Molecular Pain最新文献

{"title":"Differential expression of µ-, δ-, and κ-opioid receptors in muscle afferents from male and female rats.","authors":"Jeong Sook Kim-Han, Megan Elmslie, John R Miller, Lance Evans, Farida Elkadi, Joshua Moody, Jonathan Easterwood, Keith S Elmslie","doi":"10.1177/17448069261492539","DOIUrl":"https://doi.org/10.1177/17448069261492539","url":null,"abstract":"<p><p>Small diameter unmyelinated (group IV) and myelinated (group III) muscle afferents transmit action potentials to signal muscle pain and the exercise pressor reflex (EPR). The EPR helps to drive the cardiovascular response to exercise. µ- (µOR), δ- (δOR), and <i>κ</i>- (κOR) opioid receptors (OR) have been shown to be expressed by dorsal root ganglia (DRG) neurons, but only peripheral µOR activation has been shown to inhibit the EPR mediated by group IV afferents. To determine if this results from differential OR expression, we identified group IV neurons in DRG and axons in gastrocnemius muscles from both male and female rats, and used immunocytochemistry to compare the expression of µOR, δOR, and κOR. We show that µOR labeling was more frequently observed in group IV somata and axons vs. δOR or κOR. OR axonal labeling was lower than somata labeling, particularly for δOR & κOR. There were no significant differences in OR staining between male and female animals. The relatively high µOR axonal expression suggests that µOR are selectively transported to the peripheral group IV axons and can explain the selective effect of µOR agonists to inhibit group IV afferent activity that generates the EPR and muscle pain.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261492539"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The anterior cingulate cortex mediates cisplatin-induced mechanical allodynia and represents a target for cannabigerol antinociception.","authors":"Matheus Vinicius Ferreira, Nathan Morris, Quinn Wade, Joice Maria da Cunha, Nicholas Graziane","doi":"10.1177/17448069261491110","DOIUrl":"10.1177/17448069261491110","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating consequence of cancer treatment with limited effective therapeutic options. While peripheral nerve injury is a key driver, emerging evidence suggests that maladaptive plasticity within central pain circuits, including the anterior cingulate cortex (ACC), contributes to the maintenance of neuropathic pain. Here, we tested the hypothesis that the ACC is a critical substrate for cisplatin-induced mechanical allodynia and a target for cannabigerol (CBG)-mediated antinociception. Adult male C57BL/6 mice received cisplatin (5 mg/kg, i.p., once weekly for four weeks) to induce CIPN. Mechanical allodynia was assessed using electronic von Frey testing. Systemic administration of CBG (20 mg/kg, i.p.) significantly reversed mechanical allodynia in CIPN mice without affecting baseline thresholds in non-neuropathic animals, indicating a state-dependent effect. Chemogenetic inhibition of ACC neurons using hM4Di DREADDs similarly attenuated mechanical allodynia, identifying the ACC as a functionally relevant component of the CIPN pain state. To determine whether CBG acts within this circuit, bilateral intra-ACC microinjections of CBG (20 nM and 20 µM) were performed, both of which produced transient antinociceptive effects. These findings demonstrate that the ACC contributes to the maintenance of mechanical allodynia in CIPN and establish this region as a site of action for CBG. Together, our results support a model in which the ACC represents a convergent cortical mechanism underlying pathological pain and highlight the potential for centrally targeted, non-euphoriant cannabinoid-based therapies.