Women are disproportionately affected by chronic pain, exhibiting greater incidence, severity, and duration of pain across a wide range of conditions. Women with chronic pain are also more likely to develop comorbid affective disorders, such as depression and anxiety. Although societal and environmental factors contribute to this sex bias, biological factors are also thought to play a role in these sex differences. One biological factor is calcitonin gene-related peptide (CGRP), a neuropeptide with established roles in the pathogenesis of several chronic pain conditions, including migraine. A prevailing hypothesis is that differences in the expression of CGRP and its receptor are involved in sex differences in chronic pain. We explore the evidence for this by reviewing the literature. We find that only a few studies, typically with small sample sizes, address this hypothesis. In aggregate, these studies provide nuanced and contradictory evidence for sex differences in the expression of CGRP and its receptor. However, we present published data that support the conclusion that the CGRP pathway functions differently in males and females.
Patients with neuropathic pain frequently experience clinically important sleep disturbance, but accessible biomarkers associated with sleep impairment remain limited. In this prospective longitudinal observational cohort study, 135 patients aged 40–65 years with DN4-confirmed neuropathic pain were assessed at baseline and 1 month after pulsed radiofrequency (PRF). Severe sleep disturbance was prespecified as a Pittsburgh Sleep Quality Index (PSQI) score > 10. Baseline systemic immune-inflammation index (SII), calculated from platelet, neutrophil, and lymphocyte counts, and first-morning urinary melatonin were compared between patients with and without severe sleep disturbance. At baseline, 73 patients met the severe sleep-disturbance criterion and 62 did not. Baseline SII was higher and urinary melatonin was lower in the severe sleep-disturbance group (both P < 0.01). SII correlated positively with PSQI score (r = 0.575, P < 0.001) and remained associated with severe sleep disturbance after adjustment for sex and body mass index (adjusted OR per unit increase, 1.011; 95% CI, 1.007–1.014, P < 0.001). Exploratory receiver operating characteristic analysis yielded an area under the curve of 0.833 (95% CI, 0.764–0.903). At 1 month, fewer patients met the severe sleep-disturbance criterion, SII and PSQI scores were lower, and urinary melatonin was higher than at baseline. Because there was no untreated or sham comparator, these longitudinal changes cannot be attributed specifically to PRF. Higher SII was associated with more severe sleep disturbance in this heterogeneous neuropathic-pain cohort. These findings support SII as a candidate biomarker for identifying patients at increased risk of severe sleep disturbance, although external validation and mechanistic studies are required before clinical application.
DNA methylation (DNAm) may link environmental exposures to pain susceptibility. We examined preoperative DNAm patterns (using next-generation enzymatic-methylation sequencing) associated with chronic postsurgical pain (CPSP), a major biopsychosocial problem in adolescents undergoing musculoskeletal surgeries, recruited across six sites (n = 166; 15.5 (IQR 14.3-16.8) years; 51% male). Pain and functional measures were followed longitudinally. CPSP was defined as pain>3/10 beyond two months post-surgery. We identified 289 differentially methylated loci (DML; HB p < 0.1) that satisfied robustness criteria after bootstrapping, and 20 regions (DMR) (FDR p < 0.05) associated with CPSP. Using CPSP-specific background, DMLs, annotated to 57 genes, were enriched for biological processes (Cellular response to cAMP (p = 0.001), neuronal action potential (p = 0.01), sodium ion transmembrane transport (p = 0.03), potassium ion transmembrane transport (P = 0.035) and regulation of postsynaptic membrane potential (P = 0.041)), molecular functions (Intracellular camp-activated cation channel activity (p = 0.001), cAMP binding (p = 0.003), voltage-gated sodium channel activity (p = 0.01), and voltage-gated potassium channel activity (p = 0.02)), and cellular components (HCN channel complex (p = 0.002), presynaptic active zone membrane (p = 0.006), and postsynaptic membrane (p = 0.049)). DMRs did not enrich gene pathways but showed transcription factor motif enrichment for stress response (TGF-β/SMAD), neuronal differentiation/plasticity (NR4A/TEAD), inflammation/immunity (STATs), and circadian signaling (RORA/RORB/NPAS2). Study findings suggest potential DNAm signatures associated with CPSP and generate hypotheses regarding their possible role in CPSP development.
