrexone), and botulinum toxin variants, which have evidence from various clinical trials. Non-pharmacological approaches for trigeminal neuralgia may include neurosurgical methods. Non-invasive methods, physical therapy, and psychotherapy (cognitive behavioral therapy, acceptance and commitment therapy and mindfulness-based stress reduction) may be recommended for patients with neuropathic pain in multiple sclerosis. The choice of treatment depends on the severity and type of pain as well as other factors, such as patient preferences and comorbidities. There is a pressing need for healthcare professionals and researchers to prioritize the development of better strategies for managing multiple sclerosis-induced neuropathic pain.

Tumor necrosis factor α-induced protein 8-like-2 controls microglia phenotype via metabolic reprogramming in BV2 microglial cells and responses to neuropathic pain.

Microglial are major players in neuroinflammation that have recently emerged as potential therapeutic targets for neuropathic pain. Glucose metabolic programming has been linked to differential activation state and function in microglia. Tumor necrosis factor α-induced protein 8-like-2 (TNFAIP8L2) is an important component in regulating the anti-inflammatory response. However, the role of TNFAIP8L2 in microglia differential state during neuropathic pain and its interplay with glucose metabolic reprogramming in microglia has not yet been determined. Thus, we aimed to investigate the role of TNFAIP8L2 in the status of microglia in vitro and in vivo. BV2 microglial cells were treated with lipopolysaccharides plus interferon-gamma (LPS/IFNγ) or interleukin-4 (IL-4) to induce the two different phenotypes of microglia in vitro. In vivo experiments were conducted by chronic constriction injury of the sciatic nerve (CCI). We investigated whether TNFAIP8L2 regulates glucose metabolic programming in BV2 microglial cells. The data in vitro showed that TNFAIP8L2 lowers glycolysis and increases mitochondrial oxidative phosphorylation (OXPHOS) in inflammatory microglia. Blockade of glycolytic pathway abolished TNFAIP8L2-mediated differential activation of microglia. TNFAIP8L2 suppresses inflammatory microglial activation and promotes restorative microglial activation in BV2 microglial cells and in spinal cord microglia after neuropathic pain. Furthermore, TNFAIP8L2 controls differential activation of microglia and glucose metabolic reprogramming through the MAPK/mTOR/HIF-1α signaling axis. This study reveals that TNFAIP8L2 plays a critical role in neuropathic pain, providing important insights into glucose metabolic reprogramming and microglial phenotypic transition, which indicates that TNFAIP8L2 may be used as a potential drug target for the prevention of neuropathic pain.