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Musculoskeletal pain has a high prevalence of transition to chronic pain and/or persistence as chronic pain for years or even a lifetime. Possible mechanisms for the development of such pain states are often reflected in inflammatory or neuropathic processes involving, among others, cytokines and other molecules. Since biologics such as blockers of TNF or IL-6 can attenuate inflammation and pain in a subset of patients with rheumatoid arthritis, the question arises to what extent cytokines are involved in the generation of pain in human musculoskeletal diseases. In numerous experimental non-human studies, cytokines have been shown to alter neuronal sensitivity in the peripheral and central nociceptive systems. In this review, we addressed the involvement of cytokines in postoperative pain, complex regional pain syndrome, rheumatoid arthritis, osteoarthritis, temporomandibular joint disease, low back pain and fibromyalgia using PubMed searches including meta-analyses of data. There is evidence that certain pro- and anti-inflammatory cytokines are regulated in all of these diseases, often in both acute and chronic disease states. However, within these data, we found a great deal of heterogeneity in the association between cytokine levels and pain. Neutralization of cytokines showed antinociceptive effects in subgroups of patients with chronic pain (e.g., in a proportion of patients with rheumatoid arthritis), but failed to reduce chronic pain in other diseases (e.g., osteoarthritis). More systematic studies are needed to unravel the pathogenic role of cytokines in human musculoskeletal pain, taking into account the disease process and the mechanisms of pain initiation and maintenance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The role of the complement system in pain syndromes has garnered attention on the back of preclinical and clinical evidence supporting its potential as a target for new analgesic pharmacotherapies. Of the components that make up the complement system, component 5a (C5a) and component 3a (C3a) are most strongly and consistently associated with pain. Receptors for C5a are widely found in immune resident cells (microglia, astrocytes, sensory neuron-associated macrophages (sNAMs)) in the central nervous system (CNS) as well as hematogenous immune cells (mast cells, macrophages, T-lymphocytes, etc.). When active, as is often observed in chronic pain conditions, these cells produce various inflammatory mediators including pro-inflammatory cytokines. These events can trigger nervous tissue inflammation (neuroinflammation) which coexists with and potentially maintains peripheral and central sensitization. C5a has a likely critical role in initiating this process highlighting its potential as a promising non-opioid target for treating pain. This review summarizes the most up-to-date research on the role of the complement system in pain with emphasis on the C5 pathway in peripheral tissue, dorsal root ganglia (DRG) and the CNS, and explores advances in complement-targeted drug development and sex differences. A perspective on the optimal application of different C5a inhibitors for different types (e.g., neuropathic, post-surgical and chemotherapy-induced pain, osteoarthritis pain) and stages (e.g., acute, subacute, chronic) of pain is also provided to help guide future clinical trials. PERSPECTIVE: This review highlights the role and mechanisms of complement components and their receptors in physiological and pathological pain. The potential of complement-targeted therapeutics for the treatment of chronic pain is also explored with a focus on C5a inhibitors to help guide future clinical trials., Competing Interests: Declaration of Competing Interest The authors of the paper declare that there are no conflicts of interest regarding the publication of this manuscript., (Copyright © 2024. Published by Elsevier Inc.)

Background: Tumor progression and chronic postsurgical pain (CPSP) in patients with breast cancer are both significantly influenced by inflammation. The associations between immunoinflammatory biomarkers and long-term survival, as well as CPSP, remain ambiguous. This study examined the predictive value of immunoinflammatory biomarkers for both long-term survival and CPSP., Methods: Data on the clinicopathological characteristics and perioperative peripheral blood immunoinflammatory biomarkers of 80 patients who underwent breast cancer surgery were retrospectively collected. Optimal cut-off values for preoperative immunoinflammatory biomarkers, including the preoperative systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil-to-lymphocyte ratio (NLR), and pan-immune-inflammation value (PIV), were established via receiver operating characteristic (ROC) curves. Kaplan-Meier curves and Cox regression analysis were used to evaluate the relationships between preoperative immunoinflammatory biomarkers and long-term survival. The relationships among the perioperative neutrophil count (NEU), monocyte count (MONO), lymphocyte count (LYM), platelet count (PLT), SII, SIRI, NLR, PIV, dynamic changes in peripheral blood cell counts, and CPSP were further assessed using logistic regression analysis., Results: Kaplan-Meier curves revealed a considerable prolongation of disease-free survival (DFS) and overall survival (OS) in the low preoperative SII, SIRI, NLR, and PIV groups. Multivariate Cox regression analysis revealed that only an elevated preoperative SIRI was an independent risk factor for postoperative DFS (HR=8.890, P=0.038). The incidence of CPSP was 28.75%. Univariate logistic regression analysis revealed that body mass index (BMI), postoperative NEU, MONO, SIRI, and PIV were negatively correlated with the occurrence of CPSP, whereas subsequent multivariate logistic regression analysis revealed that only BMI was independently associated with CPSP (OR=0.262, P=0.023)., Conclusion: Elevated preoperative SIRI was an independent risk factor for poor DFS in breast cancer patients after surgery. In contrast, perioperative immunoinflammatory biomarkers had limited potential for predicting CPSP in patients who underwent breast cancer surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Li, Che, Li, Min, Ai, Wu, Wang, Tan, Fu, Yang, Fang, Zheng and Yan.)

