Neurobiology of Pain最新文献

{"title":"Context dependent roles of FGF13B-NaV1.7 interaction in pain signaling","authors":"Erick J. Rodríguez-Palma ,&nbsp;Samantha Perez-Miller ,&nbsp;Kimberly Gomez ,&nbsp;Rajesh Khanna","doi":"10.1016/j.ynpai.2026.100208","DOIUrl":"10.1016/j.ynpai.2026.100208","url":null,"abstract":"<div><div>Voltage-gated sodium channels, such as Na_V1.7, serve as pivotal regulators of sensory neuron excitability and nociception. While gain- and loss-of-function mutations in <em>SCN9A</em> cause inherited pain syndromes or congenital insensitivity to pain, the functional regulation of Na_V1.7channels by intracellular protein partners remains incompletely defined. Among these, the fibroblast growth factor 13 isoform B (FGF13B) has emerged as a critical, yet controversial, modulator of Na_V1.7. FGF13B binds the Na_V1.7C-terminal domain, but reported consequences of this interaction appear conflicting, with studies describing both suppression and enhancement of channel function and nociceptor excitability. Here, we review recent genetic, electrophysiological, and pharmacology advances and propose that FGF13B functions as a context-dependent regulatory rheostat of Na_V1.7 rather than as a unidirectional modulator. We highlight how the net functional outcome of this interaction depends on cellular and signaling context and discuss the therapeutic potential of targeting the FGF13B/Na_V1.7complex in pain conditions.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"19 ","pages":"Article 100208"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146189230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NGF stimulation alters the transcriptome and surface TrkB expression in axons of dorsal root ganglion neurons.","authors":"Maximilian Koch, Manas Kshirsagar, Ankita Rawat, Abdolhossein Zare, Felicitas Schlott, Thorsten Bischler, Panagiota Arampatzi, Michael Briese, Michael Sendtner","doi":"10.1016/j.ynpai.2025.100194","DOIUrl":"10.1016/j.ynpai.2025.100194","url":null,"abstract":"<p><p>Nerve growth factor (NGF) is released after injury from macrophages and other cell types and induces an inflammatory response in neurons, characterized by local subcellular reactions and transcriptomic modulation. NGF-induced axonal transcriptome modulation may be crucial for pain initiation and maintenance. To explore these acute modulations, we cultured dorsal root ganglion neurons in microfluidic chambers and stimulated the axons with NGF. We found that axonal levels of the <i>Il7</i> transcript encoding interleukin-7 (IL-7) are increased after NGF stimulation, followed by IL-7 release from axons. In growth cones of sensory neurons, we also observed a reorganization of the ribosomal subunits 60S and 40S in response to NGF stimulation. In addition, a dynamic change in the spatio-temporal distribution of the Tropomyosin Kinase B (TrkB) receptor occurs at the plasma membrane of sensory neuron growth cones. TrkB is recruited from the endoplasmic reticulum (ER) leading to increased cell surface levels. De-novo synthesis of TrkB seems to be limited to somatic regions of sensory neurons. Thus, cytosolic mechanisms within distal regions of the sensory neurons may autonomously regulate signaling and translation in response to external NGF stimuli.</p>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"100194"},"PeriodicalIF":0.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASIC1a-associated mechanical hypersensitivity in the GlaKO Fabry disease mouse model","authors":"Mayra Micaela Montes ,&nbsp;Libia Catalina Salinas Castellanos ,&nbsp;Georgina Oriana Mingolo Malnati ,&nbsp;Juan Santiago Guidobono ,&nbsp;Ariel Félix Gualtieri ,&nbsp;Mariela Lacave ,&nbsp;Romina De Lucca ,&nbsp;María Natalia Gobetto ,&nbsp;Pablo Gabriel Vetta ,&nbsp;Zaira Soledad Verónica Náguila ,&nbsp;Fernanda Toledo ,&nbsp;Osvaldo Daniel Uchitel ,&nbsp;Carina Weissmann","doi":"10.1016/j.ynpai.2025.100189","DOIUrl":"10.1016/j.ynpai.2025.100189","url":null,"abstract":"<div><div>Different lines of evidence point to a role for Acid-sensing ion channel 1 (ASIC1) in pain perception, acting as sensors in both the central nervous system and peripheral tissues. While elevated ASIC1 protein expression has been documented in various pain conditions, our study focuses on its involvement in the context of Fabry disease (FD).</div><div>Using a mouse model of FD, we observed a significant increase in ASIC1 protein expression in pain-related areas including the anterior cingulate cortex (ACC), as well as the spinal cord (SC) and dorsal root ganglia (DRG) at the lumbar, thoracic, and cervical levels. This upregulation was accompanied by increased ASIC1a mRNA levels and ERK phosphorylation. Moreover, in FD mice, ASIC1 protein expression was found to be modulated by age and sex: it was higher in female mice than in males, and increased with age in both sexes.