Papers: 18 Jun 2022 - 24 Jun 2022

Inhibition of cathepsin D (Cat D) sensitizes cancer cells to anticancer drugs via RNF183-mediated downregulation of Bcl-xL expression. Although NF-κB activation is involved in the upregulation of RNF183 expression, the molecular mechanism of NF-κB activation by Cat D inhibition is unknown. We conducted this study to investigate the molecular mechanism underlying Cat D-mediated NF-κB activation. Interestingly, Cat D inhibition-induced IκB degradation in an autophagy-dependent manner. Knockdown of autophagy-related genes (ATG7 and Beclin1) and lysosome inhibitors (chloroquine and bafilomycin A1) blocked IκB degradation via Cat D inhibition. Itch induced K63-linked ubiquitination of IκB and then modulated the protein stability of IκB by Cat D inhibition. Inhibition of Cat D-mediated Itch activation was modulated by the JNK signaling pathway, and phosphorylated Itch could bind to IκB, resulting in polyubiquitination of IκB. Additionally, inhibition of Cat D increased autophagy flux via activation of the LKB1-AMPK-ULK1 pathway. Therefore, our results suggested that Cat D inhibition activated NF-κB signaling via degradation of autophagy-dependent IκB, which is associated with the upregulation of RNF183, an E3 ligase of Bcl-xL. Cat D inhibition enhances TRAIL-induced apoptosis through Bcl-xL degradation via upregulation of RNF183.

Oral health is essential to human health. Conditions associated with poor oral health involve all organ systems and many major disease categories including infectious disease, cardiovascular disease, chronic pain, cancer, and mental health. Outcomes are also associated with health equity. Medical education organizations including the Association of American Medical Colleges and National Academy of Medicine recommend that oral health be part of medical education. However, oral health is not traditionally included in many medical school, physician assistant, or nurse practitioner curricula. Several challenges explain this exclusion including lack of time, expertise, and prioritization; we therefore provide suggestions for integrating oral health education into the health professions school curriculum. These recommendations offer guidance for enhancing the oral health curriculum across institutions. We include key organizational and foundational steps, strategies to link oral health with existing content, and approaches to achieve curricular sustainability.

The purpose of this review is to examine the impact of smoking and its role on the development of chronic pain and provide a critical review of recent literature.

Chronic cancer pain is one of the most common symptoms affecting oncology patients and cancer survivors. Epidemiological trends show that its recognition and management are increasingly important. The ICD-11 provides a better analysis of this problem based on the pathophysiological characteristics of cancer-related pain. This article proposes to review the mechanisms of cancer-related pain in relation to this classification.

Health-related quality of life (hrQoL) is a core outcome in evaluating interdisciplinary pain rehabilitation (IPR). This systematic review aimed to identify prognostic factors for hrQoL at least six months after IPR in chronic pain patients.

Opioid prescriptions for chronic pain have risen sharply over the last 25 years; harms associated with these drugs are related to dose and length of use.

The interplay between pain of different chronicity and cardiovascular disease (CVD) is incompletely understood.

Fatigue is common in rheumatoid arthritis (RA). We aimed to explore its longitudinal course, predictors and association with disease activity in early RA.

Globally, 20-25% of people will experience chronic pain in their lifetime. Dance is a physical activity with psychosocial benefits which may positively impact pain. This review aimed to investigate the effect of dance interventions on the experience of pain, by quantitative measures and qualitative themes.

Intervertebral disc degeneration (IDD) is a common age-related disease with clinical manifestations of lumbar and leg pain and limited mobility. The pathogenesis of IDD is mainly mediated by the death of intervertebral disc (IVD) cells and the imbalance of extracellular matrix (ECM) synthesis and degradation. Oxidative stress and inflammatory reactions are the important factors causing this pathological change. Therefore, the regulation of reactive oxygen species and production of inflammatory factors may be an effective strategy to delay the progression of IDD. In recent years, nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream regulated protein heme oxygenase-1 (HO-1) have received special attention due to their antioxidant, anti-inflammatory and anti-apoptotic protective effects. Recent studies have elucidated the important role of these two proteins in the treatment of IDD disease. However, Nrf2 and HO-1 have not been systematically reported in IDD-related diseases. Therefore, this review describes the biological characteristics of Nrf2 and HO-1, the relationship between Nrf2- and HO-1-regulated oxidative stress and the inflammatory response and IDD, and the progress in research on some extracts targeting Nrf2 and HO-1 to improve IDD. Understanding the role and mechanism of Nrf2 and HO-1 in IDD may provide novel ideas for the clinical treatment and development of Nrf2- and HO-1-targeted drugs.