Introduction: Chronic postsurgical pain (CPSP) represents a widely underdiagnosed and often poorly treated medical problem, affecting 10-50% of all surgical patients, exhibiting neuropathic features in 35-60%. It is hypothesised that surgery-induced tissue damage and the subsequent immune response cause sensory alterations in the early postoperative period, ultimately leading to a chronic neuropathic or nociplastic pain state. The 'Sensory Changes and Immunological parameters in Postsurgical pain' study (SCIP-Pain study) was designed to test this hypothesis and identify sensory alterations and changes in the immunological response that are related to the development of CPSP with neuropathic features., Methods and Analysis: This protocol describes the SCIP-Pain study-an ongoing prospective observational cohort study involving 150 adult patients undergoing elective lower extremity orthopaedic surgery. Study participants complete questionnaires, undergo quantitative sensory testing (QST) and provide blood samples to assess the immunological response at various time points: before surgery, 2 weeks and 3 months after surgery. To reduce dimensionality, cluster analyses will be conducted on QST and immunological parameters. Cluster allocation, along with other preselected candidate predictors, will subsequently be used in a generalised mixed-effects model to predict CPSP with neuropathic features within 3 months after surgery as the primary outcome., Ethics and Dissemination: This study received approval from the Medical Ethics Committee NedMec (protocol NL77085.041.21), as well as from all participating centres. The study results are expected to be published in peer-reviewed journals and disseminated at international conferences., Competing Interests: Competing interests: MR and NE are consultants for Synerkine Pharma, not receiving funding related to present study. FJPMH reports institutional fees from Synerkine, grants from Boston Scientific, grants and personal fees from ABOTT, Saluda and personal fees from Grunenthal outside the submitted work. MECvD, NvV, LMV, LK, LT, RJHC and DD declare that they have no competing interests., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Chronic pain is a multidimensional experience that not only involves persistent nociception but is also frequently accompanied by significant emotional disorders, such as anxiety and depression, which complicate its management and amplify its impact. This review provides an in-depth exploration of the neurobiological mechanisms underlying the comorbidity of chronic pain and emotional disturbances. Key areas of focus include the dysregulation of major neurotransmitter systems (serotonin, gamma-aminobutyric acid, and glutamate) and the resulting functional remodeling of critical neural circuits implicated in pain processing, emotional regulation, and reward. Given the contribution of neuroimmune mechanisms to pain chronicity and mood disorders, we further conducted an in-depth investigation into the role of neuroimmune factors, including resident immune cells, infiltrating immune cells, and the release of inflammatory mediators. This review further discusses current therapeutic strategies, encompassing pharmacological interventions, neuromodulation, and integrative approaches, and emphasizes the necessity of targeted treatments that address both pain and emotional components. Finally, it identifies gaps in the current understanding and outlines future research directions aimed at elucidating the complex interplay between chronic pain and emotional disorders, thereby laying the foundation for more effective and holistic treatment paradigms.

Chronic pain typically lasts or recurs for more than three months and is an unpleasant sensory and emotional experience, including neuropathic pain, long-term tissue damage, tumors, and viral or bacterial infections.The unpleasantness associated with pain affects the basic life of patients and has become a truly global problem. Macrophages, a powerful immune effector cell whose functional plasticity leads to polarization into different subtypes and opposite effects in different environments, are also indispensable in the development of pain.In recent years, there has been an increasing number of studies on the effects of macrophages on pain, and there are multiple pathways that regulate macrophage polarization, including lipopolysaccharide induction and IL-4/IL-13 stimulation.In addition, pathways involving macrophages and macrophage polarization have been found to have an exacerbating or mitigating role in the progression of chronic pain, with M1 macrophages generally exacerbating pain progression and M2 macrophages mitigating pain progression.Therefore, modulating macrophage polarization holds great promise as an intervention in chronic pain. In this paper, we synthesize multiple macrophage pathways as well as mechanisms affecting their pain processes in the context of different types of chronic pain, providing new avenues for chronic pain relief., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Siyao Deng reports writing assistance was provided by Siyao Deng. Siyao Deng reports a relationship with School of Medicine, Tarim University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain., Recent Findings: In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood., Competing Interests: Declarations. Competing Interests: CLR is a section editor at CPHR. Human and Animal Rights: All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pain is one of the most debilitating symptoms of rheumatoid arthritis (RA), and yet remains poorly understood, especially when pain occurs in the absence of synovitis. Without active inflammation, experts most often attribute joint pain to central nervous system dysfunction. However, advances in the past 5 years in both immunology and neuroscience research suggest that chronic pain in RA is also driven by a variety of abnormal interactions between peripheral neurons and mediators produced by resident cells in the local joint environment. In this Review, we discuss these novel insights from an interdisciplinary neuro-immune perspective. We outline a potential working model for the peripheral drivers of pain in RA, which includes autoantibodies, resident immune and mesenchymal cells and their interactions with different subtypes of peripheral sensory neurons. We also offer suggestions for how future collaborative research could be designed to accelerate analgesic drug development., (© 2024. Springer Nature Limited.)

Purpose of Review: This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management., Recent Findings: In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called "neuroinflammation" in human pain has been an object of contention for decades. Here, I present the results of multiple positron emission tomography (PET) studies measuring the levels of the 18 kDa translocator protein (TSPO), a putative neuroimmune marker, in individuals with various pain conditions. Overall, these studies suggest that brain TSPO PET signal: (1) is elevated, compared to healthy volunteers, in individuals with chronic low back pain (with additional elevations in spinal cord and neuroforamina), fibromyalgia, migraine and other conditions characterized by persistent pain; (2) has a spatial distribution exhibiting a degree of disorder specificity; (3) is parametrically linked to pain characteristics or comorbid symptoms (eg, nociplastic pain, fatigue, depression), as well as measures of brain function (ie, functional connectivity), in a regionally-specific manner. In this narrative, I also discuss important caveats to consider in the interpretation of this work (eg, regarding the cellular source of the signal and the complexities inherent in its acquisition and analysis). While the biological and clinical significance of these findings awaits further work, this emerging preclinical literature supports a role of neuron-glia-immune interactions as possible pathophysiological underpinnings of human chronic pain. Gaining a deeper understanding of the role of neuroimmune function in human pain would likely have important practical implications, possibly paving the way for novel interventions., (Copyright © 2024 International Association for the Study of Pain.)

