ObjectiveAdipogenesis, the process of adipocyte differentiation, plays a central role in obesity development. However, the molecular mechanisms underlying adipogenesis and its regulation remain incompletely understood. This study aimed to investigate metabolomic changes during adipocyte differentiation in 3T3-L1 cells and elucidate the associated molecular mechanisms, with potential implications for obesity-related metabolic diseases.MethodsMurine 3T3-L1 pre-adipocytes were cultured and induced to differentiate into mature adipocytes over an 8-day period. Samples were collected at pre-differentiation (Pre), 4-day differentiation (Middle) and 8-day differentiation (Mature) stages. Metabolites were extracted using hydrophilic and hydrophobic methods and analyzed by ultra-performance liquid chromatography coupled with mass spectrometry. Data analysis employed kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to identify differential metabolites and their associated metabolic pathways.ResultsSignificant differences in metabolite profiles were observed among Pre, Middle and Mature. We identified 170 differential metabolites between Pre and Middle (164 increased, 6 decreased), 246 differential metabolites between Pre and Mature (223 increased, 23 decreased), and 124 differential metabolites between Middle and Mature (102 increased, 22 decreased). The most pronounced changes occurred in lipid metabolites, particularly triglycerides and phosphatidylcholines. KEGG enrichment analysis revealed that these differential metabolites were mainly involved in glycerolipid metabolism, glycerophospholipid metabolism, and insulin resistance pathways. Correlation network analysis further identified key genes associated with these metabolites, highlighting the interplay between lipid and amino acid metabolism during adipogenesis.ConclusionThis study provides a comprehensive metabolomic profile of adipocyte differentiation in 3T3-L1 cells, revealing significant alterations in lipid metabolism and key metabolic pathways. These findings enhance our understanding of the molecular mechanisms underlying adipogenesis and may contribute to the development of novel diagnostic tools and therapeutic strategies for obesity-related metabolic diseases.

BACKGROUND:Paclitaxel-induced peripheral neuropathy (PIPN) is a severe and dose-limiting side effect. This study investigated the therapeutic potential of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its underlying mechanism. METHODS:A murine PIPN model was established. Behavioral tests assessed neuropathic pain. Molecular and cellular analyzes, including western blot, ELISA, and transmission electron microscopy, evaluated oxidative stress, mitochondrial function, and key protein expression in dorsal root ganglia (DRG) and SH-SY5Y cells. The PGC-1α inhibitor SR-18292 was used for mechanistic validation. RESULTS:High-dose PACAP (100 μg/kg) significantly alleviated PTX-induced mechanical allodynia and thermal/cold hyperalgesia. It reduced oxidative stress (lowered ROS/MDA, increased SOD) and restored mitochondrial function (improved membrane potential, ATP, and ultrastructure) in DRG neurons. PACAP upregulated PGC-1α and HO-1 expression, and its protective effects were abolished by PGC-1α inhibition. Crucially, PACAP did not interfere with PTX's antitumor efficacy. CONCLUSION:PACAP alleviates PIPN by activating the PGC-1α pathway to improve mitochondrial function and counteract oxidative stress, presenting a promising adjunct therapy that does not compromise chemotherapy.

Pituitary adenylate cyclase-activating peptide (PACAP) is a pleiotropic neuropeptide widely distributed in the nervous system, exhibiting potent cytoprotective effects across a spectrum of neurological disorders. Its neuroprotection is largely mediated through three G protein-coupled receptors (PAC1, VPAC1, VPAC2), activating downstream pathways that converge on preserving mitochondrial integrity. Mitochondrial dysfunction, characterized by bioenergetic failure, oxidative stress, perturbed dynamics (such as fusion and fission), and impaired quality control, is a hallmark of traumatic nerve injury, cerebral ischemia, and retinal neuropathy. This review systematically synthesizes recent evidence elucidating how PACAP counteracts these pathological processes. We detail its mechanisms in 1) mitigating neuropathic pain and promoting axonal regeneration after peripheral nerve trauma; 2) attenuating excitotoxicity, apoptosis, and neuroinflammation following cerebral ischemia by regulating mitochondrial permeability, fission/fusion balance, and NLRP3 inflammasome activation; and 3) protecting retinal ganglion cells against diabetic retinopathy and glaucomatous damage via modulating oxidative stress and apoptotic signaling. Furthermore, we discuss the translational potential of PACAP, including its biomarker value in cerebrospinal fluid and plasma for injury prognosis, and the promise of innovative delivery routes to enhance brain bioavailability. By focusing on mitochondrial-centric mechanisms, this review underscores PACAP as a neuroprotective regulator and highlights its candidacy for developing next-generation neurotherapeutics.