The use of veterinary acupuncture for pain relief is expanding among small animal practitioners. Although acupuncture was developed as part of the medical system in Ancient China, research into the scientific basis of its effects is expanding rapidly. Acupuncture is very effective for analgesia on a local, segmental, and suprasegmental level. Many forms of acupuncture can be used independently or as part of a balanced multi-modal approach for the control of acute and chronic pain. In the hands of a skilled practitioner, acupuncture can be a safe and effective modality for treating pain in companion animals. This article outlines the mechanisms of action of acupuncture, its related neurophysiology and provides examples from the literature demonstrating its effectiveness.

Taxanes are associated with a distal sensory neuropathy, significantly affecting cancer survivor quality of life. However, chemotherapy-induced peripheral neuropathy (CIPN) assessments are primarily based on clinical symptoms rather than objective neurophysiologic findings. Therefore, we investigated neurophysiologic changes in symptomatic subjects, comparing them with symptom severity.

Commonly applied diagnostic criteria for growing pains (GP) have evolved without determination by an authoritative representative body. GP and restless legs syndrome (RLS) share anatomical, distributional, temporal, and other clinical features and are associated in individuals over time, in families, and in population samples. In this study, we tested the hypothesis that GP, diagnosed by widely used criteria, is confounded by cases of painful restless legs syndrome (RLS-Painful).

Systematic reviews associate peripheral nerve blocks based on anatomic landmarks or nerve stimulation with reduced pain and need for systemic analgesia in hip fracture patients. We aimed to investigate the effect of ultrasound-guided nerve blocks compared to conventional analgesia for preoperative pain management in hip fractures. Five databases were searched until June 2021 to identify randomised controlled trials. Two independent authors extracted data and assessed risk of bias. Data was pooled for meta-analysis and quality of evidence was evaluated using Grades of Recommendation Assessment, Development and Evaluation (GRADE). We included 12 trials (976 participants) comparing ultrasound-guided nerve blocks to conventional systemic analgesia. In favour of ultrasound, pain measured closest to two hours after block placement decreased with a mean difference of -2.26 (VAS 0 to 10); (p < 0.001) 95% CI [-2.97 to -1.55]. In favour of ultrasound, preoperative analgesic usage of iv. morphine equivalents in milligram decreased with a mean difference of -5.34 (p=0.003) 95% CI [-8.11 to -2.58]. Time from admission until surgery ranged from six hours to more than three days. Further, ultrasound-guided nerve blocks may be associated with a lower frequency of delirium: risk ratio 0.6 (p = 0.03) 95% CI [0.38 to 0.94], fewer serious adverse events: risk ratio 0.33 (p = 0.006) 95% CI [0.15 to 0.73] and higher patient satisfaction: mean difference 25.9 (VAS 0 to 100) (p < 0.001) 95% CI [19.74 to 32.07]. However, the quality of evidence was judged low or very low. In conclusion, despite low quality of evidence, ultrasound-guided blocks were associated with benefits compared to conventional systemic analgesia.

Electroacupuncture (EA) has benefits for neuropathic pain. However, the underlying mechanisms are still unknown. The current study explores the underlying mechanisms of EA in neuropathic pain of chronic constriction injury (CCI) rats. . Overall, 126 Sprague-Dawley (200-250 g) rats were divided into nine groups randomly: the sham-operated, CCI, CCI+EA, CCI+sham EA, CCI+NS, CCI+AAV-NC, CCI+AAV-miR-206-3p, CCI+EA+NS, and CCI+EA+AAV-miR-206-3p groups. The animals were sacrificed 14 days postsurgery. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests were used to determine differences in neurobehavioral manifestations. qPCR, western blotting, and immunofluorescence (IF) were carried out to detect the expression levels of miR-206-3p, BDNF, BAX/Bcl-2, TNF-, and IL-6. Nissl staining was measured to observe morphological changes in neurons. Transmission electron microscopy (TEM) was employed to evaluate microscopic changes in dorsal horn synapses.