Chronic pain dramatically affects life qualities of the sufferers. It has posed a heavy burden to both patients and the health care system. However, the current treatments for chronic pain are usually insufficient and cause many unwanted side effects. Chemokine C-X-C motif ligand 13 (CXCL13), formerly recognized as a B cell chemokine, binds with the cognate receptor CXCR5, a G-protein-coupled receptor (GPCR), to participate in immune cell recruitments and immune modulations. Recent studies further demonstrated that CXCL13-CXCR5 signaling is implicated in chronic pain via promoting neuroimmune interaction and neuroinflammation in the sensory system. In addition, some latest work also pointed out the involvement of CXCL13-CXCR5 in the pathogenesis of certain neurological diseases, including ischemic stroke and amyotrophic lateral sclerosis. Therefore, we aim to outline the recent findings in regard to the involvement of CXCL13-CXCR5 signaling in chronic pain as well as certain neurological diseases, with the focus on how this chemokine signaling contributes to the pathogenesis of these neurological diseases via regulating neuroimmune interaction and neuroinflammation. Strategies that can specifically target CXCL13-CXCR5 signaling in distinct locations may provide new therapeutic options for these neurological diseases., (© 2024. The Author(s).)

Background: Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function., Methods: Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered., Results: Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41)., Conclusion: This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype., Significance Statement: Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Obstructive sleep apnea (OSA) is a prevalent sleep disorder that is associated with increased incidence of chronic musculoskeletal pain. We investigated the mechanism of this association in a mouse model of chronic intermittent hypoxia (CIH) that mimics the repetitive hypoxemias of OSA. After 14 days of CIH, both male and female mice exhibited behaviors indicative of persistent pain, with biochemical markers in the spinal cord dorsal horn and sensory neurons of the dorsal root ganglia consistent with hyperalgesic priming. CIH, but not sleep fragmentation alone, induced an increase in macrophage recruitment to peripheral sensory tissues (sciatic nerve and dorsal root ganglia), an increase in inflammatory cytokines in the circulation, and nociceptor sensitization. Peripheral macrophage ablation blocked CIH-induced hyperalgesic priming. The findings suggest that correcting the hypoxia or targeting macrophage signaling might suppress persistent pain in patients with OSA.

Abstract: Recent evidence highlights the importance of the neuroimmune interface, including periphery-to-central nervous system (CNS) neuroimmune crosstalk, in chronic pain. Although neuroinflammatory processes have been implicated in central sensitization for a long time, their potential neuroprotective and analgesic effects remain relatively elusive. We have explored the relationships between cytokine expression and symptom severity, and candidates for periphery-to-CNS crosstalk. Patients with degenerative disk disease (DDD) (nociceptive pain) or patients with lumbar disk herniation (LDH) with radiculopathy (predominantly neuropathic pain) completed questionnaires regarding pain and functional disability, underwent quantitative sensory testing, and provided blood and cerebrospinal fluid (CSF) samples. Proximity extension assay (PEA) was used to measure the levels of 92 inflammatory proteins in the CSF and serum from a total of 160 patients and controls, and CSF/serum albumin quotients was calculated for patients with DDD and patients with LDH. We found signs of neuroimmune activation, in the absence of systemic inflammation. Regarding periphery-to-CNS neuroimmune crosstalk, there were significant associations between several cytokines and albumin quotient, despite the latter being primarily at subclinical levels. The cytokines CCL11, CD5, IL8, and MMP-10 were elevated in the CSF, had positive correlations between CSF and serum levels, and associated in a nonlinear manner with back, but not leg, pain intensity in the LDH, but not the DDD, group. In conclusion, we found evidence for neuroimmune activation in the CNS of both patient groups in the absence of systemic inflammation and signs of a communication between CSF and serum. Complex and disease-specific associations were found between cytokines in CSF and back pain intensity., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Introduction: Chronic Pelvic Pain Syndrome or Chronic Prostatitis (CPPS/CP) is the most prevalent urologic affliction among young adult men. It is a challenging condition to treat, which significantly decreases patient quality of life, mostly because of its still uncertain aetiology. In that regard, an autoimmune origin is a prominent supported theory. Indeed, studies in patients and in rodent models of Experimental Autoimmune Prostatitis (EAP) have provided compelling evidence suggesting a key role of CD4 Th1 cells in disease pathogenesis. However, the implication of other prominent effectors of the immune system, such as CD8 T cells, has yet to be studied., Methods: We herein analyzed the induction of prostatitis and the development of chronic pelvic pain in EAP using CD8 T cell-deficient animals., Results: We found similarly elevated PA-specific immune responses, with high frequencies of specific IFNg+CD4+ and IL17+CD4+ T cells in prostate draining lymph nodes from PA-immunized either CD8 KO or wild type animals with respect to controls. Moreover, these peripheral immune responses were paralleled by the development of significant chronic pelvic pain, and accompanied by prostate histological lesions, characterized by hemorrhage, epithelial cell desquamation, marked periglandular leukocyte infiltration, and increased collagen deposition in both, PA-immunized CD8 KO and wild type animals. As expected, control animals did not develop prostate histological lesions., Discussion: Our results indicate that CD8 T cells do not play a major role in EAP pathogenesis and chronic pelvic pain development. Moreover, our results corroborate the previous notion that a CD4 Th1 associated immune response drives the induction of prostate tissue inflammation and the development of chronic pelvic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Salazar, Martinez, Paira, Chocobar, Olivera, Godoy, Acosta-Rodriguez, Rivero and Motrich.)