</div><div>These findings, together with our previous work showing unaltered ASIC1a mRNA levels but microRNA-mediated regulation of ASIC1a protein in the formalin-induced acute pain model, highlight distinct mechanisms of ASIC1a regulation in FD-associated versus acute pain. Additionally, our study revealed heightened mechanical sensitivity in FD mice that could be prevented using a channel blocker, further highlighting the involvement of ASIC1a channels in pain pathways associated with Fabry disease. Our findings suggest that ASIC1a channels may serve as promising therapeutic targets for pain management in Fabry disease.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100189"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-toxic analgesic elicits cell-specific genomic and epigenomic modulation by targeting the PAG brain region","authors":"Hernan A. Bazan ,&nbsp;Brian L. Giles ,&nbsp;Surjyadipta Bhattacharjee ,&nbsp;Scott Edwards ,&nbsp;Nicolas G. Bazan","doi":"10.1016/j.ynpai.2025.100192","DOIUrl":"10.1016/j.ynpai.2025.100192","url":null,"abstract":"<div><div>Acetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP’s limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, from the periaqueductal gray (PAG) midbrain region, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund’s adjuvant (CFA)-induced inflammatory pain against no treatment and vehicle controls. Our analysis revealed differential activity in three transcription factor families (SOX, SP/KLF, and AP-1) with cell-specific patterns and altered neuron-neuron interactions through neurexin-neuregulin signaling. SRP-001 and ApAP demonstrated similar genetic and epigenetic outcomes, indicating that SRP-001 is a favorable alternative due to its non-hepatotoxic properties while maintaining the same antinociceptive effects as ApAP.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100192"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological actions of a humanized P2X4 scFv on peripheral and central neurons in male mice with neuropathic pain","authors":"Sachin Goyal ,&nbsp;Ian Adams ,&nbsp;Marena Montera ,&nbsp;Nesia A. Zurek ,&nbsp;Shivali Goyal ,&nbsp;Adinarayana Kunamneni ,&nbsp;Karin N. Westlund ,&nbsp;Sascha R.A. Alles","doi":"10.1016/j.ynpai.2025.100198","DOIUrl":"10.1016/j.ynpai.2025.100198","url":null,"abstract":"<div><div>Neuropathic pain remains a challenging clinical condition due to its resistance to conventional analgesics. The purinergic P2X4 receptor (P2X4R), an ATP-gated ion channel, is upregulated in sensory neurons and glial cells following nerve injury and is pivotal in chronic pain pathogenesis. This study evaluates the therapeutic potential of a novel humanized single-chain variable fragment antibody (hP2X4R scFv) targeting P2X4R in male mice models of neuropathic pain. Using spared nerve injury (SNI) and foramen rotundum inflammatory compression of the trigeminal infraorbital nerve (FRICT-ION) models, we demonstrate that a single intraperitoneal dose of hP2X4R scFv significantly reverses mechanical hypersensitivity for up to four weeks. Electrophysiological recordings from FosTRAP mice revealed that hP2X4R scFv reduced the excitability of Fos+ neurons in the spinal dorsal horn and ventrolateral periaqueductal gray (vlPAG), key regions involved in pain processing. <em>In vitro</em>, patch-clamp studies further showed that hP2X4R scFv selectively decreased action potential firing in larger diameter dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons from SNI and FRICT-ION mice, respectively, without affecting naïve neurons. These findings suggest that hP2X4R scFv modulates both central and peripheral neuronal excitability associated with chronic pain. The specificity and long-lasting efficacy of hP2X4R scFv highlights its promise as a non-opioid therapeutic candidate for neuropathic pain management.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100198"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145104592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of depression on the peak alpha frequency as a biomarker of pain sensitivity","authors":"Mingge Shi ,&nbsp;Luiza Bonfim Pacheco ,&nbsp;Natalia Egorova-Brumley","doi":"10.1016/j.ynpai.2025.100193","DOIUrl":"10.1016/j.ynpai.2025.100193","url":null,"abstract":"<div><h3>Objective</h3><div>To assess how Peak Alpha Frequency (PAF) as a neurophysiological biomarker of pain sensitivity is influenced by conditions often comorbid with chronic pain, e.g., depression, and how methodological differences in deriving PAF, e.g., from Eyes-open (EO) vs. Eyes-closed (EC) EEG recordings affect this association.</div></div><div><h3>Methods</h3><div>We analyzed data from 47 participants (70 % female) aged 18–51 years (<em>M</em> = 25.0, <em>SD</em> = 6.50). Among them, all participants underwent EO EEG recording but only a subset of 25 participants underwent both EO and EC recording. Depression (Patient Health Quotient – 9 M = 4.49, SD = 3.96) and sensitivity to heat pain were measured.