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C_LTMR following paclitaxel treatment. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. Additionally, Camk1d is involved in temperature hyperalgesia in CIPN, a key clinical symptom observed in human patients with CIPN. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.

Chikungunya fever (CHIKF), caused by the Chikungunya virus (CHIKV) and transmitted by Aedes mosquitoes, has rapidly evolved from localized outbreaks to a significant global health threat. While the initial high fever is often debilitating, it is the severe and frequently long-lasting pain, affecting joints (arthralgia), muscles (myalgia), and sometimes nerves (neuropathic pain), that truly characterizes the disease’s impact on sufferers. This review explores how CHIKV infection triggers both acute pain and persistent chronic pain. We examine the mechanisms by which the virus directly damages tissues, incites extensive inflammation, invades the nervous system, and potentially manipulates the immune response, leading to autoimmune-like attacks. Understanding these processes is essential, as current treatments mainly focus on symptom management, and there are no specific antiviral therapies available. Identifying the factors that contribute to the persistence of pain is critical for developing targeted and more effective therapeutic interventions, ultimately alleviating the long-term burden of this debilitating disease.

BACKGROUND:Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of chemotherapy, with limited therapeutic options due to unclear mechanisms. Cavidine (CAV), a natural alkaloid, has been shown to possess both anti-inflammatory and neuroprotective properties. However, further research is required to elucidate its role in CIPN and the underlying mechanisms by which it exerts its effects. PURPOSE:To examine the therapeutic efficacy of CAV in relation to CIPN, with a view to elucidating its underlying mechanism, which is associated with mitophagy and PKM2-mediated histone lactylation. METHODS:The post-CAV treatment assessment included the evaluation of mechanical allodynia, thermal hyperalgesia, and footpad immunofluorescence. To identify the regulated pathways of CAV, RNA-seq and lactate metabolomics were performed. The evaluation of mitophagy was conducted through the utilization of immunofluorescence, along with transmission electron microscopy. In addition, the analysis of histone lactylation at H3K18la was undertaken. The use of molecular docking and biolayer interferometry assay confirmed the interactions between CAV-PKM2. RESULTS:CAV significantly alleviated both mechanical and thermal pain, as well as peripheral nerve injury, in mice suffering from CIPN. Mechanistically, CAV suppressed PKM2 activity, reducing lactate accumulation and histone H3K18 lactylation. This inhibition promoted mitochondrial autophagy, evidenced by decreased LC3B-II, upregulated PINK1/Parkin, and reduced p62, and promoted the integration of autophagosomes and lysosomes. Molecular docking and biolayer interferometry assay demonstrated high-affinity binding between CAV and the allosteric site of PKM2. CONCLUSION:CAV alleviates CIPN by enhancing mitophagy via inhibition of PKM2-driven histone lactylation, thus providing a novel therapeutic strategy for CIPN.

Neuronal injury is a major pathological issue that cannot be ignored during viral infections. Mitochondria, the energy factories of the cell, play a unique role in this scenario and are severely impacted when viruses infect host cells. Viruses invade and infect cells via specific mechanisms, causing changes in cellular structure and function. These changes not only directly affect mitochondria but also disrupt their normal function through indirect pathways. This paper reviews the mechanisms of mitochondrial damage induced by infections with SARS-CoV-2, herpesviruses, human immunodeficiency virus (HIV), and hepatitis C virus (HCV), providing new insights and strategies for preventing and treating neuronal injury.

ObjectiveThis study aimed to investigate the role of Tmem45b, a gene expressed in itch-associated Dorsal root ganglion (DRG) neurons, in the regulation of itch sensation.MethodsThe expression of Tmem45b was examined in DRG neurons. These neurons included Nppb-, Mrgpra3-, and Mrgprd-positive subtypes, which are known to mediate itch. Behavioral response to various pruritogens including β-alanine, chloroquine, histamine, serotonin, and N-met-LTC4 were assessed on Mrgprd-cre::Tmem45bflox/flox conditional knockout (cKO) mice. Chronic itch was evaluated using both atopic dermatitis-like and dry skin-like mouse models. To investigate intracellular calcium dynamics, calcium imaging was performed on dissociated DRG neurons. Additionally, bulk RNA-seq was conducted on DRG from Tmem45b cKO mice to assess transcriptomic changes. Serca1 expression and the calcium storage capacity of the endoplasmic reticulum (ER) were analyzed following Tmem45b deletion.ResultsTmem45b was found to be expressed in itch-associated DRG neurons. In Tmem45b cKO mice, scratching behavior was reduced in response to β-alanine but increased in response to chloroquine. Notably, chronic itch was alleviated in Tmem45b-deficient mice. Calcium imaging revealed that Tmem45b cKO impaired calcium responses to β-alanine and allyl isothiocyanate, but not to chloroquine. Mechanistically, Tmem45b deficiency led to a significant downregulation of Serca1, reducing ER calcium storage capacity. Pharmacological inhibition of Serca1 in DRG neurons similarly suppressed intracellular calcium release in response to β-alanine and chloroquine.ConclusionTmem45b plays a critical role in nonhistaminergic itch by regulating ER calcium homeostasis through Serca1. Its deficiency reduces itch behavior and impairs calcium signaling in DRG neurons, suggesting that Tmem45b is a potential therapeutic target for chronic itch.