Background: That neuroimmune interaction occurs in chronic pain conditions has been established for over a century, since the discovery of neurogenic inflammation in the periphery. However, the central aspects of neuroimmune interactions have not been fully appreciated until the late 1900s, when a growing interest in how cytokines in the cerebrospinal fluid (CSF) might be relevant in chronic pain conditions emerged. Since then, the field has evolved, and nowadays neuroinflammation is considered to be involved in the pathophysiology of chronic pain. Whether or not pain conditions can be called "neuroinflammatory" is a matter of debate. This review summarizes the results from studies investigating cytokines in the CSF in various pain conditions, and critically discusses neuroimmune aspects of pain conditions using previously proposed hallmarks of neuroinflammation as a framework., Summary: Fifty-two papers were summarized and their results evaluated according to (a) the level of the measured cytokines in patients compared to controls, and (b) the correlation between cytokine level and pain intensity. A subdivision based on pain type was also conducted for each of the 52 studies. A total of 49 proteins have been studied in at least 5 studies, 21 of which were upregulated in a majority of studies. IL-8 was specifically upregulated in a majority of studies of nociceptive pain conditions. Regarding correlation to pain intensity, there is a scarcity of data but 31 proteins were upregulated and correlated with pain in at least one study. Of these, 24 proteins were negatively correlated with pain, and 7 were positively correlated. None of the most studied cytokines, such as TNF, IL-1b, IL-6, IL-8, CCL2/MCP1, BDNF, or bNGF, were consistently correlated to pain., Key Messages: There is sufficient evidence to say that chronic pain conditions come with an upregulation of several cytokines. However, the majority of correlations to symptomatology seem to be negative, indicating that the cytokines might play a protective role that has not been broadly considered. Calling chronic pain conditions neuroinflammatory seems wrong; instead, a more suitable term for depicting the findings would, perhaps, be to talk about neuroimmune activation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP., (© 2022. The Author(s).)

Chronic pain is a prevalent medical problem, and its molecular basis remains poorly understood. Here, we demonstrate the significance of the transmembrane protein (Tmem) 160 for nerve injury-induced neuropathic pain. An extensive behavioral assessment suggests a pain modality- and entity-specific phenotype in male Tmem160 global knockout (KO) mice: delayed establishment of tactile hypersensitivity and alterations in self-grooming after nerve injury. In contrast, Tmem160 seems to be dispensable for other nerve injury-induced pain modalities, such as non-evoked and movement-evoked pain, and for other pain entities. Mechanistically, we show that global KO males exhibit dampened neuroimmune signaling and diminished TRPA1-mediated activity in cultured dorsal root ganglia. Neither these changes nor altered pain-related behaviors are observed in global KO female and male peripheral sensory neuron-specific KO mice. Our findings reveal Tmem160 as a sexually dimorphic factor contributing to the establishment, but not maintenance, of discrete nerve injury-induced pain behaviors in male mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Non-opioid single-chain variable fragment (scFv) small antibodies were generated as pain-reducing block of P2X4R receptor (P2X4R). A panel of scFvs targeting an extracellular peptide sequence of P2X4R was generated followed by cell-free ribosome display for recombinant antibody selection. After three rounds of bio-panning, a panel of recombinant antibodies was isolated and characterized by ELISA, cross-reactivity analysis, and immunoblotting/immunostaining. Generated scFv antibodies feature binding activity similar to monoclonal antibodies but with stronger affinity and increased tissue penetrability due to their ~30% smaller size. Two anti-P2X4R scFv clones (95, 12) with high specificity and affinity binding were selected for in vivo testing in male and female mice with trigeminal nerve chronic neuropathic pain (FRICT-ION model) persisting for several months in untreated BALBc mice. A single dose of P2X4R scFv (4 mg/kg, i.p.) successfully, completely, and permanently reversed chronic neuropathic pain-like measures in male mice only, providing retention of baseline behaviors indefinitely. Untreated mice retained hypersensitivity, and developed anxiety- and depression-like behaviors within 5 weeks. In vitro P2X4R scFv 95 treatment significantly increased the rheobase of larger-diameter (>25 µm) trigeminal ganglia (TG) neurons from FRICT-ION mice compared to controls. The data support use of engineered scFv antibodies as non-opioid biotherapeutic interventions for chronic pain.

In some chronic primary pain conditions such as temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS), mild or chronic stress enhances pain. TMD and FMS often occur together, but the underlying mechanisms are unclear. The purpose of this study was to investigate the role of cholecystokinin (CCK) in the spinal cord in somatic hyperalgesia induced by orofacial inflammation combined with stress. Somatic hyperalgesia was detected by the thermal withdrawal latency and mechanical withdrawal threshold. The expression of CCK 1 receptors, CCK 2 receptors, ERK1/2 and p-ERK1/2 in the spinal cord was examined by Western blot. After the stimulation of orofacial inflammation combined with 3 day forced swim, the expression of CCK 2 receptors and p-ERK1/2 protein in the L4-L5 spinal dorsal horn increased significantly, while the expression of CCK 1 receptors and ERK1/2 protein remained unchanged. Intrathecal injection of the CCK 2 receptor antagonist YM-022 or mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked somatic hyperalgesia induced by orofacial inflammation combined with stress. Intrathecal administration of the MEK inhibitor blocked somatic sensitization caused by the CCK receptor agonist CCK8. The CCK 2 receptor antagonist YM-022 significantly reduced the expression of p-ERK1/2. These data indicate that upregulation of CCK 2 receptors through the MAPK pathway contributes to somatic hyperalgesia in this comorbid pain model. Thus, CCK 2 receptors and MAPK pathway may be potential targets for the treatment of TMD comorbid with FMS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-β are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-β can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections., Competing Interests: R-RJ is a consultant of Boston Scientific and received a research grant from the company. This activity is not related to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tan, Ji, Yeh and Ji.)