The aim of this review was to assess diagnostic and treatment challenges of adolescents with SI joint pain. We diagnosed 13 of the patients who were referred to our chronic pain clinic because of low back pain (30%) with SI joint pain based on provocative tests response. We performed SI joint steroid infiltration. Six patients (46%) felt better immediately after the procedure and 1 (8%) patient had a one-side only pain relief after a bilateral block. Four of these patients (31%) did not experience any further episode of pain during the follow-up and three patients reported recurring pain on average 2 months after the initial procedure. The 2nd procedure was successful in two patients and the third one experienced pain again 12 months later, requiring a third successful infiltration. Six patients (46%) experienced pain again within a few hours or days after the infiltration and their pain score were unchanged compared with what they had reported prior to the procedure. We were unable to place the needle within the joint under fluoroscopy in 1 patient; however, we were successful repeating the procedure under CT guidance. One patient experienced a motor and sensory block in the distribution of the sciatic nerve immediately after the procedure, which resolved within 24 and 48 hours, respectively. SI joint pain is a distinctive pathology that can be present in children and adolescents and is often overlooked by practitioners. Its diagnosis and management are challenging in this population as it is in adults. SI joint steroids injections may play a role in the management of these patients.

Rapid-onset opioids (ROOs) are effective treatments for breakthrough cancer pain (BTcP) given their rapid onset of action and relatively short duration of analgesia. The aim of this article is to describe specific considerations for the use of ROOs in daily practice, focusing on dose titration and treatment of specific populations.

Museum engagement may be an effective approach for decreasing social disconnection and pain among individuals living with chronic pain. In October 2019, we launched a randomized controlled trial to assess the feasibility of museum engagement for individuals living with chronic pain; the study was halted in March, 2020 due to Covid-19-related safety concerns. This paper describes the process of transitioning from in-person to virtual museum programing in order to continue the study. Virtual museum programing is a feasible option for individuals living with chronic pain that is amenable to research and which may improve accessibility, inclusivity, and scalability relative to in-person programing.

Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model. An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates. We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals. In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases.

Despite recent progress regarding inexpensive medical approaches, many individuals suffer from moderate to severe pain globally. The discovery and advent of exosomes, as biological nano-sized vesicles, has revolutionized current knowledge about underlying mechanisms associated with several pathological conditions. Indeed, these particles are touted as biological bio-shuttles with the potential to carry specific signaling biomolecules to cells in proximity and remote sites, maintaining cell-to-cell communication in a paracrine manner. A piece of evidence points to an intricate relationship between exosome biogenesis and autophagy signaling pathways at different molecular levels. A close collaboration of autophagic response with exosome release can affect the body's hemostasis and physiology of different cell types. This review is a preliminary attempt to highlight the possible interface of autophagy flux and exosome biogenesis on pain management with a special focus on neuropathic pain. It is thought that this review article will help us to understand the interplay of autophagic response and exosome biogenesis in the management of pain under pathological conditions. The application of therapies targeting autophagy pathway and exosome abscission can be an alternative strategy in the regulation of pain.

Chronic migraine is one of the most devastating headache disorders. The estimated prevalence is 1.4-2.2% in the population. The factors which may predispose to the process of migraine progression include high frequency of migraine attacks, medication overuse, comorbid pain syndromes, and obesity. Several studies showed that chronic migraine results in the substantial anatomical and physiological changes in the brain. Despite no clear explanation regarding the pathophysiologic process leading to the progression, certain features such as increased sensory sensitivity, cutaneous allodynia, impaired habituation, identify the neuronal hyperexcitability as the plausible mechanism. In this review, we describe two main mechanisms which can lead to this hyperexcitability. The first is persistent sensitization caused by repetitive and prolonged trigeminal nociceptive activation. This process results in changes in several brain networks related to both pain and non-pain behaviours. The second mechanism is the decrease in endogenous brainstem inhibitory control, hence increasing the excitability of neurons in the trigeminal noceptive system and cerebral cortex. The combination of increased pain matrix connectivity, including hypothalamic hyperactivity and a weak serotonergic system, may contribute to migraine chronification.

