Pathophysiology Of Pain Research Articles

Mechanisms and Therapeutic Potential of GPX4 in Pain Modulation.

Pain, a complex symptom encompassing both sensory and emotional dimensions, constitutes a significant global public health issue. Oxidative stress is a pivotal factor in the complex pathophysiology of pain, with glutathione peroxidase 4 (GPX4) recognized as a crucial antioxidant enzyme involved in both antioxidant defense mechanisms and ferroptosis pathways. This review systematically explores GPX4's functions across various pain models, including neuropathic, inflammatory, low back, and cancer-related pain. Specifically, the focus includes GPX4's physiological roles, antioxidant defense mechanisms, regulation of ferroptosis, involvement in signal transduction pathways, and metabolic regulation. By summarizing current research, we highlight the potential of GPX4-targeted therapies in pain management.

Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project)

Pathophysiology of Pain and Mechanisms of Neuromodulation: A Narrative Review (A Neuron Project)

Addressing gaps in pain research from an integrated whole person perspective

Abstract While our understanding of pain is rapidly growing, some areas of pain research are lagging behind. This article discusses two current and inter-related gaps in knowledge that are in need of addressing: first, the connections between “brain” and “body” components of pain; and second, the process of endogenous pain resolution. Historical reasons for these research gaps are discussed and solutions are outlined based on an integrative, whole person research approach. These include comprehensive mapping of the mechanosensory and nociceptive innervation of deep tissues; developing objective, non-invasive measurements to quantify the metabolic, structural and mechanical components of the peripheral tissue environment; integrating our understanding of pain pathophysiology, across whole organs and whole body, as well as across bio-psycho-social domains; and understanding the interplay of nervous system and peripheral tissue mechanisms that promote the endogenous resolution of pain and prevent its acute-to-chronic transition. Current NIH-led efforts in these areas are outlined, including several studies within the NIH HEAL (or Help End Addition Long Term) initiative and the National Center for Complementary and Integrative Health's strategic priorities in whole person research.

A nociceptive-nociplastic spectrum of myofascial orofacial pain: insights from neuronal ion channel studies.

Myofascial orofacial pain, traditionally viewed as a nociceptive pain condition, also exhibits characteristics consistent with nociplastic pain-pain arising from altered nociception without clear evidence of tissue damage. Evidence supporting myofascial orofacial pain as nociplastic pain includes clinical observations of central sensitisation in patients, even in the absence of visible inflammation. Sensitisation is characterised by heightened responsiveness of nociceptive neurons to normal stimuli or activation by normally subthreshold stimuli, either in the peripheral or central nervous system. It is linked to maladaptive neuroplastic changes, including increased functional potentiation and altered expression of neuronal ion channels, receptors and neurotransmitters. This mini-review presents insights from existing evidence regarding altered nociception and its relation to changes in the expression of neuronal ion channels in myofascial orofacial pain. Increased expression of transient receptor potential (TRP) vanilloid 1 channels (TRPV1), TRPV4, TRP ankyrin 1 channels (TRPA1), Piezo2 channels, P2X3 purinergic receptors, N-Methyl-D-Aspartate (NMDA) receptors and voltage-gated calcium channels in the trigeminal ganglion of rodents has been observed in association with myofascial orofacial pain. This evidence highlights the role of neuronal ion channels in the pathophysiology of myofascial orofacial pain and supports the involvement of nociplastic mechanisms.

MiRNA Expression in Long-Distance Runners with Musculoskeletal Pain: Implications for Pain Pathophysiology

Background: miRNAs are short, non-coding RNAs whose deregulation has been shown in painful processes, including musculoskeletal pain. This condition, which causes disability, impacts quality of life, and contributes to substantial healthcare costs, is also a critical issue in sports. In this case-control study, we evaluated the expression of four miRNAs involved in inflammation in runners with musculoskeletal pain and elucidated their functions and pathophysiological implications. Methods: A total of 17 runners with musculoskeletal pain and 17 age- and sex-matched runners without pain participated in this study. The levels of the miRNAs were evaluated by qRT-PCR. Bioinformatic tools were employed to identify the target genes and biological processes regulated by these miRNAs. Results: Compared to the controls, the runners with musculoskeletal pain exhibited significantly higher plasma levels of miR-133b (p = 0.02), miR-155-5p (p = 0.003) and let-7a-5p (p = 0.02). Multivariable regression analysis indicated that these three miRNAs exhibit a positive correlation (p < 0.05) with the presence of musculoskeletal pain, adjusted for age. Bioinformatic analysis suggested that the miRNAs hub genes are involved in regulatory processes, neuroinflammatory pathways, and human diseases that are associated with pain pathology. Conclusions: These results enhance our understanding of the potential role of miR-133b, miR-155-5p and let-7a-5p in pain-associated biological processes. The miRNA-mediated negative regulation of genes identified could explain the inflammatory and tissue repair processes in this population. Further studies are needed to confirm and validate the role of these miRNAs in painful conditions, especially considering the significant public health implications of managing inflammatory pain in sports.