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261491110"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precursor signaling redefined: Proneurotrophin-3, not neurotrophin-3, in primary sensory neurons as an instigator in neuropathic pain.","authors":"Huijie Shang, Ruhika Iyer, Bing Wang, Yuan-Xiang Tao","doi":"10.1177/17448069261460645","DOIUrl":"10.1177/17448069261460645","url":null,"abstract":"<p><p>Neurotrophin-3 (NT3), one member of the nerve growth factor family of neurotrophins, is initially synthesized as a large precursor, termed proneurotrophin-3 (proNT3), which undergoes proteolytic cleavage to generate mature NT3. A growing body of evidence suggests that proNT3 and its mature form, NT3, have opposing roles in the nervous system. A systematic literature search of PubMed was conducted using predefined search terms related to NT3, proNT3, expression, dorsal root ganglion (DRG), and pain. The role of NT3 in neuropathic pain has been debated in earlier studies. Importantly, more recent studies have shown that proNT3, rather than NT3, is expressed in the DRG. In this review, we delineate the expression and distribution pattern of proNT3 in primary sensory neurons of the DRG under normal conditions, as well as its upregulation in injured DRG following peripheral nerve injury. We highlight that DRG proNT3 upregulation is required for the development and maintenance of neuropathic pain and discuss the role of C-C chemokine ligand 2 in mediating the contribution of proNT3-triggered TrkC activation to neuropathic pain in the DRG.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261460645"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148176074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cells modulate the development and maintenance of painful paclitaxel-induced peripheral neuropathy in RNU rats.","authors":"Ahmed Olalekan Bakare, Gerard Limerick, Vasudha Goel, Ratan K Banik, Lei Zheng, Andrew J Shepherd, Kristine Glunde, Qin Zheng, Eellan Sivanesan","doi":"10.1177/17448069261418431","DOIUrl":"10.1177/17448069261418431","url":null,"abstract":"<p><p>The role of T cells in chemotherapy-induced peripheral neuropathy (CIPN) is complex and shaped by biological and experimental factors, including sex, hormonal status, genetic background, and cancer model. This complexity has contributed to inconsistent findings among studies, limiting therapeutic progress. In this study, we investigate how T cells contribute to painful paclitaxel (PTX)-induced peripheral neuropathy (PIPN). Adult male T cell-competent (RNU^+/-) and T cell-deficient (RNU^-/-) rats were subcutaneously inoculated with tumor cells and subsequently treated with intraperitoneal PTX (8 mg/kg total dose). Reflexive (mechanical, heat, cold) and non-reflexive (burrowing, gait) pain behaviors were assessed from baseline through week 6. Immunohistochemistry (CD68, CX3CR1, CD206) and flow cytometry (CD163, CD86, CD11b/c, CD3, CD161a, CD45RA) were used to assess macrophage and lymphocyte populations. T cell-competent, but not -deficient, rats developed and maintained cold hypersensitivity following PTX. T cells also reduced the onset intensity of PTX-induced mechanical hypersensitivity. In T cell-competent rats, PTX reduced T and B cell counts and increased the CD4+/CD8+ T cell ratio across DRG, sciatic nerve, and spleen. PTX shifted macrophage polarization toward the M1 phenotype and reduced the M2/M1 ratio, independent of T cells. However, M2 macrophages (M2γ and M2a) increased specifically in the sciatic nerves of T cell-deficient rats. Additionally, natural killer (NK) cells decreased in PTX-treated, T cell-deficient rats but remained unchanged in T cell-competent rats. These findings highlight the complex role of T cells in PIPN. In PIPN, T cells play a critical role in driving PTX-induced cold hypersensitivity. A decrease in their number worsens pain intensity, possibly by altering the CD4+/CD8+ T cell balance. In contrast, NK cell reductions in T cell-deficient rats may contribute to hypersensitivity in the absence of T cells.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261418431"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12886724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145966517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lithium prevents the neurotoxic effects of paclitaxel mediated through TRPA1 channels.","authors":"Julio C Sánchez, Aníbal Valencia-Vásquez, Juan C Olaya, Alexander Alemán, Jenifer Guerrero, Martín Torres, Luís F Martínez, Laura V Muñoz","doi":"10.1177/17448069251410396","DOIUrl":"10.1177/17448069251410396","url":null,"abstract":"<p><p>Paclitaxel (PTX) is a drug commonly used in cancer chemotherapy despite its neurotoxicity. TRPA1 channels are essential mediators of sensory transduction and nociception. These cation channels are linked to PTX-induced neurotoxicity, which Li⁺ prevents. This study aimed to examine the effects of Li+ on PTX-induced neurotoxicity and on TRPA1 