Lactate transport is an important means of communication between astrocytes and neurons and is implicated in a variety of neurobiological processes. However, the connection between astrocyte-neuron lactate transport and nociceptive modulation has not been well established. Here, we found that Complete Freund's adjuvant (CFA)-induced inflammation pain leads to a significant increase in extracellular lactate levels in the anterior cingulate cortex (ACC). Inhibition of glycogenolysis and lactate release in the ACC disrupted the persistent, but not acute, inflammation pain induced by CFA, and this effect was reversed by exogenous L-lactate administration. Knocking down the expression of lactate transporters (MCT1, MCT4, or MCT2) also disrupted the long lasting inflammation pain induced by CFA. Moreover, glycogenolysis in the ACC is critical for the induction of molecular changes related to neuronal plasticity, including the induction of phospho- (p-) ERK, p-CREB, and Fos. Taken together, our findings indicate that astrocyte-neuron lactate transport in the ACC is critical for the occurrence of persistent inflammation pain, suggesting a novel mechanism underlying chronic pain., (Copyright © 2021. Published by Elsevier B.V.)

During persistent pain, the dorsal spinal cord responds to painful inputs from the site of injury, but the molecular modulatory processes have not been comprehensively examined. Using transcriptomics and multiplex in situ hybridization, we identified the most highly regulated receptors and signaling molecules in rat dorsal spinal cord in peripheral inflammatory and post-surgical incisional pain models. We examined a time course of the response including acute (2 hours) and longer term (2 day) time points after peripheral injury representing the early onset and instantiation of hyperalgesic processes. From this analysis, we identify a key population of superficial dorsal spinal cord neurons marked by somatotopic upregulation of the opioid neuropeptide precursor prodynorphin, and 2 receptors: the neurokinin 1 receptor, and anaplastic lymphoma kinase. These alterations occur specifically in the glutamatergic subpopulation of superficial dynorphinergic neurons. In addition to specific neuronal gene regulation, both models showed induction of broad transcriptional signatures for tissue remodeling, synaptic rearrangement, and immune signaling defined by complement and interferon induction. These signatures were predominantly induced ipsilateral to tissue injury, implying linkage to primary afferent drive. We present a comprehensive set of gene regulatory events across 2 models that can be targeted for the development of non-opioid analgesics. PERSPECTIVE: The deadly impact of the opioid crisis and the need to replace morphine and other opioids in clinical practice is well recognized. Embedded within this research is an overarching goal of obtaining foundational knowledge from transcriptomics to search for non-opioid analgesic targets. Developing such analgesics would address unmet clinical needs., (Published by Elsevier Inc.)

Daphnetin (7, 8-dihydroxycoumarin, DAPH), a coumarin derivative isolated from Daphne odora var., recently draws much more attention as a promising drug candidate to treat neuroinflammatory diseases due to its protective effects against neuroinflammation. However, itscontribution to chronic inflammatory pain is largely unknown. In the current work, we investigated the effects of DAPH in a murine model of inflammatory pain induced by complete Freund's adjuvant (CFA) and its possible underlying mechanisms. Our results showed that DAPH treatment significantly attenuated mechanical allodynia provoked by CFA. A profound inhibition of spinal glial activation, followed by attenuated expression levels of spinal pro-inflammatory cytokines, was observed in DAPH-treated inflammatory pain mice. Further study demonstrated that DAPH mediated negative regulation of spinal NF-κB pathway, as well as its preferential activation of Nrf2/HO-1 signaling pathway in inflammatory pain mice. This study, for the first time, indicated that DAPH might preventthe development of mechanical allodynia in mice with inflammatory pain. And more importantly, these data provide evidence for the potential application of DAPH in the treatment of chronic inflammatory pain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: As one of the most common conditions in urological outpatients, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) puzzles many individuals because of its unclear etiology and lack of effective treatment. Recently, immunological alterations underpinning CP/CPPS have been extensively investigated., Methods: The PubMed, Web of Science, Cochrane library, and EMBASE databases were used to search original articles on immune mediators in patients with CP/CPPS and in experimental autoimmune prostatitis (EAP) models through April 10, 2020. Standardized mean differences (SMD) were calculated to summarize the differences in immune mediator levels between groups. Funnel plot, Begg's funnel plot, Egger's regression test, and the sensitivity analysis were applied to determine and visualize the stability of our findings., Results: A total of 34 original studies were included in the meta-analysis, including 24 studies on patients with CP/CPPS and 10 studies on EAP models. We found that TNF-α, IL-1β, IL-6, and IL-8 were the four immune mediators that elevated in most of the samples derived from patients with CP/CPPS and the EAP models. The adjusted publication bias analysis indicated that publication bias was not existed, and the sensitivity analyses showed that the results were stable., Conclusions: Immune responses play significant roles during the pathogenesis of CP/CPPS by promoting intraprostatic inflammation. Our findings provide potential diagnostic and therapeutic targets for CP/CPPS patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: We sought to determine whether pollen triggers urological chronic pelvic pain syndrome flares., Materials and Methods: We assessed flare status every 2 weeks for 1 year as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain case-crossover analysis of flare triggers (NCT01098279). Flare symptoms, flare start date and exposures in the 3 days before a flare were queried for the first 3 flares and at 3 randomly selected nonflare times. These data were linked to daily pollen count by date and the first 3 digits of participants' zip codes. Pollen count in the 3 days before and day of a flare, as well as pollen rises past established thresholds, were compared to nonflare values by conditional logistic regression. Poisson regression was used to estimate flare rates in the 3 weeks following pollen rises past established thresholds in the full longitudinal study. Analyses were performed in all participants and separately in those who reported allergies or respiratory tract disorders., Results: Although no associations were observed for daily pollen count and flare onset, positive associations were observed for pollen count rises past medium or higher thresholds in participants with allergies or respiratory tract disorders in the case-crossover (OR 1.31, 95% CI 1.04-1.66) and full longitudinal (RR 1.23, 95% CI 1.03-1.46) samples., Conclusions: We found some evidence to suggest that rising pollen count may trigger flares of urological chronic pelvic pain syndrome. If confirmed in future studies, these findings may help to inform flare pathophysiology, prevention and treatment, and control over the unpredictability of flares.