The Effect of Pexidartinib on Neuropathic Pain via Influences on Microglia and Neuroinflammation in Mice.

Chronic pain is a debilitating medical condition that lacks effective treatments. Increasing evidence suggests that microglia and neuroinflammation underlie pain pathophysiology, which therefore supports a potential strategy for developing pain therapeutics. Here, our study is testing the hypothesis that the promise of pain amelioration can be achieved using the small-molecule pexidartinib (PLX-3397), a previously food and drug administration (FDA)-approved cancer medicine and a colony-stimulating factor-1 receptor (CSF-1R) inhibitor that display microglia-depleting properties. We used the previously reported chronic constriction injury (CCI) mouse model, in which PLX-3397 or vehicle was orally administrated to mice daily for 21 days, then applied to the CCI model, followed by PLX-3397 or vehicle administration for an additional 28 days. Additionally, we examined microglia-related neuroinflammation markers using positron emission tomography (PET) neuroimaging and immunofluorescence (IF). We showed that PLX-3397 significantly ameliorated pain-related behavioral changes throughout the entire experimental period after CCI (vehicle versus PLX-3397 at day 14, effect size: 2.57, P = .002). Microglia changes were first analyzed by live-animal PET neuroimaging, revealing PLX-3397-associated reduction of microglia by probing receptor-interacting serine/threonine-protein kinase 1 (RIPK1), a protein primarily expressed in microglia, which were further corroborated by postmortem immunohistochemistry (IHC) analysis using antibodies for microglia, including ionized Ca2+ binding adaptor molecule 1 (Iba-1) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 3.6, P = .011) and RIPK1 (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size 2.9, P = .023. The expression of both markers decreased in the PLX-3397 group. Furthermore, we found that PLX-3397 led to significant reductions in various proteins, including inducible nitric oxide synthase (iNOS) (somatosensory cortex, hindlimb area; vehicle versus PLX-3397, effect size: 2.3, P = .048), involved in neuroinflammation through IHC. Collectively, our study showed PLX-3397-related efficacy in ameliorating pain linked to the reduction of microglia and neuroinflammation in mice. Furthermore, our research provided new proof-of-concept data supporting the promise of testing PLX-3397 as an analgesic.

Abdominal Pain in Inflammatory Bowel Disease-Epidemiology, Pathophysiology, and Management: A Narrative Review.

Abdominal pain is a major symptom of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, and has a significant impact on patients' quality of life. Given the evolving understanding of IBD pathology and management strategies, there is an urgent need to review the recent research findings. In this review, we have analyzed the epidemiology, pathophysiology, and management of abdominal pain in IBD over the past decade. We draw on the current literature and highlight emerging trends, challenges, and advances in this field. By synthesizing key findings, this review provides insights into the complex interplay between abdominal pain, disease progression, and therapeutic interventions for IBD.

Unmet Needs in Spondyloarthritis: Understanding and Managing Chronic Pain.

Among patients with axial spondyloarthritis (axSpA), persistent pain remains a critical unmet need. In this review, we discuss the prevalence of chronic pain and fibromyalgia in patients with axSpA and examine the existing knowledge on the pathophysiology of chronic pain in SpA, osteoarthritis, and rheumatoid arthritis. Finally, we discuss the specific unmet needs that must be addressed to improve long-term outcomes in axSpA, specifically those that will improve chronic pain in this patient population.

Glial-modulating agents for the treatment of pain: a systematic review.

Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention.