channels. We utilized the SH-SY5Y cell line to assess cell viability via the MTT assay. Intracellular Ca²⁺ concentration in Fura-2-loaded cells was measured using spectrofluorometry. TRPA1 channel activity was evaluated with whole-cell patch-clamp recordings. The effects of PTX, Li⁺, and TRPA1 agonists and antagonists were tested. Motor function, thermal response, and cognitive performance were assessed in adult Wistar rats with neuropathy induced by PTX. PTX (100 nM) significantly reduced cell viability, and Li⁺ (10 mM) alleviated this effect. AITC (300 µM), a TRPA1-selective agonist, decreased cell viability, with a more pronounced impact when PTX was present. A967079 (10 µM), a selective TRPA1 antagonist, significantly lessened the cytotoxicity caused by PTX. Li⁺ reduced the cytotoxic effects of TRPA1 activation both with and without PTX. PTX increased TRPA1 currents and amplified TRPA1-mediated intracellular Ca²⁺ increase, while Li⁺ neutralized both effects. Additionally, PTX causes sensorimotor and cognitive neuropathy, which was reversed by Li⁺ treatment. These findings suggest that Li⁺ may act as a neuroprotective agent, preventing neuronal damage caused by PTX via TRPA1 channel pathways.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251410396"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145724312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spinal overexpression of CAPN1 in CaMKII neurons mediates paclitaxel-induced neuropathic pain via NCS-1-TRPV4 signaling.","authors":"Ya-Ning Zhang, Shao-Xia Chen, Qiao-Yun Li, Jia-Qi You, Yao-Hui Zhou, Ying Zang","doi":"10.1177/17448069251413873","DOIUrl":"10.1177/17448069251413873","url":null,"abstract":"<p><strong>Background: </strong>Paclitaxel (PTX), a widely administered chemotherapeutic drug, is known to cause neuropathic pain as a severe adverse effect. Elevated calpain expression in tumor tissues not only mediates chemoresistance but may also participate in the paclitaxel-induced neuropathic pain (PINP). There is still controversy over whether Calpain-1 (CAPN1), a subtype of calpain protease, exerts neuroprotective effects or nociceptive effects. The role and underlying mechanism of calpain1 in PINP remain unclear.</p><p><strong>Results: </strong>To clarify the contribution of calpain to CIPN, we examined the protein expressions of CAPN1, CAPN2, Neuronal Calcium Sensor-1(NCS-1), and Transient Receptor Potential Vanilloid 4 (TRPV4) in the DRGs and spinal dorsal horn (SDH) of PTX-treated rats. Results showed no significant changes in CAPN1 and CAPN2 protein levels in the DRGs, but marked upregulation in the SDH, along with heightened calpain activity, as evidenced by the accumulation of spectrin degradation products (a known substrate of calpain). The abnormal enhancement of CAPN1 in PTX-treated rats, contrasting with its reduced expression in most chronic pain models, prompted further investigation into its potential involvement in chronic pain. Immunofluorescence double-staining confirmed that CAPN1 localization was predominantly neuronal. Intraspinal CAPN1 overexpression restricted to CaMKII neurons in the naive rats effectively reproduced paclitaxel-induced neuropathic pain (PINP) with a comparable extent and duration of pain threshold reduction. Western blot analysis revealed that CAPN1 overexpression in spinal CaMKII neurons elevated NCS-1 expression, a calcium-binding protein essential for maintaining calcium homeostasis, which in turn strengthen the expression of CAPN2 as well as the calpain enzymatic activity. These data indicate that CAPN1 does not confer neuroprotective effects in paclitaxel-induced pain models. Rather, its overexpression in spinal CaMKII neurons directly promotes nociceptive signaling, most likely through disruption of plasma membrane calcium dynamics. Collectively, the results identify CAPN1 as a candidate therapeutic target for the clinical treatment and prevention of PINP.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069251413873"},"PeriodicalIF":2.