Background: Pain empathy engages multiple neural networks. Neuroimaging research has identified anterior insula (aINS) and the sensorimotor network in processing pain empathy among women with primary dysmenorrhea (PDM). However, it remains unclear how the interaction between the two networks modulates pain empathy during menstrual pain. Methods: This case-control study included 56 women with PDM and 55 healthy controls (HCs). Participants were instructed to take functional MRI (fMRI) scans during the menstrual phase and view images depicting painful and non-painful situations to elicit empathy, as well as the short form of McGill Pain Questionnaire to elicit pain intensity. Functional connectivity (FC) analyses of the aINS-related and sensorimotor networks, and their interactions, were conducted to investigate their relationship with pain and pain empathy. Mediation analysis was performed to investigate the role of FC mediating menstrual pain and empathy. Results: PDM patients exhibited higher scores of pain empathy, which was significantly correlated with pain intensity. With comparable bilateral aINS-precentral/postcentral FC, left aINS-postcentral connectivity showed positive correlations with both pain intensity and empathy in PDM patients, whereas. the positive interaction between the left aINS- and precentral-centered networks was inversely associated with pain empathy in HCs. Furthermore, correlation and mediation analyses revealed that left aINS-right postcentral FC mediated the relationship between menstrual pain and pain empathy in PDM women. Conclusion: aINS-sensorimotor network interactions play a critical role in pain empathy, which may nonetheless engage in divergent regulatory processes under menstrual pain, shaping psychological adaptation and empathic responses.
Regulatory T cells (Tregs) maintain immune homeostasis and suppress inflammation, and emerging evidence indicates they also modulate neuronal function and regeneration. Dorsal root ganglion (DRG) sensory neurons transmit pain signals and are damaged by chemotherapeutic agents such as paclitaxel (PTX), leading to neuropathic pain. Although Tregs show therapeutic promise in neuropathic pain, the mechanisms of Treg-neuron interactions remain poorly defined. Using in vitro co-culture, we examined interactions between primary DRG neurons and Tregs and their effect on PTX-induced neurotoxicity. Live-cell imaging showed that activated Tregs enhanced neurite length and branching and preferentially localised to neuron/neurite-rich regions. Additionally, activated Tregs rescued PTX-induced inhibition of neurite outgrowth. Pharmacological blockade identified Treg-derived amphiregulin (AREG) as essential for neurite outgrowth, while both AREG and neuropeptide Y were required for Treg-mediated protection against PTX-induced neurotoxicity. These findings identify Tregs as direct promoters of sensory neuron growth and protection from PTX-induced neurotoxicity through specific molecular mediators, supporting their potential therapeutic relevance in peripheral neuropathic pain.
Pain arises from coordinated activity across distributed brain networks. The claustrum, a thin subcortical nucleus with extensive bidirectional connectivity with the neocortex, has recently emerged as a potential hub in this network. Although historically difficult to isolate due to its thin anatomical structure and proximity to other pain-associated regions, recent advances in neuroimaging and circuit-specific manipulations have revealed new insights into its role in pain. This review synthesizes the evidence from human and animal studies and evaluates the evidential strength of current approaches, ranging from incidental reporting in whole-brain neuroimaging studies to claustrum-targeted imaging, electrophysiology and projection-specific manipulations. The literature suggests that the claustrum contributes to pain not as a primary sensory relay, but as a modulatory and integrative structure influencing various facets of cognition. We have organized these findings into three theory-guided frameworks: (1) sensory filtering of salient stimuli, (2) cognitive network engagement, and (3) offline consolidation of pain-related memory during rest and sleep. In chronic pain, claustrocortical function is altered in ways that map onto each of these frameworks, with rodent models pointing to depressed claustrocingulate output and loss of inhibitory control, and human imaging linking claustrum signals to catastrophizing, expectancy, and altered network recruitment. Taken together, the evidence highlights the claustrum as a promising but incompletely understood node in pain circuitry and underscores the need for more anatomically precise and mechanistically decisive studies to define its contribution to normal and pathological pain states.
Bone cancer pain (BCP) affects most patients with bone metastases and is poorly managed by current analgesics. This study evaluated tetrathiomolybdate (TTM), a clinical copper chelator, for its potential to simultaneously target osteoclast activation and copper-dependent tumor growth in BCP. Using a mouse model with intrafemoral Lewis lung carcinoma cells, TTM (20-40 mg·kg-1 daily) significantly reduced mechanical allodynia and thermal hyperalgesia, even when treatment began after pain establishment. TTM suppressed osteoclast differentiation markers in bone tissue and bone marrow-derived macrophages cultures. It also directly inhibited tumor cell viability in vitro and reduced tumor burden in vivo by 43%. Mechanistically, TTM downregulated lysyl oxidase (LOX) in tumor bone, and exogenous LOX partially reversed the inhibitory effect of TTM on osteoclasts differentiation. These findings suggest that TTM alleviates BCP potentially through inhibition of copper-dependent tumor progression and attenuation of LOX-associated osteoclast activation. Our results support further investigation of copper-dependent signaling pathways as potential modulators of tumor-associated bone destruction and cancer-induced pain.
