Early-life stress (ELS) causes pain hypersensitivity in neonatal mice and alters the transcriptional profile of the immature dorsal root ganglia (DRG), highlighted by a marked reduction in the expression of a neuropeptide, somatostatin (Sst), which is known to constitutively suppress peripheral nociceptive transmission during adulthood. However, the mechanisms that drive plasticity in gene expression within the developing DRG and neonatal pain after ELS remain unclear. Here, we investigated the degree to which ELS-induced neonatal pain was mediated by corticosterone signaling onto sensory neurons and potential changes in peripheral Sst transmission. The conditional knockout of the mineralocorticoid receptor (MR), but not the glucocorticoid receptor, from immature DRG neurons prevented ELS-evoked neonatal pain. In contrast, the systemic administration of the selective MR antagonist eplerenone failed to acutely influence pain after ELS, thus suggesting that MR activation enhances pain during the neonatal period via canonical effects on gene transcription. Meanwhile, hind paw injection of the Sst receptor antagonist cyclo-somatostatin increased spontaneous nocifensive behaviors in control pups, but not in pups previously subjected to ELS, raising the possibility that a disruption in tonic antinociception mediated by peripheral Sst contributes to neonatal pain after ELS. Furthermore, administration of the peripherally restricted Sst analog octreotide reversed noxious cold and pressure hypersensitivity in neonatal mice after ELS. Finally, the selective deletion of MR from sensory neurons prevented the ELS-induced decrease in Sst expression. Collectively, these results provide novel mechanistic insight into the effects of chronic early-life adversity on nociceptive processing in the developing nervous system.

Why some surgical patients develop pain that extends beyond the original site of injury while others do not remains poorly understood. The recently proposed Risk of Pain Spread (ROPS) framework integrates multiple psychosocial risk factors associated with widespread pain, but its generalizability to surgical populations has not been established. Using 2 large presurgical cohorts of participants undergoing total knee arthroplasty or thoracic surgery, we evaluated the generalizability of the ROPS framework and examined relationships among psychosocial and sociodemographic factors, surgical-site pain, nonsurgical-site pain, and widespread pain using complementary latent-variable, regression, Bayesian network, and mediation analyses. Across cohorts and analytical approaches, fatigue emerged as the most consistent correlate of pain outcomes, independent of other measured risk factors. Fatigue also occupied a central position within the conditional dependency structure of psychosocial and pain variables and accounted for substantial shared variance linking sleep disturbance, depressive symptoms, neuroticism, adverse childhood experiences, and socioeconomic disadvantage with pain intensity. Nonsurgical-site pain consistently occupied a position linking pain intensity with widespread pain across complementary analyses. Together, these findings externally validate the ROPS framework in clinically relevant surgical populations and identify fatigue as a central correlate linking biopsychosocial vulnerability with pain burden.

Neuropathic pain after peripheral nerve injury is a multifactorial condition mediated partly by inflammation in the spinal cord that results in potentiation of excitatory synaptic transmission in nociceptive circuits. Glial cells including astrocytes are key mediators of the underlying inflammation, but the signaling checkpoints that regulate astrocyte-driven spinal cord inflammation and sensitization of nociceptive circuits are not well understood. Here, we identify Orai1-mediated store-operated Ca2+ entry (SOCE) as an important regulator of spinal astrocyte cytokine production, metabolic reprogramming, and pain hypersensitivity in mice. Conditional deletion of Orai1 in astrocytes attenuated mechanical allodynia after nerve injury in male but not female mice, despite comparable SOCE suppression in both sexes. Orai1 deficiency also attenuated production of proinflammatory cytokines after SOCE activation, including TNFα, IL-6, and IL-33, both in vivo and in vitro. Electrophysiological recordings revealed that astrocyte Orai1 deletion prevented injury-induced enhancement of glutamatergic synaptic transmission in dorsal horn neurons, linking astrocytic Ca2+ signaling to central sensitization. Metabolomic profiling showed that Orai1 loss disrupted glycolysis and TCA cycle intermediates while promoting accumulation of immunomodulatory metabolites such as itaconate, consistent with a less inflammatory astrocyte metabolic state. These findings identify Orai1 channels as integrators of astrocyte Ca2+ signaling, immunometabolism, and excitatory synaptic potentiation after nerve injury, and identify a sexually dimorphic astrocyte mechanism governing neuropathic pain pathogenesis. Targeting astrocyte Orai1 channels may provide a selective therapeutic strategy for male-predominant chronic pain.