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12855738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus co-expression analysis identifies a common set of co-expressed genes associated with diabetic peripheral neuropathy and chemotherapy-induced peripheral neuropathy.","authors":"Kord M Kober, Esther Chavez-Iglesias, Nam Woo Cho, Sue S Yom, Niharika Dixit, Marina Sirota, Alexandre Chan, Adam Olshen","doi":"10.1177/17448069261435315","DOIUrl":"10.1177/17448069261435315","url":null,"abstract":"<p><strong>Background: </strong>Diabetic peripheral neuropathy (DPN) and chemotherapy-induced peripheral neuropathy (CIPN) are major clinical challenges with limited therapeutic options. While these conditions arise from different causes, they may share common molecular mechanisms that could be targeted for intervention.</p><p><strong>Methods: </strong>We performed consensus weighted gene co-expression network analysis (WGCNA) on two publicly available datasets: GSE185011 (DPN vs healthy controls in peripheral blood mononuclear cells) and GSE173610 (paclitaxel-treated vs control iPSC-derived sensory neurons). After filtering all but the most variable genes, consensus analysis was used to identify conserved co-expression modules across both conditions.</p><p><strong>Results: </strong>Consensus analysis identified a 193-gene module (ME3/brown) significantly associated with both DPN (correlation = 0.817, <i>p</i> = 0.0040) and CIPN (correlation = 0.971, <i>p</i> = 0.0060). Functional enrichment analysis of this module revealed pathways related to Glycolysis, FoxO signaling, Apoptosis, and Autophagy.</p><p><strong>Conclusions: </strong>Our analysis reveals a convergent molecular signature underlying both DPN and CIPN, centered on metabolic reprogramming, transcriptional stress, and programmed cell death. These findings provide a systems-level framework for developing therapies targeting shared pathological mechanisms.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261435315"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13039646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP gene variants show preliminary evidence of association with patient-reported outcomes in active-duty service members with chronic pain.","authors":"Nathan L Tintle, Nathan A Ryder, Jason Westra, Dahee Wi, Sotaro Shimada, Nicholas Ieronimakis, Honor M McQuinn, Tyler J Snow, Ardith Z Doorenbos, Diane M Flynn","doi":"10.1177/17448069261454823","DOIUrl":"10.1177/17448069261454823","url":null,"abstract":"<p><p>Chronic pain is highly prevalent among active-duty service members (ADSMs) and contributes to substantial physical, psychological, and social burden. Genetic factors are recognized as central to pain susceptibility and treatment response. While few studies have examined the genes involved in cortisol synthesis, changes in the coding of cytochrome P450 (CYP) enzymes responsible for cortisol production have been implicated in chronic pain. We evaluated whether exonic variants in <i>CYP11B1</i> and <i>CYP17A1</i> are associated with salivary cortisol and pain-related outcomes in ADSMs with chronic pain using baseline genomic, salivary cortisol, and web survey data from 118 participants in a pragmatic clinical trial. We identified 40 variants across <i>CYP11B1</i> and <i>CYP17A1</i> exons and examined both common and rare variant burden scores. Linear regression models estimated associations with 11 outcomes, including pain intensity, sleep-related impairment, depression, and physical and social functioning. Mediation by cortisol was also assessed. Variants in both genes showed consistent associations with pain outcomes. Rare <i>CYP11B1</i> variants (minor allele frequency <5%) demonstrated the strongest relationships with pain intensity, pain impact, depression, fatigue, and sleep-related impairment. <i>CYP17A1</i> variants were strongly associated with sleep-related impairment, depression, fatigue, anxiety, and pain impact. Rare <i>CYP11B1</i> variants were associated with salivary cortisol; however, mediation analyses indicated that cortisol accounted for only a modest proportion (4%-18%) of the gene-pain associations. These exploratory findings suggest that functional variation in cortisol-related CYP genes may contribute to pain-related outcomes among ADSMs with chronic pain, warranting replication in larger cohorts. The research protocol was registered in ClinicalTrials.gov (NCT03297905).