ABSTRACT:Accumulating evidence indicates that glial cells play a critical role in the initiation, maintenance, and resolution of neuropathic pain. However, there is lack of glia-specific molecular targets for pain management. We recently identified the G protein-coupled receptor GPR37-like 1 (GPR37L1) as a glia-selective receptor expressed in astrocytes and satellite glial cells (SGCs), and GPR37L1 protects against the development of neuropathic pain, highlighting it as a promising target for neuroglial modulation. Building on our discovery that the proresolving lipid mediator Maresin1 acts as an endogenous ligand for GPR37L1, this study aimed to identify small-molecule GPR37L1 agonists with improved synthetic accessibility and analgesic duration. Using virtual screening combined with molecular dynamics simulations, we identified compound P06 as a top candidate with the highest predicted binding affinity. In vitro, P06 induced a dose-dependent potassium influx in cells expressing GPR37L1. The analgesic efficacy of P06 was evaluated in mouse models of neuropathic pain after chemotherapy-induced peripheral neuropathy and spared nerve injury (SNI). A single intrathecal injection of P06 produced robust and long-lasting inhibition of chemotherapy-induced mechanical allodynia for more than 24 hours. This effect was completely abolished in Gpr37l1 knockout mice, confirming a receptor-dependent mechanism. P06 also alleviated SNI-induced mechanical/cold allodynia and mitigated nerve injury-induced reactive gliosis in SGCs of dorsal root ganglia. Mechanistically, P06 directly acted on human and mouse SGCs to enhance potassium levels and suppress paclitaxel-induced Interleukin-1β release. Together, these findings establish GPR37L1 as a glia-specific therapeutic target and demonstrate that small-molecule activation of GPR37L1 provides effective relief from neuropathic pain.
ABSTRACT:Substantial evidence from animal and human studies supports the hippocampus' role in pain, positioning it as a key contributor to the pain experience. Here, we comprehensively incorporate the hippocampus in our understanding of pain perception and provide critical insight and novelty for future interdisciplinary research in pain.
ABSTRACT:Pain perception involves complex sensory and emotional processes, yet the supraspinal circuits that sustain neuropathic pain remain incompletely understood. Here, we demonstrate that parabrachial nucleus (PBN) neurons expressing the inhibitory G-protein-coupled neuropeptide Y Y1 receptor (Npy1r) are critical modulators of neuropathic pain. Approximately 19% of lateral PBN neurons express Npy1r. Stimulus-evoked Fos activation and calcium dynamics of these neurons increases in mice with spared nerve injury (SNI) compared to sham controls. Pharmacological activation of Y1 receptors or chemogenetic inhibition of Npy1r neurons attenuates SNI-induced mechanical and cold allodynia, without altering baseline sensitivity or conditioned place preference (a measure of affective pain). Preemptive ablation of parabrachial Npy1r neurons before SNI delayed the development of neuropathic hypersensitivity. Conversely, repeated chemogenetic activation of Npy1r neurons produced persistent mechanical and cold hypersensitivity in uninjured animals; this outlasted neuronal activation, indicating sufficiency to drive pain-like states. Viral tracing revealed dense Npy1r projections from lateral parabrachial neurons to forebrain regions including the central amygdala, lateral hypothalamus, zona incerta, and ventromedial thalamus, sites implicated in the sensory and affective dimension of pain. These findings demonstrate that Npy1r-expressing PBN neurons selectively regulate the sensory-discriminative component of neuropathic pain and can maintain long-lasting hypersensitivity even in the absence of injury.