Despite successful research efforts aimed at understanding pain mechanisms, there is still no adequate treatment for many patients suffering from chronic pain. The contribution of neuroinflammation to chronic pain is widely acknowledged. Here, we summarize findings indicating that T cells play a key role in the suppression of pain. An active contribution of the immune system to resolution of pain may explain why immunosuppressive drugs are often not sufficient to control pain. This would also imply that dysregulation of certain immune functions promote transition to chronic pain. Conversely, stimulating the endogenous immune-mediated resolution pathways may provide a potent approach to treat chronic pain., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mounting evidence indicates that disruptions in bidirectional communication pathways between the central nervous system (CNS) and peripheral immune system underlie the etiology of pathologic pain conditions. The purpose of this review is to focus on the cross-talk between these two systems in mediating nociceptive circuitry under various conditions, including nervous system disorders. Elevated and prolonged proinflammatory signaling in the CNS is argued to play a role in psychiatric illnesses and chronic pain states. Here we review current research on the dynamic interplay between altered nociceptive mechanisms, both peripheral and central, and physiological and behavioral changes associated with CNS disorders.

Chronic neuropathic pain (CNP) is caused by a lesion or disease of the somatosensory nervous system. It affects ~8% of the general population and negatively impacts a person's level of functioning and quality of life. Its resistance to available pain therapies makes CNP a major unmet medical need. Immune cells have been shown to play a role for development, maintenance and recovery of CNP and therefore are attractive targets for novel pain therapies. In particular, in neuropathic mice and humans, microglia are activated in the dorsal horn and peripheral immune cells infiltrate the nervous system to promote chronic neuroinflammation and contribute to the initiation and progression of CNP. Importantly, immunity not only controls pain development and maintenance, but is also essential for pain resolution. In particular, regulatory T cells, a subpopulation of T lymphocytes with immune regulatory function, and macrophages were shown to be important contributors to pain recovery. In this review we summarize the interactions of the peripheral immune system with the nervous system and outline their contribution to the development and recovery of pain., Competing Interests: JB and RF are named inventors on patent applications covering the use of TNFR2 agonists. RF is a named inventor on patent applications covering the TNFR2 agonist technology., (Copyright © 2021 Bethea and Fischer.)

Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations., (Copyright © 2021 the authors.)

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.

Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acute-to-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition., (©2020 Society for Leukocyte Biology.)

Osteoarthritis results in chronic pain and loss of function. Proinflammatory cytokines create both osteoarthritis pathology and pain. Current treatments are poorly effective, have significant side effects, and have not targeted the cytokines central to osteoarthritis development and maintenance. Interleukin-10 is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. However, interleukin-10 protein has a short half-life in vivo and poor joint permeability. For sustained IL-10 activity, we developed a plasmid DNA-based therapy that expresses a long-acting human interleukin-10 variant (hIL-10var). Here, we describe the 6-month GLP toxicology study of this therapy. Intra-articular injections of hIL-10var pDNA into canine stifle joints up to 1.5 mg bilaterally were well-tolerated and without pathologic findings. This represents the first long-term toxicologic assessment of intra-articular pDNA therapy. We also report results of a small double-blind, placebo-controlled study of the effect of intra-articular hIL-10var pDNA on pain measures in companion (pet) dogs with naturally occurring osteoarthritis. This human IL-10-based targeted therapy reduced pain measures in the dogs, based on veterinary and owner ratings, without any adverse findings. These results with hIL-10var pDNA therapy, well-tolerated and without toxicologic effects, establish the basis for clinical trials of a new class of safe and effective therapies for OA., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite being a life-restricting condition, chronic pain remains poorly treated. A better understanding of the underlying mechanisms of chronic pain and thence development of innovative targets is therefore essential. Recently we have started to elucidate the importance of the role of microRNAs (miRs) in preclinical chronic pain. miRs are small, non-coding RNAs that regulate genes including those involved in nociceptive signalling. MiRs can exert their effects both intracellularly and extracellularly, the latter of which requires that they are released either as naked species or packaged in exosomes. Here we discuss changes in miR expression that occur in the dorsal root ganglia in murine models of chronic pain. We consider the downstream targets of changes in miR expression, including voltage-gated ion channels, as well as discuss extracellular consequences such as changes in macrophage phenotype that constitute of means by which neuron-immune cell crosstalk occurs. Such miR-mediated intracellular communication could provide a novel target for the treatment of chronic pain, which would be most effective if tailored to the specific cause of pain. Indeed, we conclude by reviewing evidence for the involvement of miRs in clinical cases of chronic pain, supporting the notion that tailored, miR-targeted therapies could prove to be an effective new strategy for the treatment of chronic pain clinically., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects., Areas Covered: In an effort to better address cLBP, anti-nerve growth factor (NGF) monoclonal antibodies (mAbs) are nearing marketing approval. This class of medications has been primarily evaluated for osteoarthritis, but are being examined at higher doses for use in cLBP. We review the efficacy of this class in treating LBP as well as their potential side effects based on nine phase II or III published clinical trials. Five trials evaluated Tanezumab and four trials evaluated Fasinumab, with seven trials evaluating nonspecific LBP, one evaluating sciatica related cLBP, and one evaluating vertebral fracture related cLBP., Expert Opinion: The results of available clinical trials indicate modest effectiveness with regard to reduction of pain in the low back, and improved functionality, compared to placebo in keeping with the effect size of other pharmacologic treatment modalities. Rapidly progressive osteoarthritis was infrequently reported. However, the continued observation of this serious side effects warrants careful patient selection and balancing the risks and benefits of anti-NGF mAbs in treating cLBP.