Varicella-zoster virus (VZV) can induce herpes zoster (HZ) and postherpetic neuralgia (PHN). Immune cells play an important role in regulating HZ and PHN pathogenesis, but the dynamic immune profiles and molecular mechanisms remain unclear. This study aimed to screen dynamic immune signatures during HZ progression and elucidate the mechanism of VZV-specific T cells in PHN.

Phantom limb pain is a rare cause of chronic pain in children but it is associated with extremely refractory pain and disability. The reason for limb amputation is often due to treatment for cancer or trauma and it has a lower incidence compared to adults. The mechanism of why phantom pain exists remains uncertain and may be a result of cortical reorganisation as well as ectopic peripheral input. Treatment is aimed at reducing both symptoms as well as managing pain related disability and functional restoration. Neuromodulatory approaches using deep brain stimulation for phantom limb pain is reserved for only the most refractory cases. The targets for brain stimulation include the thalamic nuclei and motor cortex. Novel targets such as the anterior cingulate cortex remain experimental as cases of serious adverse effects such as seziures have limited their widespread uptake. A multidisciplinary approach is crucial to successful rehabilitation using a biopsychosocial pain management approach.

Pain is the most common presenting physical symptom and a primary reason for seeking medical care, which chronically affects people's mental health and social life. Ca3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the Ca3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro Ca3.2 knock-down, site-directed mutagenesis, and double-mutant cycle analysis were employed to explore the pain-related receptors and ligand-receptor direct interaction. We found that toddaculin efficiently inhibits the Ca3.2 channel and significantly reduced the excitability of dorsal root ganglion neurons and pain behaviors. The Carbonyl group of coumarins directly interacts with the pore domain of Ca3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the Ca3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on Ca3.2 might be a promising docking site for the design of drugs.

To understand differences between people with arthritis who do not know their type (DK) compared to those reporting osteoarthritis (OA) or inflammatory and autoimmune types of arthritis (IAA), including the receipt of appropriate health care, information, and services.

Exercise and education is recommended as first-line treatment by evidence-based, international guidelines for low back pain (LBP). Despite consensus regarding the treatment, there is a gap between guidelines and what is offered to patients. Digital LBP treatments are an emerging way of delivering first-line treatment.

Biopsychosocial conceptualizations of clinical pain conditions recognize the multi-faceted nature of pain experience and its intersection with mental health. A primary cognitive-behavioral framework is the Fear-Avoidance Model, which posits that pain catastrophizing and fear of pain (including avoidance, cognitions, and physiological reactivity) are key antecedents to, and drivers of, pain intensity and disability, in addition to pain-related psychological distress. This study aimed to provide a comprehensive analysis of the magnitude of the cross-sectional association between the primary components of the Fear-Avoidance Model (pain catastrophizing, fear of pain, pain vigilance) with negative affect, anxiety, depression, pain intensity, and disabilities in studies of clinical pain.

Cyclin dependent kinase 5 (Cdk5) is a key neuronal kinase whose activity can modulate thermo-, mechano-, and chemo-nociception. Cdk5 can modulate nociceptor firing by phosphorylating pain transducing ion channels like the transient receptor potential vanilloid 1 (TRPV1), a thermoreceptor that is activated by noxious heat, acidity, and capsaicin. TRPV1 is phosphorylated by Cdk5 at threonine-407(T407), which then inhibits Ca2+ dependent desensitization. To explore the in vivo implications of Cdk5-mediated TRPV1 phosphorylation on pain perception, we engineered a phospho-null mouse where we replaced T407 with alanine (T407A). The T407A point mutation did not affect the expression of TRPV1 in nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia (TG). However, behavioral tests showed that the TRPV1T407A knock-in (KI) mice have reduced aversion to oral capsaicin along with a trend towards decreased facial displays of pain after a subcutaneous injection of capsaicin into the vibrissal pad. In addition, the TRPV1T407A mice display basal thermal hypoalgesia with increased paw withdrawal latency while tested on a hot plate. These results indicate that phosphorylation of TRPV1 by Cdk5 can have important consequences on pain perception, as loss of the Cdk5 phosphorylation site reduced capsaicin- and heat-evoked pain behaviors in mice.