Introduction:Osteoarthritis (OA) is a chronic, progressive joint disorder with higher prevalence and pain severity in women than men. The endocannabinoid system (ECS) modulates pain and shows sexual dimorphism, yet sex-specific alterations in central ECS signalling in OA pain remain under-investigated. Objectives:We investigated sex-dependent differences in pain-related behaviours and central ECS signalling in the rat monoiodoacetate (MIA) model of knee OA pain. Methods:Adult male and female Sprague-Dawley rats (8-9 weeks old) received an intra-articular injection of either MIA (2 mg/50 μL) or saline (Sham control) in the left knee. Pain-related behaviours were assessed over 63 days post-injection. The influence of oestrous cycle stage on pain-related behaviours was examined in 100 additional MIA-injected female rats. Endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines [palmitoylethanolamide (PEA), oleoylethanolamide (OEA)] were quantified in brain and spinal cord regions (LC-MS/MS), and ECS-related gene expression (Faah, Mgll, Cnr1, Cnr2) was assessed (RT-qPCR). Results:MIA females exhibited greater weight-bearing deficits and hind paw mechanical hypersensitivity than males throughout the study period. Oestrous cycle stage did not influence MIA-induced pain-related behaviours. MIA males showed lateralised ECS signalling in the amygdala, with elevated endocannabinoid and N-acylethanolamine levels in the ipsilateral/left amygdala, a pattern absent in females. A bilateral reduction of Mgll expression in the amygdala was observed in MIA female rats compared to Sham controls. Conclusions:In the MIA model, female rats demonstrate greater nociceptive behaviour and a different amygdala ECS profile, compared with males, paving the way for further investigation of ECS-mediated mechanisms underlying sex differences in OA pain.
Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in COL7A1 gene, leading to chronic injury, inflammation, and debilitating sensory symptoms, including pain and itch. While structural defects in the dermo-epidermal junction are well characterized, the mechanisms underlying impaired sensory reinnervation and neuropathic manifestations remain poorly understood. Here, we investigated whether defective reinnervation in RDEB is driven by intrinsic neuronal deficits or by alterations in the cutaneous microenvironment. Using a prospective cohort of RDEB patients with small fiber neuropathy (SFN), combined with high-resolution digital PCR and multiplex cytokine profiling, we analyzed the transcriptional and secretory responses of wounded skin and primary keratinocytes. RDEB tissue exhibited a markedly blunted transcriptional response to injury, with failure to induce key inflammatory, proteolytic, and axonal guidance genes, despite a sustained pro-inflammatory secretome characterized by elevated IL-6, TNF-α, IL-1β, CCL2, and MMP9. Functionally, RDEB blister fluid induced growth cone collapse and impaired neurite outgrowth in sensory neurons. These findings reveal a dissociation between transcriptional activation and extracellular signalling, resulting in a non-permissive niche for nerve regeneration. We propose that this altered microenvironment simultaneously impairs reinnervation and promotes maladaptive nociceptive signalling, providing a mechanistic link between chronic denervation and neuropathic pain in RDEB.
Background:The mechanisms driving the transient reduction in pain sensitivity following a single bout of physical exercise-a phenomenon known as exercise-induced hypoalgesia (EIH)-remain unclear despite proposed contributions from central and peripheral processes. So far it is unknown whether EIH selectively modulates the perception of specific types of nociceptive stimuli and whether this modulation is confined to exercising limbs or generalized to the entire body. Methods:In 38 healthy males (18-30 years) the effects of a single session of moderate/high-intensity cycling exercise (25 min at 75% of the heart rate reserve) were assessed against a control condition (25 min of light cycling exercise) on the sensitivity to stimuli preferentially activating skin mechano- and heat-sensitive nociceptors versus deep-tissue nociceptors, applied to the exercising lower limbs versus the non-exercising upper limbs. Pressure pain thresholds (PPT), heat pain thresholds (HPT), cold detection thresholds (CDT), and mechanical pinprick ratings (PP), as well as auditory detection thresholds (ADT) serving as control, were recorded before and immediately after the exercise and control conditions. Results:Linear mixed models revealed that exercise increased the PPT selectively at the exercising limb. No significant effects of exercise were found for other types of stimuli, except for a reduction of CDT at the exercising limb, which was not significant when controlling for skin temperature. Conclusions:These findings suggest that processes preferentially modulating deep-tissue nociceptor sensitivity within exercising muscles contribute to EIH in young healthy males.