The early shortage of novel coronavirus disease (COVID-19) tests in the United States led many hospitals to first screen for common respiratory pathogens, and only if this screen was negative to proceed with COVID-19 testing. We report a case of a 56-year-old woman with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coinfection with group A Streptococcus . The initial testing strategy resulted in delays in both diagnosis and implementation of appropriate precautions. Underlined is the importance of testing for both SARS-CoV-2 and other common respiratory pathogens during the current pandemic.

Background: The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear., Methods: To address this question, we intra-articularly injected complete Freund's adjuvant (CFA) into TDAG8 +/+ , TDAG8 -/- or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection., Results: We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function., Conclusions: This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.

Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Chronic pain conditions such as neuropathic pain and persistent inflammatory pain are difficult to manage. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate nociceptive processing at the spinal dorsal horn. Previous studies have shown that intrathecal AMPA receptor antagonists exert antinociception in various pain states. Perampanel is a selective, noncompetitive inhibitor of the AMPA receptor and used clinically as an antiepileptic drug. Little is known about antinociceptive action of perampanel in the spinal cord. Here, we explored whether intrathecal perampanel attenuates neuropathic and inflammatory pain. A chronic constriction injury (CCI) to the sciatic nerve was induced in male Sprague-Dawley rats. We evaluated the effects of intrathecal perampanel (10, 30, or 100 μg) on mechanical and cold hyperalgesia using the electronic von Frey and cold plate tests, respectively. Normal rats were assessed in terms of inflammatory nociception using the formalin test, and motor function employing the rotarod test. In the CCI rats, spinally applied perampanel inhibited mechanical and cold hyperalgesia dose-dependently. In normal rats, perampanel remarkably suppressed the early- and late-phase responses in the formalin test, and it weakly affected motor performance for a short period at the highest dose. These results suggest that perampanel exerts antinociceptive actions on neuropathic and persistent inflammatory pain in the spinal cord. Perampanel may be safe and beneficial remedy for patients with such pain conditions. In addition, AMPA receptor can be a promising target for treatment of chronic pain., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Among the various regulators of the nervous system, the gut microbiota has been recently described to have the potential to modulate neuronal cells activation. While bacteria-derived products can induce aversive responses and influence pain perception, recent work suggests that "abnormal" microbiota is associated with neurological diseases such as Alzheimer's, Parkinson's disease or autism spectrum disorder (ASD). Here we review how the gut microbiota modulates afferent sensory neurons function and pain, highlighting the role of the microbiota/gut/brain axis in the control of behaviors and neurological diseases. We outline the changes in gut microbiota, known as dysbiosis, and their influence on painful gastrointestinal disorders. Furthermore, both direct host/microbiota interaction that implicates activation of "pain-sensing" neurons by metabolites, or indirect communication via immune activation is discussed. Finally, treatment options targeting the gut microbiota, including pre- or probiotics, will be proposed. Further studies on microbiota/nervous system interaction should lead to the identification of novel microbial ligands and host receptor-targeted drugs, which could ultimately improve chronic pain management and well-being.

All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor., (© 2019 Wiley Periodicals, Inc.)

Sleep disturbances and chronic pain are considered public health concerns. They are frequently associated, and the direction of its relationship and possible mechanisms underlying it are frequently debated. The exploration of the sleep-pain association is of great clinical interest to explore in order to steer potential therapeutic avenues, accommodate the patient's experience, and adapt the common practice of health professionals. In this review, the direction between sleep-pain in adult and pediatric populations will be discussed. Moreover, the possible mechanisms contributing to this relationship as endogenous pain modulation, inflammation, affect, mood and other states, the role of different endogenous substances (dopamine, orexin, melatonin, vitamin D) as well as other lesser known such as cyclic alternating pattern among others, will be explored. Finally, directions for future studies on this area will be discussed, opening up to the addition of tools such as brain imaging (e.g., fMRI), electrophysiology and non-invasive brain stimulation techniques. Such resources paired with artificial intelligence are key to personalized medicine management for patients facing pain and sleep interacting conditions.

The dorsal horns of the spinal cord and the trigeminal nuclei in the brainstem contain neuron populations that are critical to process sensory information. Neurons in these areas are highly heterogeneous in their morphology, molecular phenotype and intrinsic properties, making it difficult to identify functionally distinct cell populations, and to determine how these are engaged in pathophysiological conditions. There is a growing consensus concerning the classification of neuron populations, based on transcriptomic and transductomic analyses of the dorsal horn. These approaches have led to the discovery of several molecularly defined cell types that have been implicated in cutaneous mechanical allodynia, a highly prevalent and difficult-to-treat symptom of chronic pain, in which touch becomes painful. The main objective of this review is to provide a contemporary view of dorsal horn neuronal populations, and describe recent advances in our understanding of on how they participate in cutaneous mechanical allodynia.