Peripheral sensitization is a key process in the development of painful inflammatory conditions, driven in part by immune-cell mediator release following tissue injury. The G protein-coupled receptor, GPR183, predominantly expressed on immune cells, regulates their migration, positioning, and mediator production. However, its role in peripheral sensitization and the specific immune cells involved remains insufficiently understood. In rats, intraplantar injection of 7α,25-dihydroxycholesterol (7α,25-OHC), the most potent endogenous GPR183 ligand, produced long-lasting nociception that was prevented by the selective GPR183 antagonist SAE-14. As GPR183 activates extracellular signal-regulated kinase signaling, which influences pain pathways including nitric oxide synthase (NOS) activity and NO formation, we used NOS inhibitors and knockout animals to test the contribution of inducible and neuronal NOS isoforms to 7α,25-OHC-induced sensitization. We found that both isoforms influence this response, independent of cyclooxygenases. In a well-characterized rat incisional injury model, GPR183 protein expression increased in injured paw tissue, and SAE-14 reversed hypersensitivity. Meta-analysis of human postsurgical skin samples similarly showed elevated GPR183 expression and transcriptional changes favoring 7α,25-OHC production after injury. We identified macrophages, Langerhans cells (LCs), and T cells as the principal GPR183-expressing cell types in human skin. Ablation of LCs and removal of mature B and T cells revealed that 7α,25-OHC-evoked hypersensitivity does not depend on these cell types, leaving GPR183+ macrophages as the most likely drivers of GPR183-induced hypersensitivity. Overall, our findings define the cellular and molecular pathways linking GPR183 to peripheral sensitization and highlight GPR183 antagonism as a promising strategy for pain management.

Pain is commonly described in sensory terms, yet its spatial characteristics are rarely quantified. We investigated whether lay beliefs about pain distribution influence theoretical decisions to seek care and treatment preferences. In a cross-sectional survey (N = 503; 49% reporting pain), participants completed thought experiments in which both visually presented pain distribution patterns (small, moderate, or large) and pain intensity (Numerical Rating Scale scores: 2, 5, 8/10) were systematically varied. For each scenario, they rated the likelihood of (1) seeking professional help (LoSH) and (2) taking analgesic medication (LoTM) on 0 to 100 scale. Participants also completed a spatial-intensity trade-off task, in which they chose between a fixed 20% reduction in intensity and variable reductions in pain distribution (20%-80%). A reversed version contrasted a fixed 80% reduction in pain distribution with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater pain distribution (P < 0.001), mirroring the gradient observed for pain intensity. In the spatial-intensity trade-off task, participants' choice followed a sigmoid-like function (P < 0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of pain distribution. This ratio was lower in individuals experiencing pain compared with pain-free individuals. Moreover, 61% reported that pain distribution should be routinely considered in pain management alongside intensity. Results suggest that pain distribution is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

Breakthrough cancer pain episodes often require oral immediate release opioids or parenteral opioid treatment. Different formulations and application modalities have been approved for this condition. This study aimed to identify the most effective of the available substances and applications to treat breakthrough cancer pain. We conducted a comprehensive systematic review with network meta-analysis. The database search included MEDLINE, CENTRAL, Embase, and Web of Science. Eligible were randomized controlled trials comparing opioids and application modalities for the treatment of breakthrough cancer pain episodes. Primary end points were the pain intensity difference (PID) at 15 and 30 minutes. Secondary end points were side effects and adverse events, as well as dichotomous outcomes of treatment success. Frequentist network meta-analysis was conducted using the package netmeta in R. From 5133 records initially identified by the literature review, 23 studies were eligible for quantitative analysis. Compared with placebo, the most effective interventions at 15 minutes (PID) were intravenous or subcutaneous applications of morphine, and intranasal fentanyl or sublingual fentanyl tablets. After 30 minutes (PID), the most effective interventions were still subcutaneous and intravenous morphine, but also sublingual fentanyl tablets. Intranasal fentanyl spray was equally effective as buccal and other transmucosal applications by 30 minutes. The quality of evidence on the topic is poor as most studies are phase III trials for drug approval. The risk of publication bias is therefore high. Sublingual fentanyl tablets were as effective as intravenous or subcutaneous morphine and are a practical modality for self-administration.