</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":" ","pages":"17448069261454823"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrathecal injection in MaFIA mouse model inflicts localized reduction of macrophage populations within the dorsal root ganglia.","authors":"Samuel B Chivers, Cassandra L McLay, Nathaniel A Jeske","doi":"10.1177/17448069261479081","DOIUrl":"10.1177/17448069261479081","url":null,"abstract":"<p><p>Macrophages represent an essential component of the innate immune system that regulates multiple nervous system functions. This is highlighted in previous research that identifies an important somatosensory role for macrophages in peripheral dorsal root ganglia (DRG). In several pre-clinical pain models, DRG macrophage numbers increase with little evidence as to the origin. The objective of this work was to investigate this phenomenon with the innovative Macrophage Fas-Induced Apoptosis (MaFIA) mouse transgenic animal model and establish the source of macrophage expansion in a chronic intermittent hypoxia model. Intrathecal administration of AP20187 was performed in MaFIA mice to take advantage of the blood brain barrier impermeability of AP20187 and prevent exposure to systemic tissues in order to determine whether knocking down DRG tissue resident macrophages would alter hypoxia-related doubling of cell numbers in DRG. Localized AP20187 exposure to the central nervous system and adjacent DRG structures reduced macrophage in restricted neuronal tissues including spinal column and DRG without affecting macrophage populations in bone marrow, circulating blood, and sciatic nerve. Furthermore, MaFIA mice treated with AP20187 produced no increase in DRG macrophage cell numbers following exposure to chronic intermittent hypoxia. These findings indicate that targeted intrathecal administration of AP20187 reduces DRG tissue-resident macrophages and prevents chronic intermittent hypoxia-induced expansion of the innate immune cell population, negating a role for circulating monocytes in the phenomenon.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261479081"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orofacial neuropathic pain and enhanced excitability of non-nociceptive-like and nociceptive-like trigeminal Aβ-afferent neurons in mice following infraorbital nerve chronic constrictive injury.","authors":"Tatsuo Ueda, Saurav Gupta, Amit Raj Sharma, Jennifer Ling, Jianguo G Gu","doi":"10.1177/17448069261499167","DOIUrl":"https://doi.org/10.1177/17448069261499167","url":null,"abstract":"<p><p>Orofacial neuropathic pain is a debilitating pain condition. It is poorly treated, partially due to an incomplete understanding of its underlying neurophysiological mechanisms. Orofacial neuropathic pain is often caused by injury or dysfunction of trigeminal nerve branches, including the infraorbital nerve (IoN). Clinically, a main symptom of orofacial neuropathic pain is mechanical allodynia, excruciating pain induced by gentle touch. While previous studies on neuropathic pain have mainly focused on the involvement of C- and Aδ-afferents, the potential contribution of Aβ-afferents to orofacial neuropathic pain has not been well explored. In the present study, we have established a mouse model of chronic constrictive injury of the IoN (IoN-CCI) and assessed orofacial pain behaviors and excitability of Aβ-afferent trigeminal ganglion (TG) neurons. Behavioral assessment using the von Frey test has revealed significantly increased mechanical sensitivity 3-4 weeks post-surgery in IoN-CCI mice compared with the sham group. Machine-learning-based eyelid distance measurement has demonstrated orbital tightening in IoN-CCI mice, suggesting spontaneous pain. Using <i>ex vivo</i> TG preparations and patch-clamp recordings, we have found that action potential (AP) thresholds are significantly reduced in both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons of IoN-CCI mice. Consistently, there is a significant increase in voltage-gated Na⁺ currents in both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons following IoN-CCI. Our findings demonstrate that both non-nociceptive-like and nociceptive-like Aβ-afferent TG neurons undergo hyperexcitability following infraorbital nerve injury, raising the possibility that both types of Aβ-afferent TG neurons may contribute to orofacial neuropathic pain following infraorbital nerve injury.</p>","PeriodicalId":19010,"journal":{"name":"Molecular Pain","volume":"22 ","pages":"17448069261499167"},"PeriodicalIF":3.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}