Abstract Bone cancer pain (BCP) is one of the most prominent and disabling symptoms in patients with primary bone malignancies (e.g. osteosarcoma, Ewing’s sarcoma) and metastatic bone tumors (e.g. multiple myeloma), severely impacting quality of life and treatment efficacy. Conventional analgesic approaches are often limited in effectiveness or associated with significant side effects. This chapter will delve into the complex pathological mechanisms underlying the development and persistence of BCP. It will focus on elucidating the intricate interactions within the tumor micro-environment involving cancer cells, immune cells (e.g. macrophages, T cells), osteoclasts, osteoblasts, and sensory neurons. Key mechanisms include sensitization of nociceptors by allogeneic mediators (protons, nerve growth factor, cytokines, chemokines) released from tumor and stromal cells; activation of nerve terminals by factors (e.g. ATP, acid) released during bone matrix destruction; tumor and immune cell infiltration of nerves; and peripheral and central nervous system sensitization and remodeling. Building upon this mechanistic understanding, the chapter will systematically review current and emerging targeted therapeutic strategies. These include monoclonal antibodies, small molecule inhibitors, gene therapies, and neuromodulation techniques targeting key pain-signaling pathways (e.g. NGF/TrkA, GDNF, CXCL12/CXCR4, RANK/RANKL). The aim is to provide the theoretical foundation and translational insights necessary for developing more effective and better-tolerated precision treatments for BCP.

Although the molecular mechanisms of chronic pain have been extensively studied, a global picture of alternatively spliced genes and events in the peripheral and central nervous systems of chronic pain is poorly understood. The current study analyzed the changing pattern of alternative splicing (AS) in mouse brain, dorsal root ganglion, and spinal cord tissue under inflammatory and neuropathic pain. In total, we identified 6495 differentially alternatively spliced (DAS) genes. The molecular functions of shared DAS genes between these two models are mainly enriched in calcium signaling pathways, synapse organization, axon regeneration, and neurodegeneration disease. Additionally, we identified 509 DAS in differentially expressed genes (DEGs) shared by these two models, accounting for a small proportion of total DEGs. Our findings supported the hypothesis that the AS has an independent regulation pattern different from transcriptional regulation. Taken together, these findings indicate that AS is one of the important molecular mechanisms of chronic pain in mammals. This study presents a global description of AS profile changes in the full path of neuropathic and inflammatory pain models, providing new insights into the underlying mechanisms of chronic pain and guiding genomic clinical diagnosis methods and rational medication.

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 (circVLTslytic), which contain multiple exons and different isoforms within the same back-splicing breakpoint. To understand the functional significance of these circVLTslytic, 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 circVLTslytic. The circVLTslytic is dispensable for VZV replication, but the mutation downstream of circVLTslytic exon 5 leads to increased acyclovir sensitivity in VZV infection models. This suggests that circVLTslytic 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.

Neuropathic pain triggered by chemotherapy poses a significant clinical challenge. Investigating cell type-specific alterations through single-cell transcriptome analysis holds promise in understanding symptom development and pathogenesis. In this study, we performed single nuclei RNA (snRNA) sequencing of dorsal root ganglions (DRG) to explore the molecular mechanism underlying paclitaxel-induced neuropathic pain. Mouse exposed to repeated paclitaxel doses developed persistent pain hypersensitivity lasting at least 21 days. The snRNA sequencing unveiled seven major cell types within DRGs, with neurons further subdivided into 12 distinct subclusters using known markers. Notably, type C low-threshold mechanoreceptors (C\_LTMR) exhibited the most pronounced transcriptomic changes post-paclitaxel administration. Differential gene expression and Gene Ontology (GO) analysis highlighted suppressed potassium-related currents, microtubule transport, and mitochondrial functions in C\_LTMR following paclitaxel treatment. Meanwhile, Gene Set Enrichment Analysis (GSEA) suggested increased Interleukin 17 production in C\_LTMR after paclitaxel exposure. Pseudo-time analysis uncovered nine distinct states (state 1 to 9) of C\_LTMR. State 1 exhibits higher prevalence in paclitaxel-treated mice and altered neurotransmission properties, likely contributing to paclitaxel-induced pain hypersensitivity. This comprehensive exploration sheds light on the molecular mechanisms driving paclitaxel-induced neuropathic pain, offering potential avenues for therapeutic intervention.### Competing Interest StatementThe authors have declared no competing interest.