Greater occipital nerve block (GONB) is a minimally invasive procedure frequently used in patients with chronic migraine (CM); however, the quality of the evidence supporting its use is still unknown. Therefore, we aimed to conduct a systematic review, meta-analysis and quality assessment of GONB local anaesthetics combined or not with corticosteroids to prevent CM.

To date, several variables have been associated with anti-CGRP receptor or ligand-antibody response with disparate results. Our objective is to determine whether machine learning (ML)-based models can predict 6, 9 and 12 months response to anti-CGRP receptor or ligand therapies among migraine patients.

Pain catastrophizing is a maladaptive cognitive strategy that is associated with increased emotional responses and poor pain outcomes. Total knee replacement procedures are on the rise and 20% of those who have the procedure go on to have ongoing pain. Pain catastrophizing complicates this pain and management of this is important for recovery from surgery and prevention of chronic pain. This study examines the effect of interventions on PC for patients undergoing total knee replacement (TKR).

Osteoarthritis (OA) is a major cause of pain and disability worldwide. Despite the relatively high burden of the disease, the currently available non-surgical treatment options are directed towards symptomatic relief. Therefore, we propose the use of alendronate as a disease modifying agent to help slow and prevent OA. In addition, this study will utilize Whole-Organ Magnetic Resonance Imaging Score (WORMS) to evaluate the structural integrity of cartilage in the study population. High-quality evidence, limited to a few well-conducted randomized trials, highlights contradictory results on the effect of bisphosphonates on knee function and progression of OA. Therefore, a placebo-controlled, randomized trial is needed to evaluate the combined effect of alendronate and vit D on the structure of cartilage utilizing the WORMS score and its ability to treat knee pain in OA patients.

The amygdala has emerged as a key player in the emotional response to pain and pain modulation. The lateral and capsular regions of the central nucleus of the amygdala (CeA) represent the "nociceptive amygdala" due to their high content of neurons that process pain-related information. These CeA divisions are the targets of the spino-parabrachio-amygdaloid pain pathway, which is the predominant source of calcitonin gene-related peptide (CGRP) within the amygdala. Changes in lateral and capsular CeA neurons have previously been observed in pain models, and synaptic plasticity in these areas has been linked to pain-related behavior. CGRP has been demonstrated to play an important role in peripheral and spinal mechanisms, and in pain-related amygdala plasticity in male rats in an acute arthritis pain model. However, the role of CGRP in chronic neuropathic pain-related amygdala function and behaviors remains to be determined for both male and female rats. Here we tested the hypothesis that the CGRP1 receptor is involved in neuropathic pain-related amygdala activity, and that blockade of this receptor can inhibit neuropathic pain behaviors in both sexes. CGRP mRNA expression levels in the CeA of male rats were upregulated at the acute stage of the spinal nerve ligation (SNL) model of neuropathic pain, whereas female rats had significantly higher CGRP and CGRP receptor component expression at the chronic stage. A CGRP1 receptor antagonist (CGRP 8-37) administered into the CeA in chronic neuropathic rats reduced mechanical hypersensitivity (von Frey and paw compression tests) in both sexes but showed female-predominant effects on emotional-affective responses (ultrasonic vocalizations) and anxiety-like behaviors (open field test). CGRP 8-37 inhibited the activity of CeA output neurons assessed with calcium imaging in brain slices from chronic neuropathic pain rats. Together, these findings may suggest that CGRP1 receptors in the CeA are involved in neuropathic pain-related amygdala activity and contribute to sensory aspects in both sexes but to emotional-affective pain responses predominantly in females. The sexually dimorphic function of CGRP in the amygdala would make CGRP1 receptors a potential therapeutic target for neuropathic pain relief, particularly in females in chronic pain conditions.

