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Chemotherapy-induced peripheral neuropathy (CIPN) is the most common side-effect of anti-cancer therapy. To date, there are no clinically effective analgesics that could prevent and treat CIPN. However, the exact pathogenesis of CIPN is still unclear. In the present study, we use the paclitaxel-induced peripheral neuropathy (PIPN) model, aiming to better understand the transcriptomic level of the Dorsal root ganglia (DRG) neurons in rats with PIPN. mRNA from each DRG sample was reverse transcribed to cDNA and sequenced using next-generation high throughput sequencing technology. Quantitative RT-PCR verification was used to confirm the identified Differentially expressed genes (DEGs) in the DRG of PIPN rats. RNAseq results have identified 384 DEGs (adjusted P-value < 0.05; fold change ≥ 2) in the DRG of rats 14 days after paclitaxel injection in total, including 97 up-regulated genes, and 287 down-regulated genes. GO analysis revealed that these DEGs were majorly involved in neuropeptide activity, chemokine receptor activity, defense response, and inflammatory response. Kyoto Encyclopedia of Gene and Genomes analysis showed that neuroactive ligand-receptor interaction and cytokine-cytokine receptor interaction were involved in sensory neurons of rats with PIPN. Besides, comparison analysis identified that 11 DEGs in the PIPN model are shared with either inflammatory pain (Ces1d, Cfd, Retn, and Fam150b) or neuropathic pain (Atf3, Csrp3, Ecel1, Gal, Sprr1a, Tgm1, and Vip). Quantitative RT-PCR results also confirmed the validation of the RNAseq data. These results suggested that neuroactive ligand-receptor interaction and cytokine-cytokine receptor interaction are majorly involved in sensory neurons of rats with PIPN. Immune, inflammatory responses and neuron functional changes are the major pathogenesis of PIPN. Paclitaxel-induced peripheral neuropathy has shared characteristics with both inflammatory pain and neuropathic pain.

Placebo exhibits beneficial effects on pain perception in human experimental studies. Most of these studies demonstrate that placebo significantly decreased neural activities in pain modulatory brain regions and pain-evoked potentials. This study examined placebo analgesia-related effects on spontaneous brain oscillations. We examined placebo effects on four order-fixed 20-min conditions in two sessions: isotonic saline-induced control conditions (with/without placebo) followed by hypertonic saline-induced tonic muscle pain conditions (with/without placebo) in 19 subjects using continuous electroencephalography (EEG) recording. Placebo treatment exerted significant analgesic effects in 14 placebo responders, as subjective intensity of pain perception decreased. Frequency analyses were performed on whole continuous EEG data, data during pain perception rating and data after rating. The results in the first two cases revealed that placebo induced significant increases and a trend toward significant increases in the amplitude of alpha oscillation during tonic muscle pain compared to control conditions in frontal-central regions of the brain, respectively. Placebo-induced decreases in the subjective intensity of pain perception significantly and positively correlated with the increases in the amplitude of alpha oscillations during pain conditions. In conclusion, the modulation effect of placebo treatment was captured when the pain perception evaluating period was included. The strong correlation between the placebo effect on reported pain perception and alpha amplitude suggest that alpha oscillations in frontal-central regions serve as a cortical oscillatory basis of the placebo effect on tonic muscle pain. These results provide important evidence for the investigation of objective indicators of the placebo effect.

Induced by varicella zoster virus (VZV), postherpetic neuralgia (PHN) is one of the common complications of herpes zoster (HZ) with refractory pain. Animal models play pivotal roles in disclosing the pain mechanisms and developing effective treatments. However, only a few rodent models focus on the VZV-associated pain and PHN. To summarize the establishment and characteristics of popular PHN rodent models, thus offer bases for the selection and improvement of PHN models. In this review, we retrospect two promising PHN rodent models, VZV-induced PHN model and HSV1-induced PHN model in terms of pain-related evaluations, their contributions to PHN pathogenesis and pharmacology. Significant difference of two PHN models is the probability of virus proliferation; 2) Most commonly used pain evaluation of PHN model is mechanical allodynia, but pain-induced anxiety and other behaviours are worth noting; 3) From current PHN models, pain mechanisms involve changes in virus gene and host gene expression, neuroimmune-glia interactions and ion channels; 4) antiviral drugs and classical analgesics serve more on the acute stage of herpetic pain. Different PHN models assessed by various pain evaluations combine to fulfil more comprehensive understanding of PHN.