Central Neuropathic Pain

ABSTRACT OBJECTIVE This article provides an approach to the assessment, diagnosis, and treatment of central neuropathic pain. LATEST DEVELOPMENTS Recent studies of the pathophysiology of central neuropathic pain, including evidence of changes in the expression of voltage-gated sodium channels and N-methyl-d-aspartate (NMDA) receptors, may provide the basis for new therapies. Other areas of current research include the role of cannabinoid-receptor activity and microglial cell activation in various animal models of central neuropathic pain. New observations regarding changes in primary afferent neuronal activity in central neuropathic pain and the preliminary observation that peripheral nerve blocks may relieve pain due to central neuropathic etiologies provide new insights into both the mechanism and treatment of central neuropathic pain. ESSENTIAL POINTS In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. A multimodal, individualized approach to the management of central neuropathic pain is necessary to optimize pain relief and may require multiple treatment trials to achieve the best outcome.

Discriminating fingerprints of chronic neuropathic pain following spinal cord injury using artificial neural networks and mass spectrometry analysis of female mice serum

Spinal cord injury (SCI) often leads to central neuropathic pain, a condition associated with significant morbidity and is challenging in terms of the clinical management. Despite extensive efforts, identifying effective biomarkers for neuropathic pain remains elusive. Here we propose a novel approach combining matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with artificial neural networks (ANNs) to discriminate between mass spectral profiles associated with chronic neuropathic pain induced by SCI in female mice. Functional evaluations revealed persistent chronic neuropathic pain following mild SCI as well as minor locomotor disruptions, confirming the value of collecting serum samples. Mass spectra analysis revealed distinct profiles between chronic SCI and sham controls. On applying ANNs, 100% success was achieved in distinguishing between the two groups through the intensities of m/z peaks. Additionally, the ANNs also successfully discriminated between chronic and acute SCI phases. When reflexive pain response data was integrated with mass spectra, there was no improvement in the classification. These findings offer insights into neuropathic pain pathophysiology and underscore the potential of MALDI-TOF MS coupled with ANNs as a diagnostic tool for chronic neuropathic pain, potentially guiding attempts to discover biomarkers and develop treatments.

Species-specific differences and the role of Nav1.9 in pain pathophysiology

Species-specific differences and the role of Nav1.9 in pain pathophysiology

Pain pathophysiology and pharmacology of cattle: how improved understanding can enhance pain prevention, mitigation, and welfare.

Globally, humans rely on cattle for food production; however, there is rising societal concern surrounding the welfare of farm animals. From a young age, cattle raised for dairy and beef production experience pain caused by routine management procedures and common disease conditions. The fundamental mechanisms, nociceptive pathways, and central nervous system structures required for pain perception are highly conserved among mammalian species. However, there are limitations to a comparative approach to pain assessment due to interspecies differences in the expression of pain. The stoicism of prey species may impede pain identification and lead to the assumption that cattle lack pain sensitivity. This highlights the importance of establishing validated bovine-specific indicators of pain-a prerequisite for evidence-based pain assessment and mitigation. Our first objective is to provide an overview of pain pathophysiology to illustrate the importance of targeted analgesia in livestock medicine and the negative welfare outcomes associated with unmitigated pain. This is followed by a review of available analgesics, the regulations governing their use, and barriers to implementation of on-farm pain management. We then investigate the current research undertaken to evaluate the pain response in cattle-a critical aspect of the drug approval process. With an emphasis on emerging research in animal cognition and pain pathology, we conclude by discussing the significant influence that pain has on cattle welfare and areas where further research and modified practices are indicated.

Imbalance in positive and negative acceleration ratio of alpha oscillation in patients with complex regional pain syndrome