High-mobility group box 1 (HMGB1) is a nonhistone nuclear protein, the functions of which depend on its subcellular location. It is actively or passively secreted into the blood and/or cerebrospinal fluid (CSF) and can be used as a prognostic indicator of disease. HMGB1 released into the bloodstream can cause pathological reactions in distant organs, and entry into the CSF can destroy the blood-brain barrier and aggravate brain injuries. HMGB1 expression has been reported to be increased in the tissues of spinal cord injury (SCI) patients and involved in the regulation of neuroinflammation, neuronal apoptosis, and ferroptosis. SCI can lead to brain changes, resulting in neuropathic pain, depression, and cognitive dysfunction, but the specific mechanism is unknown. It remains unclear whether HMGB1 plays an important role in brain functional remodeling after SCI. Damaged cells at the site of SCI passively release HMGB1, which travels to the brain via the blood, CSF, and/or axonal transport, destroys the blood-brain barrier, and causes pathological changes in the brain. This may explain the remodeling of brain function that occurs after SCI. In this minireview, we introduce the structure and function of HMGB1 and its mechanism of action in SCI. Clarifying the functions of HMGB1 may provide insight into the links between SCI and various brain regions.

The analysis of the public interest as reflected by Internet queries has become a highly valuable tool in many fields. The Google Trends platform, providing timely and informative data, has become increasingly popular in health and medical studies. This study explores whether Internet search frequencies for the keyword "headache" have been increasing after the COVID-19 pandemic outbreak, which could signal an increased incidence of the health problem. Weekly search volume data for 5 years spanning February 2017 to February 2022 were sourced from Google Trends. Six statistical and machine-learning methods were implemented on training and testing sets via pre-set automated forecasting algorithms. Holt-Winters has been identified as overperforming in predicting web query trends through several accuracy measures and the DM test for forecasting superiority and has been employed for producing the baseline level in the estimation of excess query level over the first pandemic wave. Findings indicate that the COVID-19 pandemic resulted in an increased global incidence of headache (as proxied by related web queries) in the first 6 months after its outbreak, with an excess occurrence of 4.53% globally. However, the study also concludes that the increasing trend in headache incidence at the world level would have continued in the absence of the pandemic, but it has been accelerated by the pandemic event. Results further show mixed correlations at the country-level between COVID-19 infection rates and population web-search behavior, suggesting that the increased headache incidence is caused by pandemic-related factors (i.e. increased stress and mental health problems), rather than a direct effect of coronavirus infections. Other noteworthy findings entail that in the Philippines, the term "headache" was the most frequently searched term in the period spanning February 2020 to February 2022, indicating that headache occurrences are a significant aspect that defines population health at the country level. High relative interest is also detected in Kenya and South Africa after the pandemic outbreak. Additionally, research findings indicate that the relative interest has decreased in some countries (i.e. US, Canada, and Australia), whereas it has increased in others (i.e. India and Pakistan) after the pandemic outbreak. We conclude that observing Internet search habits can provide timely information for policymakers on collective health trends, as opposed to ex-post statistics, and can furthermore yield valuable information for the pain management drug market key players about aggregate consumer behavior.

COVID-19 has had a substantial impact on people's lives. Increasing evidence indicates that patients with chronic pain particularly are being affected; however, few articles have examined how the pandemic has affected the care or clinical presentation of patients with orofacial pain. The aim of this study was to describe COVID-19-related changes in referral patterns and numbers, in patient demographics, in patients' seeking treatment for problems, and in administrative procedures in 3 orofacial pain clinical settings.

Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus result in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first-order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain.

Autologous vein wrapping (VW) is used in the treatment of recurrent chronic constriction neuropathy and traumatic peripheral nerve injury. However, use of autologous veins is limited by the inability to obtain longer veins of sufficient length for larger sites. Frozen allograft tissue has several advantages, including its availability for large grafts, avoidance of donor-site morbidity, and shorter operation time. Here, we investigated the effect of frozen vein wrapping (FVW) in Wistar rats as a model of sciatic nerve injury.

Pain catastrophizing has dimensions of magnification, rumination, and helplessness, being an important evaluator of chronic pain. Studies with mindfulness intervention point to a possible modulation of chronic pain catastrophizing behavior. However, how these facets of mindfulness are associated with the catastrophizing subscales is uncertain. The scope of this study is to verify how the association of mindfulness facets and catastrophizing subdimensions occurs.