Pain is a leading cause of disability worldwide, yet undergraduate medical education remains insufficient to prepare future physicians for its assessment and management. The International Association for the Study of Pain (IASP) has proposed a competency-based curriculum framework; however, its implementation in Brazilian medical education is unclear. The aim of this study was to evaluate the availability of pain education in Brazilian medical schools and assess its alignment with the IASP Curriculum Outline on Pain for Medicine. We conducted a national cross-sectional documentary analysis of all medical schools registered in the Brazilian Ministry of Education database between May 2024 and December 2025. Institutional websites were systematically screened for publicly available curricular documentation, and data were independently extracted by 2 reviewers. Variables included the presence of pain-related content, existence of a dedicated pain course, course workload, timing within the curriculum, and type of offering. Among 447 identified schools, 277 (62.0%) provided accessible curricular information. Only 47 institutions (16.9%) offered a stand-alone pain course, and 29 had detailed syllabi for item-level analysis. Most analyzed courses were mandatory and delivered in the early years of training. Alignment with IASP competencies was incomplete across all domains, with greater coverage of neurobiological and pharmacological content and limited inclusion of pain assessment and measurement, psychosocial and behavioral management, public health, ethics, and care for special populations. Pain education in Brazil is inconsistently structured and only partially aligned with international recommendations, indicating the need of comprehensive, competency-based curricular reform.

Physical disuse is a major risk factor for complex regional pain syndrome type I. Using a rat chronic post-cast pain model, we investigated how oxidative stress modulates pain processing across the neuraxis and evaluated sex as a biological variable. Following immobilization, both sexes developed widespread mechanical hyperalgesia, which was markedly attenuated by the antioxidant Tempol. However, we uncovered a striking phenotypic dissociation: whereas male rats also developed tactile and cold allodynia, female rats completely lacked tactile allodynia. Peripherally, Tempol reduced neurogenic inflammation and suppressed p38 MAPK phosphorylation in peptidergic and nonpeptidergic dorsal root ganglion nociceptors, demonstrating a conserved reactive oxygen species-dependent "hardware" for mechanical pain. Centrally, Tempol inhibited plasticity-related pERK expression in neurokinin1 receptor-positive projection neurons and stimulus-evoked c-Fos in the lumbar (L5) and sacral (S2) dorsal horn. Crucially, the sex-specific behavioral divergence correlated with distinct neuroimmune profiles. Quantitative polymerase chain reaction revealed that while male rats exhibited a robust pro-inflammatory cytokine upregulation (C-C motif chemokine ligand 2, interleukin-1beta, interleukin-6) in the soleus muscle, this inflammatory cascade was markedly blunted in female rats. Consistent with this lack of peripheral inflammatory amplification, optogenetic stimulation of nonnociceptive Aβ fibers failed to induce c-Fos in the female spinal cord and central amygdala-a maladaptive sensory processing shift that Tempol successfully reversed in male rats. These findings demonstrate that disuse-induced oxidative stress initiates sensitization across the neuraxis. Importantly, our study reveals that while reactive oxygen species drives mechanical pain uniformly, the development of tactile allodynia requires a sexually dimorphic inflammatory amplification, underscoring the critical need for personalized, sex-specific therapeutic strategies in pain management.

Alpha-band oscillatory activity, assessed using electroencephalography (EEG), is among the most widely studied neurophysiological markers of pain. However, the literature has focused predominantly on resting-state measures, leaving unclear whether pain also alters evoked alpha-band dynamics, measured via cortical perturbation using transcranial magnetic stimulation (TMS). Here, we examined whether prolonged pain alters TMS-evoked alpha event-related spectral perturbation (ERSP) and intertrial coherence (ITC), reflecting cortical reactivity and phase consistency, and whether 10-Hz repetitive TMS (rTMS) modulates these responses. We performed a secondary analysis on 2 previous experiments, which used nerve growth factor (NGF) injection to induce prolonged elbow muscle pain. In experiment 1, participants underwent primary motor cortex (M1) TMS-EEG at baseline (day 0) pre-NGF injection and day 2 (peak pain) and day 7 (pain resolution) post-injection. In experiment 2, M1-TMS-EEG was assessed on day 0 before NGF injection and again on day 4 after injection, with active or sham 10-Hz rTMS delivered to M1 between these assessments. In experiment 1, M1 TMS-EEG showed reductions in alpha ERSP (P = 0.014) and alpha ITC (P = 0.041) from day 0 to day 2. In experiment 2, active rTMS produced a more positive pre-to-post change in alpha ERSP (P = 0.006) relative to sham but did not alter alpha ITC (P = 0.804). Our findings suggest that prolonged experimental pain is associated with diminished evoked alpha oscillatory activity, whereas high-frequency rTMS modulates this activity in the positive direction. These findings suggest that perturbation-evoked alpha metrics warrant further investigation as candidate biomarkers of pain state and response to neuromodulation.