This study investigates the role of circular RNAs (circRNAs) in the context of Varicella-Zoster Virus (VZV) lytic infection. We employ two sequencing technologies, short-read sequencing and long-read sequencing, following RNase R treatment on VZV-infected neuroblastoma cells to identify and characterize both cellular and viral circRNAs. Our large scanning analysis identifies and subsequent experiments confirm 200 VZV circRNAs. Moreover, we discover numerous VZV latency-associated transcripts (VLTs)-like circRNAs (circVLTs lytic ), which contain multiple exons and different isoforms within the same back-splicing breakpoint. To understand the functional significance of these circVLTs lytic , we utilize the Bacteria Artificial Chromosome system to disrupt the expression of viral circRNAs in genomic DNA location. We reveal that the sequence flanking circVLTs’ 5’ splice donor plays a pivotal role as a cis-acting element in the formation of circVLTs lytic . The circVLTs lytic is dispensable for VZV replication, but the mutation downstream of circVLTs lytic exon 5 leads to increased acyclovir sensitivity in VZV infection models. This suggests that circVLTs lytic may have a role in modulating the sensitivity to antiviral treatment. The findings shed new insight into the regulation of cellular and viral transcription during VZV lytic infection, emphasizing the intricate interplay between circRNAs and viral processes. Here, the authors identify 200 Varicella-Zoster Virus (VZV) circRNAs, confirmed in HZ patient tissues. Numerous latency-associated transcripts (VLTs)-like circRNAs (circVLTs lytic ) were found with multiple exons and splice donor sequences that influence formation. circVLTs lytic RNAs are non-essential for VZV replication but affect ACV sensitivity.

•Placebo analgesia was more pronounced and lasted longer than nocebo hyperalgesia.•Real-time pain ratings correlated with neural activity in several brain regions.•The putamen was implicated in both placebo analgesia and nocebo hyperalgesia.•Caudate and other areas were differentially involved in placebo and nocebo effects.•Distinct neural mechanisms were revealed for placebo and nocebo effects. Pain is a highly subjective and multidimensional experience, significantly influenced by various psychological factors. Placebo analgesia and nocebo hyperalgesia exemplify this influence, where inert treatments result in pain relief or exacerbation, respectively. While extensive research has elucidated the psychological and neural mechanisms behind these effects, most studies have focused on transient pain stimuli. To explore these mechanisms in the context of tonic pain, we conducted a study using a 15-minute tonic muscle pain induction procedure, where hypertonic saline was infused into the left masseter of healthy participants. We collected real-time Visual Analogue Scale (VAS) scores and functional magnetic resonance imaging (fMRI) data during the induction of placebo analgesia and nocebo hyperalgesia via conditioned learning. Our findings revealed that placebo analgesia was more pronounced and lasted longer than nocebo hyperalgesia. Real-time pain ratings correlated significantly with neural activity in several brain regions. Notably, the putamen was implicated in both effects, while the caudate and other regions were differentially involved in placebo and nocebo effects. These findings confirm that the tonic muscle pain paradigm can be used to investigate the mechanisms of placebo and nocebo effects and indicate that placebo analgesia and nocebo hyperalgesia may have more distinct than common neural bases.

The aim of this work is to provide a comprehensive and unbiased understanding at the molecular correlates of peripheral nerve injury. In this study, we screened the differentially expressed genes (DEGs) in the DRG from rats using RNA-seq technique. Moreover, the bioinformatics methods were used to figure out the signaling pathways and expression regulation pattern of the DEGs enriched in. In addition, quantitative real-time RT-PCR was carried out to further confirm the expression of DEGs. 414 genes were upregulated, while 184 genes were downregulated in the DRG of rats 7 days after partial sciatic nerve ligation (pSNL) surgery. Moreover, GO and KEGG enrichment analysis suggested that most of the altered genes were involved in inflammatory responses and signaling transduction. In addition, our results state that they shared similar characters in the DRG among four types of neuropathic pain models. Eighteen genes have been altered (17 of them were upregulated) in the DRG of all four types of neuropathic pain models, in which Vgf , Atf3 , Cd74 , Gal , Jun , Npy , Serpina3n , and Hspb1 have been reported to be involved in neuropathic pain. Quantitative real-time RT-PCR results further confirmed the mRNA expression levels of Vgf , Atf3 , Cd74 , Gal , Jun , Npy , Serpina3n , and Hspb1 in the DRG of rats with pSNL surgery. The present study suggested that these eight genes may play important roles in neuropathic pain, revealing that these genes might serve as therapeutic targets for neuropathic pain. Moreover, anti-inflammatory therapy might be an effective approach for neuropathic pain treatment and prevention.

Peripheral injection of botulinum neurotoxin A (BoNT/A) has been demonstrated to have a long-term analgesic effect in treating neuropathic pain. Around peripheral nerves, BoNT/A is taken up by primary afferent neurons and inhibits neuropeptide release. Moreover, BoNT/A could also be retrogradely transported to the spinal cord. Recent studies have suggested that BoNT/A could attenuates neuropathic pain by inhibiting the activation of spinal glial cells. However, it remains unclear whether BoNT/A directly interacts with these glial cells or via their interaction with neurons. Our aim here is to determine the direct effect of BoNT/A on primary microglia and astrocytes. We show that BoNT/A pretreatment significantly inhibits lipopolysaccharide (LPS) -induced activation and pro-inflammatory cytokine release in primary microglia (1 U/mL BoNT/A in medium), while it has no effect on the activation of astrocytes (2 U/mL BoNT/A in medium). Moreover, a single intrathecal pre-administration of a low dose of BoNT/A (1 U/kg) significantly prohibited the partial sciatic nerve ligation (PSNL)- induced upregulation of pro-inflammatory cytokines in both the spinal cord dorsal horn and dorsal root ganglions (DRGs), which in turn prevented the PSNL-induced mechanical allodynia and thermal hyperalgesia. In conclusion, our results indicate that BoNT/A pretreatment prevents PSNL-induced neuropathic pain by direct inhibition of spinal microglia activation.