</div></div><div><h3>Results</h3><div>In EO, Spearman correlations showed no significant PAF-pain relationship (p = 0.530) but a positive correlation with depression (ρ = 0.348, p = 0.019). In EC, no significant correlations emerged, though a trend (p = 0.052) suggested depression might moderate PAF-pain links. Notably, the EO-EC PAF difference negatively correlated with depression (ρ = −0.54, p &lt; 0.01).</div></div><div><h3>Conclusions</h3><div>PAF may be sensitive to depression, albeit in the opposite direction to pain, and therefore mask the association between PAF and pain in individuals with depression. Differences in EO vs. EC PAF, as well as the EO-EC difference warrant further study.</div></div><div><h3>Significance</h3><div>Depression affects PAF especially in the eyes-open recordings.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100193"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of nerve injury on the immune system across the lifespan is sexually dimorphic","authors":"Wen Bo S. Zhou ,&nbsp;Xiang Q. Shi ,&nbsp;Alain P. Zhang ,&nbsp;Magali Millecamps ,&nbsp;Jeffrey S. Mogil ,&nbsp;Ji Zhang","doi":"10.1016/j.ynpai.2025.100195","DOIUrl":"10.1016/j.ynpai.2025.100195","url":null,"abstract":"<div><div>Although nerve injury-associated neuroinflammation contributes to neuropathic pain, the long-term impact of such injury on systemic homeostasis and its potential role in pain remains elusive. In this study, we aim to understand the systemic changes that are present alongside chronic pain in nerve-injured male and female mice across their lifespan. We monitored mechanical and cold sensitivity in male and female mice starting at the age of 3–4 months old when they received spared nerve injury (SNI), up to 20-month post-injury. Alongside, we collected blood samples to track changes in immune cells with flow cytometry, and to assess inflammation-related serum proteome using a 111-target Proteome Profiler. We also transferred serum from sham/SNI mice to naïve mice to determine the potential of systemic contribution to pain. While nerve injury did not affect immune cell composition in the blood, it triggered a long-lasting disturbance of molecular profile in the serum of sham/SNI mice, in a sex-dependent manner. Compared to sham surgery, nerve injury amplified regulation of inflammatory proteins in males, but slightly reduced it in females. These changes in the serum occurred in parallel with long-lasting mechanical and cold hypersensitivity in the nerve-injured mice. Both male and female SNI serum induced hypersensitivity when transferred to naïve mice, regardless of a sex-matched or sex-mismatched transfer. Our results highlight that a local nerve injury can have persistent systemic impact. Injury-associated systemic inflammation could contribute to neuropathic pain, but the underlying mechanisms may be sexually dimorphic.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100195"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrxn3 reduces myofascial nociceptive pain","authors":"Lauren Nguyen,&nbsp;Mikhail Umorin,&nbsp;Phillip R. Kramer","doi":"10.1016/j.ynpai.2025.100197","DOIUrl":"10.1016/j.ynpai.2025.100197","url":null,"abstract":"<div><div>Neurexin 3 (Nrxn3) has a role in neuronal signaling. Previous reports indicated that reducing Nrxn3 expression in the central amygdala increased orofacial neuropathic pain. A common temporomandibular disorder is myofascial pain. Thus, we hypothesized that Nrxn3 would reduce myofascial hypersensitivity. To test this hypothesis Nrxn3 shRNA was infused into the central amygdala of male rats. Then a ligature of the tendon attachment of the anterior superficial portion of the masseter muscle was performed to induce inflammatory orofacial pain. Dark phase meal duration was measured continuously, and von Frey filament testing was completed every 7 days for 21 days to measure the nociceptive response. After testing tissues were collected and the amount of Nrxn3 was measured. Neuronal activity in the orofacial pain pathway was quantitated by c-Fos staining of the central amygdala, lateral parabrachial nucleus, trigeminal ganglia and trigeminal nucleus caudalis. Knockdown of Nrxn3 in the central amygdala significantly increased the pain response and increased the levels of c-Fos. This increased response was observed for greater than two weeks. The data suggests Nrxn3 expression within the central amygdala attenuates nociceptive orofacial pain by reducing neuronal activity.