Primary and secondary hyperalgesia develop in response to chronic joint inflammation due to peripheral and central mechanisms. Synovial macrophage and spinal microglia are involved in pain sensitization in arthritis. The level of angiotensin II type 2 receptor (ATR) is related to the severity of arthritis. This study aimed to determine the role of ATR in primary and secondary hyperalgesia in joint inflammatory pain in mice. After intra-articular CFA injection, primary hyperalgesia in the ipsilateral knee joint was measured by pressure application meter and gait analysis, secondary hypersensitivity in ipsilateral hind-paw was measured by von-Frey and Hargreaves tests following a combination of global ATR-deficient (Agtr2) mice and ATR pharmacological agonist C21. Synovial macrophage and spinal microglia were collected for flow cytometry. Morphological reconstruction of microglia was detected by immunostaining. ATR expression was investigated by quantitative polymerase chain reaction and western blot. Neuronal hyperactivity was evaluated by c-Fos and CGRP immunostaining. We found that pain hypersensitivity and synovial inflammation in Agtr2 mice were significantly exacerbated compared with wild-type mice; conversely, systemically administrated C21 attenuated both of the symptoms. Additionally, spinal microglia were activated, and an abundant increase of spinal ATR was expressed on activated microglia in response to peripheral joint inflammation. Intrathecally-administrated C21 reversed the secondary hypersensitivity, accompanied by alleviation of spinal microglial activation, spinal neuronal hyperactivity, and calcitonin gene-related peptide content. These findings revealed a beneficial role of ATR activating stimulation against pain hypersensitivity in joint inflammatory pain via direct modulation of synovial macrophage and spinal microglial activity.

Temporomandibular disorders (TMD) and orofacial pain are highly prevalent. This prevalence can be compared to that of leading non-communicable diseases (NCDs). However, it is surprising to still find a high degree of controversy regarding its diagnosis and management. Patients usually experience treatment delays, missed diagnoses, and receive unnecessary therapies. New artificial intelligence algorithms have helped diagnose numerous diseases. Nevertheless, no studies have focused on the use of artificial intelligence to diagnose these conditions.

Several studies have proved that glial cells, as well as neurons, play a role in pain pathophysiology. Most of these studies have focused on the contribution of central glial cells (e.g., microglia and astrocytes) to neuropathic pain. Likewise, some works have suggested that peripheral glial cells, particularly satellite glial cells (SGCs), and the crosstalk between these cells and the sensory neurons located in the peripheral ganglia, play a role in the phenomenon that leads to pain. Nonetheless, the study of SGCs may be challenging, as the validity of studying those cells in vitro is still controversial. In this study, a research protocol was developed to examine the potential use of primary mixed neuronal-glia cell cultures obtained from the trigeminal ganglion cells (TGCs) of neonate mice (P10-P12). Primary cultures were established and analyzed at 4 h, 24 h, and 48 h. To this purpose, phase contrast microscopy, immunocytochemistry with antibodies against anti-βIII-tubulin and Sk3, scanning electron microscopy, and time-lapse photography were used. The results indicated the presence of morphological changes in the cultured SGCs obtained from the TGCs. The SGCs exhibited a close relationship with neurons. They presented a round shape in the first 4 h, and a more fusiform shape at 24 h and 48 h of culture. On the other hand, neurons changed from a round shape to a more ramified shape from 4 h to 48 h. Intriguingly, the expression of SK3, a marker of the SGCs, was high in all samples at 4 h, with some cells double-staining for SK3 and βIII-tubulin. The expression of SK3 decreased at 24 h and increased again at 48 h in vitro. These results confirm the high plasticity that the SGCs may acquire in vitro. In this scenario, the authors hypothesize that, at 4 h, a group of the analyzed cells remained undifferentiated and, therefore, were double-stained for SK3 and βIII-tubulin. After 24 h, these cells started to differentiate into SCGs, which was clearer at 48 h in the culture. Mixed neuronal-glial TGC cultures might be implemented as a platform to study the plasticity and crosstalk between primary sensory neurons and SGCs, as well as its implications in the development of chronic orofacial pain.

Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.

Orofacial inflammation leads to transcriptional alterations in trigeminal ganglion (TG) neurons. However, diverse alterations and regulatory mechanisms following orofacial inflammatory pain in different types of TG neurons remain unclear. Here, orofacial inflammation was induced by injection of complete Freund's adjuvant (CFA) in mice. After 7 days, we performed single-cell RNA-sequencing on TG cells of mice from control and treatment groups. We identified primary sensory neurons, Schwann cells, satellite glial cells, oligodendrocyte-like cells, immune cells, fibroblasts, and endothelial cells in TG tissue. After principal component analysis and hierarchical clustering, we identified six TG neuronal subpopulations: peptidergic nociceptors (PEP1 and PEP2), non-peptidergic nociceptors (NP1 and NP2), C-fiber low-threshold mechanoreceptors (cLTMR) and myelinated neurons (-positive neurons, NF) based on annotated marker gene expression. We also performed differential gene expression analysis among TG neuronal subtypes, identifying several differential genes involved in the inflammatory response, neuronal excitability, neuroprotection, and metabolic processes. Notably, we identified several potential novel targets associated with pain modulation, including , , , and in PEP1, in PEP2, and in cLTMR. The established protein-protein interaction network identified some hub genes, implying their critical involvement in regulating orofacial inflammatory pain. Our study revealed the heterogeneity of TG neurons and their diverse neuronal transcriptomic responses to orofacial inflammation, providing a basis for the development of therapeutic strategies for orofacial inflammatory pain.

Anesthesia is the reversible inhibition of function of the central and/or peripheral nervous system using drugs or other means to ensure a successful operation. This inhibition is mainly manifested as a loss of sensation, especially pain.

Irritable bowel syndrome (IBS) can be caused by abnormal bowel movements, altered brain-gut axis, gut microbiota change, and low levels of inflammation or immune activation. The intake of food containing much fiber and lactic acid bacteria (LABs) can alleviate IBS.

Analgesic medications in dentistry are indicated for the relief of acute pain, postoperative pain, chronic pain as well as controlling adjunctive intraoperative pain. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has shown an effective reduction of postendodontic pain by action on the cyclooxygenase pathway. Another medication which is used recently is corticosteroid which enables the reduction of pain. They are hormones secreted from the adrenal gland and have strong anti-inflammatory actions. This review aims to compare the analgesic efficacy of NSAIDs and corticosteroids when administered through oral route for reducing postendodontic pain. The secondary objective was to assess the anesthetic effect of the nerve block when an oral premedication of NSAIDs or corticosteroids was administered. The databases of PubMed, ScienceDirect, LILACS, and Cochrane were searched for related topics from 1983 to April 2020. Bibliographies of clinical studies were identified in the electronic search. Clinical studies with postendodontic pain reduction using NSAIDs and corticosteroids were selected. Clinical studies that met all inclusion criteria were reviewed. Data extraction was performed independently by two reviewers. All individuals who administered single dose analgesic (NSAID or corticosteroid) before initiating root canal treatment were taken into inclusion criteria. All the relevant data were extracted from the selected studies were reviewed by two independent reviewers using a standardized data collection form, and in case of disagreement, a third reviewer was enquired to achieve a consensus. Risk of bias of the selected studies was done using Cochrane Risk of Bias Tool (version 1). Mean pain score levels at various time intervals showed an increased analgesic success rate for corticosteroids ( 32-1) in comparison to NSAIDs ( 32-21.4). Anesthetic effect of the nerve block administered was seen to be better when an oral premedication of corticosteroids (38.2%-80.8%) was given in comparison to NSAID (25.5%-73.1%). From the present study, it can be concluded that oral administration of corticosteroids provides a better analgesic efficacy when compared to NSAIDs as an oral premedication for postoperative pain reduction. It can also be concluded that corticosteroids when used as an oral premedication provide a better anesthetic effect of the nerve block administered when compared to NSAIDs given as an oral premedication. These findings could help the clinician determine which pretreatment analgesic would have a better effect in reduction of pain posttreatment as well as increasing the anesthetic efficacy of administered block. Systematic Review Registration Number: CRD42021235394.