Pain in axial spondyloarthritis (axSpA) may precede clinically detectable inflammation or persist despite adequate control of inflammation. However, the mechanisms underlying this early pain state remain incompletely understood. We investigated nerve growth factor (NGF)-TrkA-calcitonin gene-related peptide (CGRP) signaling in dorsal root ganglia (DRG) before the onset of overt clinical arthritis, using a zymosan A (ZyA)-induced SKG mouse model of inflammatory arthritis with SpA-like features. Female SKG mice received ZyA, with or without a prophylactic anti-NGF monoclonal antibody treatment. Mechanical sensitivity, NGF protein levels in skin tissue, and expression of CGRP, TrkA and phosphorylated TrkA in DRG neurons were evaluated on day 10. ZyA-treated mice developed mechanical hypersensitivity by day 10, while no increase in clinical arthritis scores was observed during this period. In DRG neurons, an altered size distribution of CGRP-positive neurons toward larger-diameter populations was observed in association with early pain-related behavioral changes. These changes may involve downstream TrkA signaling. Prophylactic anti-NGF treatment attenuated the decrease in mechanical thresholds and reduced CGRP-neuronal size distribution changes and TrkA signaling changes. These findings suggest that NGF-associated DRG sensitization contributes to early pain-related behavioral changes during a prodromal phase of ZyA-induced disease, before overt clinical arthritis is established. Our study supports a mechanistic link between early pain-related behavioral changes and NGF-associated DRG sensitization, providing a rationale for further investigation of NGF-targeted strategies for pain management in axSpA.
Neuropathic pain is a dose-limiting side effect of chemotherapeutic agents such as paclitaxel, and it is unsuccessfully treated by available analgesics. Among the mechanisms underlying paclitaxel-induced neuropathic pain, neuroimmune interactions in the dorsal root ganglia (DRGs) play a pronociceptive role. However, how immune responses evolve over time during pain maintenance and persistence is poorly understood. Here we treated mice with six injections of paclitaxel (PTX) every other day over 10 days (cumulative dose of 15 mg/kg) and detected mechanical hypersensitivity that developed at day 7 and lasted up to day 28 after first PTX injection. We observed a time-dependent accumulation of macrophages in lumbar DRGs at day 28, but not day 14 after first PTX injection. At day 28, proinflammatory macrophages MHCII+CD206- accumulate in DRG together with the emergence of galectin-3 expressing macrophages. Galectin-3 expression was also found in splenic monocytes mirroring the DRG macrophage phenotype and pointing to a coordinated, compartment specific remodelling of innate immune responses. Early adaptive immune responses were spatially and temporally restricted with transient increase in CD8+ T cells in the DRG at day 7 while splenic regulatory T cells were selectively reduced 28 days after first PTX injection. Together these findings reveal that PTX treatment drives coordinated immune responses, and emergence of galectin-3 pro-inflammatory macrophages in DRG could be a feature of persistent paclitaxel-induced neuropathic pain.
Chronic pain states are often associated with sensory hypersensitivities, including acute sensitivity to light. White light exposure has been shown to activate a significant subset of pain-facilitating neurons and suppress firing of pain-inhibiting neurons in the rostral ventromedial medulla (RVM) leading to behavioral hyperalgesia. However, some recent evidence suggests that different wavelengths of light may have distinct effects on pain sensitivity. We therefore sought to understand how specific wavelengths of light influence the activity of RVM painmodulating neurons. We recorded the activity of identified, white light-responsive ON- and OFF-cells in the RVM of lightly anesthetized female rats, and tested their responses to the blue, green, and red components of a white light stimulus that was sufficient to alter their activity. We found that the majority of RVM OFF- and ONcells responded during exposure to blue and green, but not red, light, with suppression of antinociceptive OFFcell firing and activation of pronociceptive ON-cells. This pronociceptive influence of short- and middlewavelength light was manifested as a significant thermal hyperalgesia during exposure to blue and green light. Our results demonstrate that the pain-modulating cells of the RVM can be engaged by light of specific wavelengths, and that this results in significant behavioral hyperalgesia.