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100197"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145048131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Humanized NaV1.8 rats overcome cross-species potency shifts in developing novel NaV1.8 inhibitors","authors":"Dillon S. McDevitt ,&nbsp;Joshua D. Vardigan ,&nbsp;Xiaoping Zhou ,&nbsp;Thomas W. Rosahl ,&nbsp;Heather Zhou ,&nbsp;Eric A. Price ,&nbsp;Michelle K. Clements ,&nbsp;Yuxing Li ,&nbsp;Nissi Varghese ,&nbsp;Alicja Krasowska-Zoladek ,&nbsp;Shawn J. Stachel ,&nbsp;Michael J. Breslin ,&nbsp;Christopher S. Burgey ,&nbsp;Richard L. Kraus ,&nbsp;Parul S. Pall ,&nbsp;Darrell A. Henze ,&nbsp;Vincent P. Santarelli","doi":"10.1016/j.ynpai.2025.100182","DOIUrl":"10.1016/j.ynpai.2025.100182","url":null,"abstract":"<div><div>Voltage-gated sodium channel isoform 1.8 (Na_V1.8) has emerged as a promising pharmaceutical target for the treatment of acute and chronic pain. However, highly selective and potent inhibitors for this channel have been difficult to develop and only recently have advanced to clinical testing. Our efforts to develop Na_V1.8 small molecule inhibitors yielded a series of molecules with favorable <em>in vitro</em> potency and selectivity against the human Na_V1.8 channel but exhibited dramatic rightward potency shifts against the rodent channel, severely limiting <em>in vivo</em> screening and candidate selection. In anticipation of supporting drug discovery efforts, a transgenic rat line expressing the human Na_V1.8 channel in lieu of the rodent channel was developed. Utilizing these humanized animals, the <em>in vitro</em> potency of our chemical matter in freshly isolated humanized rat DRG neurons was consistent with <em>in vitro</em> human potency values, enabling <em>in vivo</em> work to progress. We demonstrate capsaicin-induced nocifensive behaviors (CNB) as a moderate throughput <em>in vivo</em> screening assay, from which we demonstrate pharmacokinetic-pharmacodynamic (PK-PD) and <em>in vitro</em>-<em>in vivo</em> correlation (IVIVC) relationships. We identified MSD199 as a potent Na_V1.8 inhibitor with acute pain efficacy and assessed it in traditional inflammatory (Complete Freund’s Adjuvant) and neuropathic (spinal nerve ligation) behavioral chronic pain assays where it was shown to significantly reduce pain-related behaviors. Overall, we demonstrate the utility of humanized transgenic animals when cross-species potency shifts are observed within an otherwise promising chemical series.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100182"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143682473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voluntary exercise prevents and eradicates anxiety-like behavior by influencing parvalbumin-positive neurons, perineuronal nets, and microglia activation in corticolimbic regions of neuropathic pain rats","authors":"Thu Nguyen Dang ,&nbsp;Cuong Nguyen Van ,&nbsp;Ryosuke Ochi ,&nbsp;Hiroki Kuwamura ,&nbsp;Tomoyuki Kurose ,&nbsp;Yoki Nakamura ,&nbsp;Kazue Hisaoka-Nakashima ,&nbsp;Norimitsu Morioka ,&nbsp;Hisao Nishijo ,&nbsp;Naoto Fujita ,&nbsp;Susumu Urakawa","doi":"10.1016/j.ynpai.2025.100181","DOIUrl":"10.1016/j.ynpai.2025.100181","url":null,"abstract":"<div><div>Anxiety-like behavior often emerges in the later stages of neuropathic pain, exacerbating the pain condition and potentially involving parvalbumin-positive (PV⁺) neurons. This study aimed to investigate the effects of voluntary exercise on neuropathic pain-induced anxiety and its relationship with PV⁺ neurons, perineuronal nets (PNNs, labeled with Wisteria floribunda agglutinin [WFA]), and microglia in the corticolimbic regions. Male Wistar rats with partial sciatic nerve ligation (PSL) were given access to running wheels either from 3 days (early voluntary exercise [EEx]) or from 4 weeks (late voluntary exercise [LEx]) postoperatively. Nociceptive behaviors were assessed using the von Frey and acetone tests, while anxiety-like behaviors were assessed using the open field and elevated plus maze tests. Brain sections were histologically analyzed using immunohistochemistry and immunofluorescence 8 weeks post-surgery. Both early and late exercise partially restored the paw withdrawal thresholds and the arousal response. PSL-EEx rats did not exhibit anxiety-like behaviors. PSL-LEx rats transiently showed anxiety-like behaviors, but these were eradicated by exercise. PSL altered PV⁺ neurons and PNNs in specific corticolimbic subregions. Notably, voluntary exercise restored the densities of PV⁺-strong WFA⁺ neurons in the basolateral amygdala, PV⁺-WFA^-, and PV⁺-WFA⁺ neurons in the anterior cingulate cortex, and PV⁺-WFA⁺ neurons in the hippocampal cornu ammonis 1. These changes correlated with reduced anxiety-like behaviors. Exercise modulated PSL-induced microglial activation and interacted differently with these neurons. These findings suggest that voluntary exercise prevents and eliminates chronic pain-induced anxiety through neuronal mechanisms other than analgesic effects, potentially involving PV⁺ neurons, PNNs, and microglia in the corticolimbic subregions.</div></div>","PeriodicalId":52177,"journal":{"name":"Neurobiology of Pain","volume":"18 ","pages":"Article 100181"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}