ABSTRACT:Trigeminal neuralgia (TN), a devastating neuropathic pain condition, profoundly affects human well-being. Despite an initial response to carbamazepine (CBZ), many patients become refractory to pharmacotherapy and subsequent invasive procedures. Although preclinical trigeminal neuropathic pain models following extracranial chronic constriction injury (CCI) of the trigeminal nerve have been developed, the injury-induced facial hypersensitivity is rarely CBZ-responsive, questioning the models' relevance to TN. In recent reports, CBZ-responsive facial pain can be induced by intracranial CCI that better mimics the compression observed in classical TN. Nevertheless, behavioral assessment of persistent pain in these models often requires a restrained setting that could trigger unpredictable behaviors that are not necessarily pain associated. Here, we focused on spontaneous and evoked measures of pain in unrestrained mice after a CBZ-sensitive intracranial CCI, namely the FRICT-ION model. To measure these behaviors long-term, we developed a high-frame rate videography analysis that reliably captures increased chronic spontaneous asymmetric grooming and mechanically evoked facial rubbing, ipsilateral to the injury. Notably, this altered behavioral phenotype was significantly reversed by a nonsedating dose of CBZ. Using DeepLabCut tracking, we also found that the speed of head movement after facial mechanical stimulation is a significant CBZ-sensitive behavioral correlate of TN allodynia. Importantly, these behavioral measures accurately recapitulated the clinical outcomes-both success and failure-of a cohort of specific nonopioid analgesics that have previously been tested in the clinical management of TN. Together, these measures should greatly facilitate the research development of innovative TN therapies.
Abstract In pain and other research fields, placebos have traditionally been associated with deception, although harnessing placebo effects does not necessarily require deception. Open-label placebos (OLPs) represent a novel approach in which inert treatments are administered openly and transparently, allowing patients to knowingly receive an inert treatment while still experiencing therapeutic benefits (eg, pain relief). As OLP research grows, concerns have been raised regarding methodological rigor and the unique challenges posed by unblinded designs in both experimental and clinical contexts. Given the inherent transparency regarding treatment group allocation in OLP trials, particular attention is needed when defining appropriate control groups, implementing feasible blinding strategies, and providing a treatment rationale to adequately explain OLPs. Addressing these challenges is crucial to advancing both the scientific understanding of the psychoneurobiological mechanisms underlying OLP effects and their clinical relevance in pain. In this review, we outline key methodological considerations for designing and conducting OLP studies in pain research and beyond, providing guidance on control group selection, blinding strategies, and reporting standards. In addition, we integrate insights from the patient advisory board of the transregional Collaborative Research Center (CRC/TRR) 289 “Treatment Expectation” to incorporate patient perspectives on the feasibility and acceptability of OLPs. Aligning study designs with patient needs and expectations may foster a more meaningful, patient-centered approach to OLP research. By combining methodological guidance and emphasizing patient-centered insights, this review aims to enhance the quality, relevance, and clinical translation of OLP research in pain.
Abstract Group-based randomized controlled trials (RCTs) in clinical pain research in low- and middle-income settings (LMIS) face distinct challenges, including resource-related limitations and contextual barriers. In addition, evidence garnered through RCTs in high-income settings is often not directly relevant to LMIS. We briefly discuss alternative group-based study designs that can address some of these challenges. We then introduce single-case experimental designs as a complementary approach that may be more efficient than traditional group-based methods in these contexts. Single-case experimental designs focus on the individual person in relation to at least one independent variable over time under different conditions. Unlike RCTs, they require small sample sizes and provide more granular insights into how a pain intervention affects each individual rather than the average group response. Single-case experimental designs can also accommodate more diverse participants in terms of age, ethnic backgrounds, and comorbidities, making them resource-efficient, clinically relevant, and pragmatic, which can facilitate more clinical trials in LMIS, and thereby a better understanding and scientific evidence for the effects of treatments in these settings.