Pain is not a passive readout of nociceptor traffic; it reflects the brain's inference about bodily threat under uncertainty. Building on predictive processing, active inference, and the free energy principle, we frame acute, chronic, and phantom pain as regimes of hierarchical inference in which memory, affect, and context shift the relative influence of prior beliefs vs incoming nociceptive evidence. Prior work links expectations to pain, but translating these ideas into a clinically usable account that links expectation mechanisms to measurable proxies of belief updating and to principled routes for personalized intervention remains challenging. We propose a generative model that links inferred threat to action policies, so that pain intensity and pain behavior can be studied within the same inferential loop. Within this framework, chronic pain can persist when threat beliefs remain overly influential despite corrective evidence. Placebo/nocebo effects illustrate how shifting expectations can amplify or relieve pain. Phantom pain illustrates how stable body-related beliefs can sustain pain-like perception even with minimal or absent afferent input. We outline candidate measurements and falsifiable predictions by linking expectation- and precision-related effects to a cingulate-insula-centered hub and associated descending control circuitry (periaqueductal gray to spinal dorsal horn). This account suggests principles for selecting and sequencing treatments to target belief content (expectations), evidence (corrective sampling), and gain control (context and neuromodulation), for matching mechanisms to patient-specific phenotypes, and for stratifying patients by dominant mechanism (overly threat-biased beliefs, reduced corrective sampling, or biased precision/gain control) to enable more testable trials and clearer interpretation of treatment response.

Chronic pain affects brain gray matter structure, but the magnitude, pattern, and reversibility of brain changes upon pain recovery remain unclear because of inconsistent findings from small-scale studies. We analyzed data from 35,052 UK Biobank participants who completed chronic pain assessments at 2 time points, approximately 9 years apart, evaluating pain lasting 3 months or more, across 8 body sites. Brain magnetic resonance imaging data were available from the second time point. Participants were grouped into 4 categories: Pain-free controls, New chronic pain, Persistent chronic pain, and Resolved chronic pain. We examined relationships between these categories and 313 brain-wide measures across cortical surface area, cortical thickness, and subcortical volume. New chronic pain was associated with surface area reductions in sensorimotor, temporo-parietal, and medial and lateral prefrontal cortices. Persistent chronic pain showed larger and more widespread area reductions and mixed changes in cortical thickness and subcortical volumes, including cerebellar atrophy and hypertrophy in the thalamus and basal ganglia. Resolved pain demonstrated reversibility of most brain changes, except sustained surface area reductions in the primary somatosensory cortex. No areas showed effects consistent with a predisposition to pain. Brain structural changes in chronic pain reflect adaptive neuroplasticity rather than irreversible damage or preexisting vulnerability. Most changes appear reversible with pain resolution, underscoring the importance of effective pain treatment to alleviate symptoms and support recovery of brain structure and function.

Cannabinoid 1 and 2 receptor (CB1R and CB2R) agonists alleviate inflammatory and neuropathic pain symptoms. However, central nervous system (CNS) side effects mediated by CB1Rs limit their widespread use. We developed peripherally restricted cannabinoids (PRCBs), which exhibit analgesic efficacy with minimal CNS side effects. Here, we examined PRCB actions in a mouse model of dural acid-induced hypersensitivity. Supradural injections of pH-6.0 (but not pH-7.4) saline (4.5 µL) in five-week-old female C57BL/6J mice induced periorbital allodynia (assessed with von Frey filaments) with recovery by 48 hours. By 72 hours, allodynia was elicited with a supradural pH-7.0 saline injection in pH-6.0 (but not pH-7.4) mice. The CB1R/CB2R agonist PRCB, 4-{2-[(1E)-1-[(4-propylnaphthalen-1-yl) methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) (5 µM) or the selective CB1R agonist arachidonyl-2'-chloroethylamide (ACEA, 5 µM), coapplied with pH-6.0 saline, prevented both the initial and latent allodynia, but coadministering pH 6.0 with the CB2R-selective agonist RNB61 (5 µM) did not. Coadministering pH-6.0/PrNMI with CB1R- or CB2R-selective inverse agonists abolished the preventative effects of PrNMI. Supradural pH-6.0 saline-evoked allodynia followed 72 hours later by coadministration of pH 7.0/PrNMI did not prevent latent allodynia. Patch recordings obtained from dural trigeminal ganglion neurons (dTGNs) acutely isolated from FluoroGold/pH-6.0 (but not pH-7.4)-injected mice had larger acid-induced depolarizations. All dTGNs had electrophysiological properties of Aδ- or C-type nociceptors. PrNMI (1 µM) suppressed acid-induced depolarizations in dTGNs from pH-7.4 (but not pH-6.0)-treated mice, whereas RNB61 (0.5 µM) had no effect. These findings indicate that PrNMI prevents acid-induced sensitization by coactivating neuronal CB1Rs and non-neuronal CB2Rs. Cannabinoid 2 receptor activation alone is insufficient, and once sensitized, combined CB1R/CB2R activation loses efficacy.