ObjectivesTo elucidate the functional characteristics of the brain in the presence of chronic pain using electroencephalography (EEG), with a focus on the dynamics of neural excitation and inhibition. MethodsResting-state EEG was performed in: 17 patients with complex regional pain syndrome (CRPS) who exhibited chronic pain higher than 20 on the visual analogue scale (VAS), 6 patients with reduced CRPS symptoms and chronic pain less than 20 on VAS, and healthy age-matched controls. For the analysis, 50 s of electroencephalogram (EEG) signals were extracted from EEG recordings during wakefulness and rest with eyes closed. The envelope of the alpha frequency band was calculated by examining the positive and negative accelerations of the envelope oscillation, ratio of positive (Ap) to negative (An) accelerations (Ap-An ratio), and mean amplitude of the envelope. Comparisons were made between patients and controls, and correlations between these EEG measures and the subjective pain VAS were evaluated.Significant differences in the value of Ap, An and Ap-An ratio were observed at temporal and central electrodes between patients with pain symptoms and controls. Those with reduced CRPS symptoms exhibited a distinct Ap-An ratio at the majority of electrodes when compared with those exhibiting chronic pain. ConclusionsDistinct patterns in alpha wave envelope dynamics, reflecting excitatory and inhibitory activities, were associated with chronic pain in patients with CRPS. The pain-relieved state of CRPS suggested that a new balance of activities was established. This relationship indicated a potential association between altered alpha oscillation characteristics and the subjective experience of pain. SignificanceThis study introduces a novel method for analyzing alpha oscillation envelopes, providing new insights into the neural pathophysiology of chronic pain in CRPS patients. This approach has the potential to enhance our understanding of the alterations in brain function that occur under chronic pain conditions.

What has brain diffusion magnetic resonance imaging taught us about chronic primary pain: a narrative review.

Chronic pain is a pervasive and debilitating condition with increasing implications for public health, affecting millions of individuals worldwide. Despite its high prevalence, the underlying neural mechanisms and pathophysiology remain only partly understood. Since its introduction 35 years ago, brain diffusion magnetic resonance imaging (MRI) has emerged as a powerful tool to investigate changes in white matter microstructure and connectivity associated with chronic pain. This review synthesizes findings from 58 articles that constitute the current research landscape, covering methods and key discoveries. We discuss the evidence supporting the role of altered white matter microstructure and connectivity in chronic primary pain conditions, highlighting the importance of studying multiple chronic pain syndromes to identify common neurobiological pathways. We also explore the prospective clinical utility of diffusion MRI, such as its role in identifying diagnostic, prognostic, and therapeutic biomarkers. Furthermore, we address shortcomings and challenges associated with brain diffusion MRI in chronic primary pain studies, emphasizing the need for the harmonization of data acquisition and analysis methods. We conclude by highlighting emerging approaches and prospective avenues in the field that may provide new insights into the pathophysiology of chronic pain and potential new therapeutic targets. Because of the limited current body of research and unidentified targeted therapeutic strategies, we are forced to conclude that further research is required. However, we believe that brain diffusion MRI presents a promising opportunity for enhancing our understanding of chronic pain and improving clinical outcomes.

Is there an association between pelvic pain and gender-affirming testosterone therapy in trans masculine adolescents? An exploratory cross-sectional study

Background High rates of pelvic pain have been reported in trans individuals on testosterone, but the pathophysiology of pain and the potential role of testosterone are unclear. Aims The aim of this exploratory study was to determine whether the proportion of pelvic pain in trans adolescents is different among those on testosterone therapy compared to those who are not. Secondary objectives were to determine the characteristics, potential contributing factors, impact, and treatment of pelvic pain in trans adolescents. Methods An online cross-sectional study about pelvic pain was conducted among trans individuals assigned female at birth, aged 12 and over, and who had sought care at our institution since 2017. Results Among 102 participants, 79 (77.5%) reported having experienced pelvic pain over the last 6 months. The proportion of individuals who reported pelvic pain was lower in individuals on testosterone (n = 43/62, 69.4%) compared to those not on testosterone (n = 36/40, 90%), with a difference in proportion of −20.6% (95% CI −35.4 to −5.9%, p = 0.006). Half of participants reported school or work absenteeism and two thirds missed extracurricular activities because of pelvic pain. A wide range of treatment options were used, with variable rates of reported effectiveness. Conclusion Pelvic pain is frequently reported by trans adolescents. This exploratory study found a lower proportion of pelvic pain in trans adolescents using testosterone therapy compared to those who were not. Nevertheless, this study was limited by a small number of participants, its cross-sectional nature, and the risk of recruitment bias, thus limiting its generalizability. Longitudinal studies are required to better understand the development and evolution of pelvic pain in trans adolescents.

Trends on Nanomedicines as Novel therapeutics Approach in Targeting Nociceptors for Relieving Pain.