ABSTRACT:Results suggest that psychosocial treatments for chronic pain work via several mechanisms, and that they often do so to similar degrees and in similar ways. Extant research, however, has focused on individual and/or independent effects of mechanisms on outcomes. Whether successful outcomes are also partly because of sequential and meaningful relationships among and between mechanisms-mechanism-to-mechanism effects-has not been examined. Secondary analyses were conducted of an RCT that compared cognitive therapy, mindfulness-based stress reduction, and behavior therapy to treatment as usual in a sample (N = 521) of people with chronic low back pain. Results of hierarchical linear modeling revealed that (1) Treatment Condition × Mechanism interactions predicting changes in other mechanisms were nonsignificant; (2) lagged prior session mechanism changes predicted next session changes in another mechanism; (3) lagged relationships between pain catastrophizing and pain self-efficacy were reciprocal, whereas links between lagged pain catastrophizing and mindfulness changes and lagged pain catastrophizing changes and behavioral activation changes were unidirectional; and (4) individual differences in the strengths of mechanism-to-mechanism relationships predicted pre- to post-treatment changes in outcomes. Results reveal heretofore hidden therapeutic processes that cognitive therapy, mindfulness-based stress reduction, and behavior therapy may share. Namely, that mechanism-to-mechanism lagged effects do indeed emerge beyond mechanism-to-outcome effects. Findings show not only that mechanisms may change in definable sequences relative to each other but that individual differences in the strengths of mechanism-to-mechanism relationships may themselves be predictive of outcomes.
ABSTRACT:Peripheral neuropathy is a global health concern that markedly impairs quality of life. Peripheral nerve injury triggers complex interactions between the immune and nervous systems, driving persistent neuroinflammation and neuropathic pain. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has emerged as a key mediator in this process. Macrophage migration inhibitory factor binds to its primary receptor CD74, promotes cytokine release, recruits macrophages into the inflammatory milieu, and amplifies inflammatory responses. ISO-1, a small-molecule, high-affinity MIF inhibitor, targets the tautomerase active site of MIF, disrupts MIF-receptor (including canonical receptor CD74) binding, and thereby mitigates downstream inflammatory response. In this study, we investigated the anti-inflammatory and analgesic effects of ISO-1 in both male and female mice subjected to chronic constriction injury (CCI) of the sciatic nerve. A battery of behavioral, electrophysiological, immunohistochemical, and molecular approaches was used to evaluate the impact of systemic ISO-1 treatment on neuroinflammation and neuropathic pain. Electrophysiological recordings from the superficial dorsal horn neurons in acute spinal cord slices revealed that ISO-1 largely prevented the CCI-induced imbalance between excitatory and inhibitory postsynaptic currents. ISO-1 significantly reduced macrophage infiltration at the sciatic nerve injury site and within dorsal root ganglia. Notably, ISO-1 alleviated mechanical allodynia and thermal hyperalgesia in male mice, but not in female mice, a sex-specific effect corroborated by quantitative PCR analysis of inflammatory mediators. Together, these findings identify ISO-1 as a promising MIF-targeted strategy to counteract neuroinflammation and neuropathic pain after peripheral nerve injury and highlight the importance of sex-specific responses for the development of personalized immunomodulatory therapies.
ABSTRACT:Fear of movement (FoM), or kinesiophobia, is associated with functional disability in individuals with chronic pain. The Tampa Scale of Kinesiophobia (TSK) is among the most widely used instruments for assessing FoM and has undergone several revisions; however, its psychometric properties have not been evaluated in youth with chronic pain, and there is currently no consensus on the optimal version to use in pediatric pain populations. We examined data from youth with a range of chronic pain conditions (N = 1252; Mage = 14.55 years, 79.2% female sex assigned at birth) who were receiving clinical care or participating in studies across 3 study centers in the United States and Canada. Participants completed the 11- or 17-item version of the TSK as well as measures of mobility, functional disability, depressive symptoms, and pain catastrophizing. Using a combination of classical item theory techniques, Rasch analytic methods, and expert consensus, we identified a robust set of 7 TSK items (ie, the TSK-7-Y) based on item difficulty, point-measure correlations across items, and coverage of key measurement dimensions. The TSK-7-Y was compared with the 11-item set using predictive validation techniques including exploratory factor analysis and Pearson correlations with scores on 4 criterion-related instruments. Results indicated that TSK-7-Y items loaded onto 2 distinct factors comparably with the TSK-11. The total score correlated moderately with pain catastrophizing (r = 0.51) and weakly with depressive symptoms (r = 0.07). The TSK-7-Y is a brief yet psychometrically sound instrument for assessing FoM in youth with chronic pain.