Impaired descending modulation and heightened pain sensitivity are thought to contribute to pain in knee osteoarthritis (KOA) and its persistence after total knee arthroplasty (TKA). These mechanisms can be assessed using quantitative sensory testing (QST), including pressure pain thresholds (PPT), conditioned pain modulation (CPM), and mechanical temporal summation (MTS). Magnetic resonance spectroscopy (MRS) enables non-invasive quantification of neurometabolites, including gamma-aminobutyric acid (GABA), glutamate + glutamine (Glx), myoinositol (Myo), and choline (tCho), which are suggested to modulate pain perception. This study investigated region-specific neurometabolite levels and their associations with pain mechanisms in individuals with KOA before and after TKA. Single-voxel MRS quantified neurometabolites in the anterior cingulate cortex, anterior insula, posterior insula, and somatosensory cortex in 20 female KOA patients and 19 pain-free controls. We found that anterior cingulate GABA was significantly lower in KOA patients prior to TKA compared to controls (p = 0.012). Prior to TKA, significant metabolite-QST interactions included: anterior cingulate Myo was associated with improved descending modulation (p = 0.0017; interaction p < 0.001), whereas controls showed the opposite in the anterior insula (p = 0.014; interaction p = 0.012). Following TKA, increases in somatosensory Myo (p = 0.016) and tCho (p = 0.031) were associated with worsened pain sensitivity (lower pain thresholds), whereas increases in anterior cingulate Myo (p = 0.018) and anterior insula tCho (p = 0.027) were associated with improved descending modulation and pain sensitization relative to pre-TKA, respectively. These results provide a foundation for future studies investigating neurochemical contributions to pain mechanisms and their potential relevance for pain phenotyping.
REST is a transcriptional repressor that regulates neuronal gene expression and neural cell identity. Recent studies have examined whether sex influences neuropathic pain (NP), yet findings remain inconsistent. Spared Nerve Injury (SNI) induced NP is associated with increased Rest expression in the dorsal root ganglion (DRG), where REST represses Oprd1 and Cnr1 transcription-a mechanism we previously defined in male mice. To determine whether this pathway operates similarly in females, we analyzed SNI-induced pressure, mechanical, and thermal hypersensitivity in female wild-type and Rest cKO mice, along with DRG expression of Rest, Oprd1, and Cnr1. Female wild-type mice exhibited robust SNI-induced hypersensitivity comparable to males and showed increased Rest with concomitant decreases in Oprd1 and Cnr1 mRNA levels in the DRG. Rest cKO in primary sensory neurons attenuated hypersensitivity and rescued Oprd1 and Cnr1 expression in females, paralleling effects seen in males; however, the rescue of hypersensitivity occurred significantly later in females. These findings suggest that REST-mediated repression of Oprd1 and Cnr1 contributes to NP in both sexes, but that its functional impact may be modulated by additional, as-yet-undefined sex-specific regulatory mechanisms. Thus, these results suggest that a systems-level approach will be required to fully define how sex shapes NP mechanisms.
Voltage-gated sodium channel Nav1.8 is highly expressed in nociceptors, where it plays a critical role in sustaining repetitive action potential (AP) firing. Gain-of-function Nav1.8 mutations that increase nociceptor excitability have been identified in patients with painful peripheral neuropathy, but the biophysical mechanisms by which they confer nociceptor hyperexcitability are incompletely understood. Here we carry out a high-resolution dissection of the functional consequences of a Nav1.8 mutation (G1662S) identified in human subjects with severe neuropathic pain, using dynamic clamp modeling in small dorsal root ganglion (DRG) neurons. While Nav1.8WT/GS conductance did not alter resting membrane potential, rheobase, or single AP threshold, it produced a marked hyperexcitability during repetitive firing. Nav1.8WT/GS neurons generated nearly twice as many APs as wild-type controls in response to suprathreshold depolarization, an effect attributable to increased sodium charge transfer across successive spikes. Charge analysis revealed that the GS mutation disproportionately enhanced suprathreshold sodium influx, supporting greater AP fidelity without adaptation. Biophysical dissection showed that this excitability phenotype arises from frequency-dependent mechanisms: at lower firing frequencies, the depolarizing shift in steady-state inactivation increases channel availability and contributes to G1662S-mediated hyperexcitability, whereas at higher firing frequencies both the depolarized voltage-dependence of inactivation and the accelerated recovery from inactivation further sustain G1662S hyperexcitability. Together, these properties enable Nav1.8WT/GS neurons to maintain enhanced firing across a broad range of frequencies, in contrast to wild-type nociceptors that typically adapt faster. These findings provide mechanistic insight into Nav1.8-driven hyperexcitability and highlight Nav1.8 as a therapeutic target for genetic and acquired pain syndromes.