An important sensation that warns of potential harm to a specific area of the body is pain. The prevalence of pain-related conditions globally is a significant and growing public health issue. Chronic pain affects an estimated 1.5 billion people worldwide, with prevalence rates varying by region and demographic factors. Along with diabetes, cardiovascular disease, and cancer, pain is among the most frequent medical diseases. Opioid analgesics are the mainstay of current pain therapies, which are ineffective. Opioid addiction and its potentially fatal side effects necessitate novel treatment strategies. Nanotechnology offers potential advantages in pain management by enabling targeted drug delivery, which can enhance the efficacy and reduce the side effects of analgesic medications. Additionally, nanoparticles can be designed to release drugs in a controlled manner, improving pain relief duration and consistency. This approach also allows for the delivery of therapeutics across biological barriers, potentially enhancing treatment outcomes for chronic pain conditions. Nanomedicine enables sensitive and focused treatments with fewer side effects than existing clinical pain medicines; it is worth exploring as a potential solution to these problems. Furthermore, medication delivery systems that use nanomaterials are being used to treat pain. Whether it's the distribution of a single medication or a combination of therapies, this review seeks to summarise the ways in which drug delivery systems based on nanomaterials can be utilised to successfully treat and alleviate pain. For the purpose of writing this paper, we consulted several online libraries, including Pubmed, Science Direct, Pubmed Prime, and the Cochrane Library, to gather fresh and up-to-date material. This overview delves into the ins and outs of pain's pathophysiology, the present state of pain treatment, potential new pain treatment targets, and the various initiatives that have been launched and are still in the works to address pain with nanotechnology. Recent developments in nanomaterials-based scavenging, gene therapy for pain aetiology, and nanoparticle-based medicine delivery for side effect reduction are highlighted. Analgesics have been further covered in our discussion on FDA-approved pharmaceuticals and clinical advancements.

Recent Advances In Interventional Pain Management

Introduction: Due to limited access to therapy, 60 million individuals worldwide suffer from chronic pain, with a frequency of 20–25% in some nations. Low- and middle-income countries (LMICs) are disproportionately affected by this condition. The yearly cost of diabetes, cancer, and heart disease—including medical expenses, lost productivity, and disability programs—is less than that of pain complaints. Pain management techniques, the most recent discoveries in pain research, and the most recent advancements in pain therapy technology can work together to reduce the prevalence of chronic pain and lessen the financial burden that comes with pain syndrome. Objective: To determine the extent to which the latest technological developments in interventional pain management to personalized treatment techniques according to patient complaints and conditions. The scope of technological development here is not only pain intervention techniques but also advances in understanding the pathophysiology of pain, nerve and tissue regeneration, as well as the modalities of technology used for pain interventions. Review: By conducting literature searches including journals, systematic reviews, library surveys, and case reports from the last 10 years on the latest interventional pain management techniques and serial cases. Summary: Many new minimally invasive pain intervention techniques have been developed and used in the treatment of chronic pain within the past 10 years. The necessity for standardization of processes, safety, efficacy, cost, and accessibility to new technology and techniques are among the issues and debates surrounding technical advancements and strategies for managing chronic pain. Intervention pain management techniques have grown in importance as a less intrusive method of treating chronic pain. For optimal outcomes, used in conjunction with other pain management modalities such as medication, physical therapy, cognitive behavioral change therapy, and others.

Irritable bowel syndrome: When food is a pain in the gut.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal condition associated with altered bowel habits and recurrent abdominal pain, often triggered by food intake. Current treatments focus on improving stool pattern, but effective treatments for pain in IBS are still lacking due to our limited understanding of pathophysiological mechanisms. Visceral hypersensitivity (VHS), or abnormal visceral pain perception, underlies abdominal pain development in IBS, and mast cell activation has been shown to play an important role in the development of VHS. Our work recently revealed that abdominal pain in response to food intake is induced by the sensitization of colonic pain-sensing neurons by histamine produced by activated mast cells following a local IgE response to food. In this review, we summarize the current knowledge on abdominal pain and VHS pathophysiology in IBS, we outline the work leading to the discovery of the role of histamine in abdominal pain, and we introduce antihistamines as a novel treatment option to manage chronic abdominal pain in patients with IBS.

Cytokines in Cerebrospinal Fluid and Chronic Pain in Humans: Past, Present, and Future.

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. 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. 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.