ABSTRACT:Complex regional pain syndrome (CRPS) is a chronic, treatment-refractory neuropathic disorder associated with substantial functional impairment and socioeconomic burden. Although socioeconomic conditions have been implicated in vulnerability to chronic pain, evidence on the association between income dynamics and the risk of developing CRPS remains limited. Using the Korean National Health Insurance Service database, we conducted a nationwide cohort study including 3,437,021 adults in South Korea who underwent national health screening in 2012 and were followed through to 2022. Income-related indicators-including baseline income level, cumulative income exposure, income change, and income volatility during the 5 years preceding baseline-were assessed. Incident CRPS was identified using Korean Standard Classification of Diseases codes combined with registration in the Rare Intractable Disease program. Compared with the highest income quartile, individuals in the lowest income quartile had a higher CRPS risk (adjusted hazard ratio [aHR], 3.74; 95% confidence interval [CI], 3.07-4.56). Risk increased with longer duration of low-income status (aHR, 1.91; 95% CI, 1.48-2.45 for 5 vs 0 years) and decreased with longer duration of high-income status (aHR, 0.55; 95% CI, 0.44-0.70 for 5 vs 0 years). In addition, high-income volatility (highest vs lowest quartile aHR, 1.48; 95% CI, 1.23-1.78) and downward income changes (peak aHR, 1.84; 95% CI, 1.24-2.73) were independently associated with increased CRPS risk. These findings suggest that income dynamics represent an important socioeconomic risk factor for CRPS and highlight the relevance of longitudinal socioeconomic vulnerability in the development of disabling chronic pain conditions.
ABSTRACT:Pain perception relies not only on sensory neurons but also on the interplay of a heterogeneous cell population, including endothelial cells, microglia, and astrocytes. Blood-spinal cord barrier dysfunction can alter nociceptive processing and lead to pain hypersensitivity. A component of this capillary network is the astrocytic foot processes that encapsulate the blood-brain barrier, providing critical nutritional support and protection. Astrocytes are a fundamental modulator of nervous system health as well as a regulator of capillary function, with reactive astrocytes a pathological hallmark of persistent pain. However, it remains unknown whether astrocytes influence angiogenic processes in the dorsal horn to induce persistent pain. In this study, we elucidate, using spatiotemporally delivered chemogenetic astrocyte activation, the role of astrocytes in the modulation of the blood-spinal cord barrier and nociception. Adult male and female mice were intrathecally administered AAV consisting of either GFAP-hM3D(Gq)-mCherry (GFAP-hM3D(Gq)) or GFAP-mCherry. mCherry-labelled GFAP-positive astrocytes were identified in the lumbar dorsal horn following AAV injection. DREADD-induced astrogliosis in the dorsal horn was indicated by increased astrocyte number and GFAP immunoreactivity, which occurred alongside mechanical and heat hypersensitivity in GFAP-hM3D(Gq) mice. In CNO-treated GFAP-hM3D(Gq) mice, astrocyte-endothelium interactions were increased in the dorsal horn compared with vehicle-treated rodents. The capillary network (reduced CD31) and angiogenic proteome were reduced in the dorsal horn of CNO-treated GFAP-hM3D(Gq) mice. Diminished angiogenesis and pain hypersensitivity were ameliorated by VEGF-A165b supplementation. This demonstrates that astrocytes in the dorsal horn modulate the blood-spinal cord barrier, impacting upon nociceptive processing and pain hypersensitivity.