Sphenopalatine ganglion (SPG) neurostimulation has emerged as a promising therapy for patients with refractory cluster headache and selected cases of migraine. This narrative review provides a comprehensive synthesis of the current evidence on SPG neurostimulation as a novel therapeutic strategy for headache management. As a key parasympathetic ganglion involved in the trigeminal autonomic reflex, the SPG constitutes a logical and clinically relevant target for neuromodulation in the treatment of severe headache disorders. Clinical evidence supports the efficacy of SPG neurostimulation in aborting acute cluster headache attacks and reducing attack frequency in chronic cases, while limited data suggest potential acute pain relief in migraine. Long-term follow-up indicates sustained efficacy in cluster headache, including improved quality of life and reduced medication use. Adverse effects are mostly mild and transient. Serious complications are rare, but include procedure- or device-related events such as infection or venous injury reported in some studies. Future research should prioritize optimizing electrode placement, stimulation parameters, and long-term outcome evaluation, and further clarify the underlying mechanisms to improve clinical efficacy and safety.

As a typical neuropathic pain, post-herpetic neuralgia (PHN) is a common complication of herpes zoster (HZ), which seriously affects the normal life and work of patients. The unclear pathogenesis and lack of effective drugs make the clinical efficacy of PHN unsatisfactory. Here, we obtained the transcriptome profile of neuroblastoma cells (SH-SY5Y) and DRG in rats infected with varicella zoster virus (VZV) by transcriptome sequencing (RNA-Seq) combined with publicly available gene array data sets. Next, the data processing of the transcriptome map was analyzed using bioinformatics methods, including the screening of differentially expressed genes (DEGs), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Finally, real-time fluorescent quantitative PCR (qRT-PCR) was used to detect the expression of calcium-related genes, and calcium fluorescent probes and calcium colorimetry were used to evaluate the distribution and content of calcium ions in cells after VZV infection. Transcriptome data analysis (GO and KEGG enrichment analysis) showed that calcium disorder played an important role in SH-SY5Y cells infected by VZV and dorsal root ganglion (DRG) of the PHN rat model. The results of qRT-PCR showed that the expression levels of calcium-related genes BHLHA15 , CACNA1F , CACNG1 , CHRNA9 , and STC2 were significantly upregulated, while the expression levels of CHRNA10 , HRC , and TNNT3 were significantly downregulated in SH-SY5Y cells infected with VZV. Our calcium fluorescent probe and calcium colorimetric test results showed that VZV could change the distribution of calcium ions in infected cells and significantly increase the intracellular calcium content. In conclusion, our results revealed that the persistence of calcium disorder caused by VZV in nerve cells might be a crucial cause of herpetic neuralgia, and a potential target for clinical diagnosis and treatment of PHN.

Oxytocin (OT) is synthesized within the paraventricular nucleus and supraoptic nucleus of the hypothalamus. In addition to its role in uterine contraction, OT plays an important antinociceptive role; however, the underlying molecular mechanisms of antinociceptive role of OT remain elusive. We hypothesized that the antinociceptive effect of OT on neuropathic pain may occur via inhibition of TRPV1 activation in the spinal cord. The present study explores the antinociceptive role of OT and its mechanisms in neuropathic pain. Partial sciatic nerve ligation (pSNL) was performed to induce neuropathic pain. Animal behaviors were measured using a set of electronic von Frey apparatus and hot plate. Electrophysiological recordings and molecular biological experiments were performed. Intrathecal administration of OT alleviated both mechanical allodynia and thermal hyperalgesia in pSNL rats ( = 6, per group, < 0.0001, saline vs. OT group). Electrophysiological data revealed that OT significantly inhibited the enhancement of frequency and amplitude of spontaneous excitatory post-synaptic currents induced presynaptically by TRPV1 activation in the spinal cord. Moreover, the inhibitory effect of OT on capsaicin-induced facilitation of excitatory transmission was blocked by co-treatment with saclofen, while intrathecal administration of OT dramatically inhibited capsaicin-induced ongoing pain in rats, ( = 6, per group, < 0.0001, saline vs. OT group). The paw withdrawal latency in response to heat stimulation was significantly impaired in TRPV1KO mice 3 days after pSNL upon OT (i.t.) treatment, compared with wild type mice ( = 6, < 0.05). Finally, OT prevented TRPV1 up-regulation in spinal cords of pSNL model rats. OT relieves neuropathic pain through GABA release and presynaptic TRPV1 inhibition in the spinal cord. OT and its receptor system might be an intriguing target for the treatment and prevention of neuropathic pain.