The R221W mutation on the nerve growth factor gene results in reduced peripheral C-nociceptor density and behavioural indifference to painful stimuli. While functional neuroimaging has revealed altered cortical and sub-cortical pain processing in R221W carriers, structural white matter changes remain unexplored and may suggest an anatomical basis of symptoms. Heterozygous R221W carriers' (n = 11) and matched controls' (n = 11) diffusion MRI data were compared using fixel-based analysis, and complimentary edge and node analyses using graph theory and network-based statistics. Whole-brain and region of interest (ROI) fixel-based analyses revealed significantly reduced fibre density and fibre-bundle cross-section in brainstem motor tracts of R221W carriers, encompassing the corticospinal pathways, corona radiata, external capsule, cerebellar peduncles, and pontine crossing (p < 0.05). Graph theory analysis of pain-processing ROIs demonstrated significantly reduced node degree and betweenness centrality in the Left Anterior Cingulate Cortex (ACC) of R221W carriers, indicating structural isolation of this affective-motivational hub. Network-based statistics identified significantly stronger connectivity between the Right Thalamus and Right ACC in R221W carriers, in contrast to weaker connectivity connecting the Right Thalamus to the Left ACC and Left Insula (p < 0.05). These findings indicate potentially reduced brainstem motor tract integrity and altered cortical network topology, specifically the structural isolation of the Left ACC. This, alongside potentially compensatory right-sided thalamo-cortical connectivity and preserved sensory afferent pathways, supports a model of R221W pain indifference as motor under-reactivity rather than sensory insensitivity.
Most pain studies overlook the relationship between corticomotor function changes and coordinated muscle patterns in voluntary movement. A pre-post study was performed to investigate relationships between changes in corticospinal excitability (CSE) and spatial changes in muscle coordination in response to pain. Methods: Thirty pain-free participants performed an upper limb pointing task in pain-free then experimental painful conditions. Transcranial magnetic stimulation was used to assess CSE via the deltoid muscle input-output curves (slope, plateau and S50). Electromyography was used to record trapezius and deltoid muscle activity. Spatial adaptations of muscle coordination to pain were assessed using non-negative matrix factorization (NNMF), comparing the norm of coordination pattern vectors between pain and no-pain conditions, as well as the cosine of the angle between these vectors. Correlations were examined among pain-induced changes in CSE and muscle coordination. Results: Correlations revealed associations between pain-induced S50 change and both pain-induced cosine and norm changes (rS = 0.43; p = 0.05 for both). Additionally, a correlation was found between pain-induced changes in the coordination pattern's norm and both the IO curve's slope (rS = -0.46; p = 0.04) and plateau (rS = 0.45; p = 0.04). Discussion: Overall, this study showed that pain-induced CSE changes were associated with changes in muscle coordination, with participants exhibiting greater CSE changes also showing greater coordination changes.
A disintegrin and metalloprotease 17 (ADAM17) mediates the shedding of key pro-inflammatory cytokines, yet its specific contribution to neuropathic pain remains elusive. Here, we investigated the role of ADAM17 in the rat spinal nerve ligation (SNL) model. Following nerve injury, ADAM17 expression was significantly upregulated in the spinal dorsal horn (SDH) and dorsal root ganglion (DRG). Specifically, ADAM17 colocalized with TRPV1 and IB4 positive afferents in the superficial SDH, and with IB4, CGRP, and TRPV1 positive neurons in the DRG. Intrathecal administration of exogenous ADAM17 to naive rats recapitulated neuropathic pain behaviors—inducing mechanical and thermal hypersensitivity—and significantly increased the levels of TNF-α, IL-1β, and IL-6 in the SDH. Conversely, therapeutic treatment with Xpro®1595 markedly attenuated SNL-induced pain behaviors. This analgesic effect correlated with the suppression of injury-induced ADAM17 upregulation and a consequent reduction in proinflammatory cytokines. These findings demonstrate that ADAM17 is a critical driver of the neuroinflammatory cascade in neuropathic pain. Moreover, our data suggest that the analgesic efficacy of Xpro®1595 is mediated, at least in part, by disrupting this ADAM17-dependent inflammatory feedback loop.