ABSTRACT:Many children present with chronic primary headache (CPH), yet classification within the International Classification of Diseases (ICD-11) is difficult, potentially impeding treatment pathways. The ICD-11 includes adult criteria, but it lacks coding notes addressing pediatric neurodevelopmental differences, and it stipulates inconsistent time criteria. The current study thus proposes optimized diagnostic criteria for CPH, chronic tension-type headache (TTH), and chronic migraine to better fit the observed symptoms among pediatric patients with CPH. Symptoms of N = 231 pediatric patients presenting at a tertiary care center with migraine-like and/or TTH-like headache who met the ICD-11 chronic primary pain criteria were analyzed. Data-informed adjustments to diagnostic criteria were evaluated using grid search and receiver operating characteristic (ROC) analyses to identify the best criteria combination for CPH, chronic TTH, and chronic migraine. For all 3 diagnoses, the best approach was to align the time criteria with the definition of chronic primary pain-requiring at least 3 months of headache without further specification of hours or days per month. For chronic TTH, additionally allowing moderate nausea and up to 2 migraine-like symptoms yielded the best combination of sensitivity and specificity relative to migraine-like headache. The current study indicates that the diagnostic criteria included in the ICD-11 are ill-suited for diagnosing pediatric patients with CPH. To facilitate appropriate treatment for pediatric patients with headache, we strongly recommend implementing the proposed pediatric coding notes within the ICD-11.
ABSTRACT:Self-report is the gold standard for assessing pain intensity, although the method of acquiring pain reports may influence the ratings obtained. Retrospective reports of pain intensity are often found to be elevated relative to daily diary reports, possibly due to recall bias and the influence of psychosocial factors on memory. In this study, we sought to examine differences between retrospective reporting of average pain intensity in the past week vs averaged daily diary reporting of pain intensity in a sample of adolescents with juvenile fibromyalgia (JFM). We also sought to determine the predictive effects of pain catastrophizing, functional disability, and depressive symptoms on discrepancies between retrospective and daily diary report. As part of a randomized controlled trial, 317 adolescents with JFM (Mage = 15.7, SD = 1.6, 88.4% female) completed daily diary and one-week retrospective pain intensity measures, the Children's Depression Inventory-2, Functional Disability Inventory, and Pain Catastrophizing Scale at baseline, post-treatment, and 3-month follow-up. We examined the predictive effects of psychosocial factors on mean differences between averaged daily and one-week retrospective reports of pain intensity. Retrospective reports of pain intensity were significantly higher than diary reports across time. A longitudinal multiple linear regression model showed that the magnitude of discrepancies between daily diary and retrospective reports was not significantly predicted by functional disability, depressive symptoms, or pain catastrophizing. These findings raise the possibility that other factors such as cognitive biases (eg, threat interpretation, saliency, recency bias) may play a larger role than psychosocial factors in explaining pain reporting discrepancies.
ABSTRACT:Melatonin may provide benefits for managing musculoskeletal (MSK) pain, and this review evaluated its efficacy and effectiveness on pain intensity and sleep quality. We searched 6 databases from inception to April 2025 and included randomized controlled trials in people with chronic or postoperative MSK pain reporting pain or sleep outcomes. Comparators included placebo or active controls (eg, analgesics). Random-effects meta-analyses were performed using mean differences with 95% confidence intervals. Subgroup analyses were conducted by comparator type. Sensitivity analyses included only low-risk studies. Certainty of evidence was assessed using GRADE. Twenty-three studies (2028 participants) were included. For people with chronic MSK pain, melatonin was not superior to placebo in reducing pain (mean difference [MD]: -6.76/100, 95% confidence interval [CI]: -15.89 to 2.36) but was superior to active controls (MD: -11.21/100, 95% CI: -14.29 to -8.13); in sensitivity analysis, melatonin was superior to placebo (MD: -10.04, 95% CI: -17.68 to -2.39). For people with postoperative pain, melatonin was superior to placebo, with effects similar to active controls. Sleep quality favoured melatonin in people with chronic MSK pain but not in those with postoperative pain. Adverse events were mild and transient. Melatonin may provide modest benefits for pain in people with chronic MSK pain, while evidence in postoperative pain remains limited. Although treatment effect estimates were comparable with conventional analgesics, most did not reach minimal clinically important difference thresholds and the certainty of evidence was low to moderate. Melatonin may be considered as a potential adjunct rather than a primary treatment, pending randomized controlled trials with standardised dosing and longer follow-ups.