Approximately 20% of patients with shingles develop postherpetic neuralgia (PHN). We investigated the role of gut microbiota in shingle- and PHN-related pain. Patients with shingles or PHN exhibited significant alterations in their gut microbiota with microbial markers predicting PHN development among patients with shingles. Functionally, fecal microbiota transplantation from patients with PHN to mice heightened pain sensitivity. Administration of Roseburia intestinalis, a bacterium both depleted in patients with shingles and PHN, alleviated peripheral nerve injury-induced pain in mice. R. intestinalis enhanced vagal neurotransmission to the nucleus tractus solitarius (NTS) to suppress the central amygdala (CeA), a brain region involved in pain perception. R. intestinalis-generated butyrate activated vagal neurons through the receptor, G protein-coupled receptor 41 (GPR41). Vagal knockout of Gpr41 abolished the effects of R. intestinalis on the NTS-CeA circuit and reduced pain behaviors. Overall, we established a microbiota-based model for PHN risk assessment and identified R. intestinalis as a potential pain-alleviating probiotic.

Herpetic-related neuralgia (HN) caused by varicella-zoster virus (VZV) infection is one of the most typical and common neuropathic pain in the clinic. However, the potential mechanisms and therapeutic approaches for the prevention and treatment of HN are still unclear. This study aims to provide a comprehensive understanding of the molecular mechanisms and potential therapeutic targets of HN. We used an HSV-1 infection-induced HN mouse model and screened the differentially expressed genes (DEGs) in the DRG and spinal cord using an RNAseq technique. Moreover, bioinformatics methods were used to figure out the signaling pathways and expression regulation patterns of the DEGs enriched. In addition, quantitative real-time RT-PCR and western blot were carried out to further confirm the expression of DEGs. HSV-1 inoculation in mice resulted in mechanical allodynia, thermal hyperalgesia, and cold allodynia, following the infection of HSV-1 in both DRG and spinal cord. Besides, HSV-1 inoculation induced an up-regulation of ATF3, CGRP, and GAL in DRG and activation of astrocytes and microglia in the spinal cord. Moreover, 639 genes were upregulated, 249 genes were downregulated in DRG, whereas 534 genes were upregulated and 12 genes were downregulated in the spinal cord of mice 7 days after HSV-1 inoculation. GO and KEGG enrichment analysis suggested that immune responses and cytokine-cytokine receptor interaction are involved in DRG and spinal cord neurons in mice after HSV-1 infection. In addition, CCL5 and its receptor CCR5 were significantly upregulated in DRG and spinal cord upon HSV-1 infection in mice. And blockade of CCR5 exhibited a significant analgesic effect and suppressed the upregulation of inflammatory cytokines in DRG and spinal cord induced by HSV-1 infection in mice. HSV-1 infection-induced allodynia and hyperalgesia in mice through dysregulation of immune response and cytokine-cytokine receptor interaction mechanism. Blockade of CCR5 alleviated allodynia and hyperalgesia probably through the suppression of inflammatory cytokines. Therefore, CCR5 could be a therapeutic target for the alleviation of HSV-1 infection-induced HN.

带状疱疹后神经痛(postherpetic neuralgia,PHN)是由水痘-带状疱疹病毒(varicella zoster virus,VZV)感染所引起的常见并发症,多见于老年人和免疫功能低下者,严重影响病人的身心健康和生活质量.尚未明确的致病机制让PHN治疗效果欠佳,缺乏有效模拟PHN的动物模型更让PHN发病机制的研究止步不前.本文主要综述目前PHN动物模型构建的研究进展,重点介绍由VZV与单纯疱疹病毒1型(herpes simplex virus 1,HSV-1)诱导的PHN动物模型的建立方法和疼痛行为学表现.旨在比较现有PHN动物模型的研究概况,为进一步阐明PHN致病机制提供有效的研究工具,同时也为PHN动物模型的选择和改良提供参考.