Introduction: Smoking is associated with several diseases and affects the immune system. Recently, published data demonstrate an involvement of T helper 17 cells (Th17) and regulatory T cells (Tregs) in the pathogenesis of chronic pain and pain intensity. The role of these T-cell subsets in smoking patients with chronic pain is nebulous so far. We therefore analyzed Th17 cells and Tregs in smokers and nonsmokers with chronic pain., Methods: Analyses of T-cell subsets, mRNA expression and T-cell related cytokine profiles were done in 44 patients with chronic pain. Twenty-two of these patients were smokers. Numbers of T-cell subsets were quantified by flow cytometry. mRNA expression of the Th17- (RAR-related orphan receptor gamma) and Treg (forkhead box protein P3)-specific transcription factors was determined by quantitative real-time PCR, and levels of cytokines were measured by Human Cytokine Multiplex Immunoassay., Results: Compared to nonsmokers, smokers showed significantly enhanced pain levels. On cellular basis, the number of pro-inflammatory Th17 cells (smokers: 2.2 ± 2.5% vs. nonsmokers: 0.5 ± 0.4%; p = .04) was increased, whereas the number of anti-inflammatory Tregs (smokers: 2.5 ± 0.9% vs. nonsmokers: 3.1 ± 1.1%; p = .02) was significantly decreased, resulting in an altered Th17/Treg ratio (Th17/Treg ratio: 0.9 ± 1.0 in smokers vs. 0.2 ± 0.1 in nonsmokers; p < .01). These findings were confirmed by quantitative real-time PCR. Analyses of cytokines revealed only marginal changes., Conclusions: In patients with chronic pain, smoking is associated with enhanced pain levels together with an imbalance of the Th17/Treg ratio. The shift of the Th17/Treg ratio toward inflammation may explain in part the increased pain intensity in these patients., Implications: Smoking is associated with increased pain levels and a pro-inflammatory Th17/Treg shift. The altered Th17/Treg ratio in smoking patients with chronic pain may partly explain their increased pain intensity., German Clinical Trial Register (drks): Registration Trial DRKS00005954., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Nail psoriasis is a chronic condition which causes pain and functional impairment; thus, it restricts the activities of daily living and worsens the quality of life. Different chemotherapeutic options are available for treating nail psoriasis such as systemic, intralesional, and topical therapies. However, current chemotherapy suffers from several limitations and to overcome them, new advancements are being made worldwide. Various reports have been published on current progress in the treatment of nail psoriasis such as clinical efficacy studies of novel antipsoriatic agents and novel formulation strategies for current chemotherapy. There are several novel nail formulations for the treatment of nail disorders, particularly onychomycosis, such as vesicular colloidal structure (liposomes, niosomes, transfersomes, ethosomes, etc.) and nonvesicular colloidal structures (nano-emulgel, nanocapsules, thermosensitive gel, etc.) These formulations can also prove beneficial for the treatment of nail psoriasis, and will be heavily explored in the near future. This review provides a brief introduction to the disease, its pathogenesis, and its treatment modalities. The review also throws light onto progress and future perspectives in nail psoriasis treatment.

Since the first discovery that the bioactive lipid, lysophosphatidic acid (LPA) and LPA 1 receptor signaling play a role in the initiation of neuropathic pain (NeuP), accumulated reports have supported the original findings and extended the study toward possible therapeutic applications. The present review describes beneficial roles of LPA receptor signaling in a variety of chronic pain, such as peripheral NeuP induced by nerve injury, chemotherapy and diabetes, central NeuP induced by cerebral ischemia with hemorrhage and spinal cord injury, and fibromyalgia-like wide spread pain induced by repeated cold, psychological and muscular acidic stress. Emerging mechanistic findings are the feed-forward amplification of LPA production through LPA 1 , LPA 3 and microglia and the evidence for maintenance of chronic pain by LPA receptor signaling.

Our study aimed to identify differentially methylated CpGs/regions and their enriched genomic pathways associated with underlying chronic musculoskeletal pain in older individuals. We recruited cognitively healthy older adults with ( n  = 20) and without ( n  = 9) self-reported musculoskeletal pain and collected DNA from peripheral blood that was analyzed using MethylationEPIC arrays. We identified 31,739 hypermethylated CpG and 10,811 hypomethylated CpG probes ( p s ≤ 0.05). All CpG probes were clustered into 5966 regions, among which 600 regions were differentially methylated at p ≤ 0.05 level, including 294 hypermethylated regions and 306 hypomethylated regions (differentially methylated regions). Ingenuity pathway enrichment analysis revealed that the pain-related differentially methylated regions were enriched across multiple pathways. The top 10 canonical pathways were linked to cellular signaling processes related to immune responses (i.e. antigen presentation, programed cell death 1 receptor/PD-1 ligand 1, interleukin-4, OX40 signaling, T cell exhaustion, and apoptosis) and gamma-aminobutyric acid receptor signaling. Further, Weighted Gene Correlation Network Analysis revealed a comethylation network module in the pain group that was not preserved in the control group, where the hub gene was the cyclic adenosine monophosphate-dependent transcription factor ATF-2. Our preliminary findings provide new epigenetic insights into the role of aberrant immune signaling in musculoskeletal pain in older adults while further supporting involvement of dysfunctional GABAergic signaling mechanisms in chronic pain. Our findings need to be urgently replicated in larger cohorts as they may serve as a basis for developing and targeting future interventions.