Background and PurposeChemotherapy-induced neuropathic pain (CINP) currently has limited effective treatment. Although the roles of oxytocin (OXT) and the oxytocin receptor (OXTR) in central analgesia have been well documented, the expression and function of OXTR in the peripheral nervous system remain unclear. Here, we evaluated the peripheral antinociceptive profiles of OXTR in CINP. Experimental ApproachPaclitaxel (PTX) was used to establish CINP. Quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridization, and immunohistochemistry were used to observe OXTR expression in dorsal root ganglia (DRG). The antinociceptive effects of OXT were assessed by hot-plate and von Frey tests. Whole-cell patch clamp was performed to record sodium currents, excitability of DRG neurons, and excitatory synapse transmission. Key ResultsExpression of OXTR in DRG neurons was enhanced significantly after PTX treatment. Activation of OXTR exhibited antinociceptive effects, by decreasing the hyperexcitability of DRG neurons in PTX-treated mice. Additionally, OXTR activation up-regulated the phosphorylation of protein kinase C (pPKC) and, in turn, impaired voltage-gated sodium currents, particularly the voltage-gated sodium channel 1.7 (Na(V)1.7) current, that plays an indispensable role in PTX-induced neuropathic pain. OXT suppressed excitatory transmission in the spinal dorsal horn as well as excitatory inputs from primary afferents in PTX-treated mice. Conclusion and ImplicationsThe OXTR in small-sized DRG neurons is up-regulated in CINP and its activation relieved CINP by inhibiting the neural excitability by impairment of Na(V)1.7 currents via pPKC. Our results suggest that OXTR on peripheral sensory neurons is a potential therapeutic target to relieve CINP.

This review mainly introduced the research progresses in the establishment of postherpetic neuralgia (PHN) animal model at home and abroad, with emphasis on the establishment methods and pain behaviors of PHN animal model induced by varicella zoster virus (VZV) or herpes simplex virus 1 (HSV1). The aims of this paper were to compare the current research status of PHN animal model, and to provide effective research tool for further elucidating the pathogenic mechanism of PHN, and reference for selecting and improving the PHN animal model.

Chemotherapy-induced peripheral neuropathy (CIPN)-mediated paresthesias are a common complication in cancer patients undergoing chemotherapy. There are currently no treatments available to prevent or reverse CIPN. Therefore, new therapeutic targets are urgently needed to develop more effective analgesics. However, the pathogenesis of CIPN remains unclear, and the prevention and treatment strategies of CIPN are still unresolved issues in medicine. More and more studies have demonstrated that mitochondrial dysfunction has become a major factor in promoting the development and maintenance of CIPN, and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC1α) plays a significant role in maintaining the mitochondrial function, protecting peripheral nerves, and alleviating CIPN. In this review, we highlight the core role of PGC1α in regulating oxidative stress and maintaining normal mitochondrial function and summarize recent advances in its therapeutic effects and mechanisms in CIPN and other forms of peripheral neuropathy. Emerging studies suggest that PGC1α activation may positively impact CIPN mitigation by modulating oxidative stress, mitochondrial dysfunction, and inflammation. Therefore, novel therapeutic strategies targeting PGC1α could be a potential therapeutic target in CIPN.

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.

Chemotherapy-induced peripheral neuropathy is one of the most common side effects of anticancer therapy. It is anticipated that chemotherapies with different mechanisms of action may affect somatosensory neurons differently. This study aimed to explore similar and differential etiologies of oxaliplatin- and paclitaxel-induced neuropathy by comparing the transcriptomes of dorsal root ganglia (DRGs). We retrieved our previously published transcriptome data of DRGs extracted from vehicle-, oxaliplatin- and paclitaxel-treated rats (GSE160543), to analyze in parallel the differentially expressed genes (DEGs) and Gene ontology (GO) terms enrichment. We found that both oxaliplatin and paclitaxel treatments consistently produced mechanical allodynia, thermal hyperalgesia, and cold hyperalgesia in rats. Compared to vehicle, 320 and 150 DEGs were identified after oxaliplatin and paclitaxel treatment, respectively. Only 17 DEGs were commonly dysregulated by the two reagents. Activating transcription factor 3 (Atf3), a marker of nerve injury, was elevated only after paclitaxel treatment. GO analysis suggested that paclitaxel treatment was associated with neuronal changes characterized by numerous terms that are related to synaptic transmission, while oxaliplatin was more likely to affect dividing cells (e.g., the glia) and neuroinflammation. Notably, 29 biological processes GO terms were commonly enriched in response to both drugs. However, 28 out of 29 terms were oppositely modulated. This study suggests that distinct mechanisms underly paclitaxel- and oxaliplatin-induced neuropathy. Paclitaxel might directly affect somatosensory neurons while oxaliplatin primarily targets dividing cells and immune cells.