Browse by Audience
Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
Learn More >Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus-recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.
Learn More >Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain.
Neuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two F-labeled derivatives of gabapentin (trans-4-[F]fluorogabapentin and cis-4-[F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[F]fluorogabapentin having higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.
Learn More >Hind paw-directed assays are commonly used to study the analgesic effects of opioids in mice. However, opioid-induced hyperlocomotion can obscure results of such assays.
Learn More >Serious traumatic injury is a leading cause of death and disability globally, with most survivors known to develop chronic pain.
Learn More >Co-occurring pain conditions that affect overlapping body regions are complicated by the distinction between primary versus secondary pain conditions. We investigate the occurrence of headache and painful temporomandibular disorder (TMD) in a community-based, cross-sectional study of U.S. adults in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA-II) study. A specific goal was to determine if headache attributed to TMD is separable from primary headache.Using DC/TMD and ICHD-3 criteria, three groups of individuals were created: a) headache without TMD; b) headache comorbid with TMD; and c) headache attributed to TMD. Regression models compared study groups according to demographic and comorbid characteristics, and post-hoc contrasts tested for differences. Descriptive statistics and Cohen's d effect size were computed, by group, for each predictor variable. Differences in continuous predictors were analyzed using one-way ANOVA.Nearly all demographic and comorbid variables distinguished the combined headache and TMD groups from the group with headache alone. Relative to the reference group with primary headache alone, markers related to headache, TMD, somatic pain processing, psychosocial, and health conditions were substantially greater in both headache comorbid with TMD and headache attributed to TMD, attesting to their qualitative similarities. However, effect sizes relative to the reference group were large for headache comorbid with TMD and larger again for headache attributed to TMD, attesting to their separability in quantitative terms.In summary, the presence of overlapping painful TMD and headache adds substantially to the biopsychosocial burden of headache and points to the importance of comprehensive assessment and differential management.
Learn More >Chronic pain is associated with reduced work participation, but longitudinal data on the work impact of chronic pain are limited. We used data from the National Longitudinal Survey of Youth-1997 cohort to analyze how pain interference in early adulthood was associated with subsequent exit from the labor force in a longitudinal survey. Pain interference at age 29 and employment status were self-reported at subsequent biennial interviews. Exit from the labor force, return to employment, and development of new health-related work limitations after age 29 were analyzed using survival analysis methods. Among 5,819 respondents, 10% and 3% endorsed "a little" or "a lot" of pain interference at age 29, respectively. During follow-up (median of 26 months until censoring or labor force exit), 43% of respondents had exited the labor force at least once, and 10% developed a new work-related health limitation. The highest pain interference group (compared to no pain interference) had higher hazard of labor force exit (hazard ratio, HR: 1.26; 95% confidence interval, CI: 1.01, 1.57; p=0.044) and of developing new health-related work limitations (HR: 2.45; 95% CI: 1.64, 3.67; p<0.001), with similar results for the group experiencing "a little" pain interference at age 29. In this nationally representative cohort, any level of pain interference reported at age 29 was found to predict increased hazards of subsequent labor force exit and health-related work limitation. Early identification and treatment of pain problems among young workers can help reduce burdens of future unemployment and disability.
Learn More >Functional magnetic resonance imaging (fMRI) has been used to investigate nociceptive processes in patients with chronic pain. However, the results may be confounded with changes in neurovascular coupling induced by chronic pain. The objective of the present study was to examine spinal neurovascular coupling in a rat model of chronic back pain induced by muscle inflammation. Rats received 150 µl intramuscular injections of either complete Freund's adjuvant (CFA: n=18) or saline (CTL: n=18) in L5-L6 paravertebral muscles. Under 1.2 % isoflurane anesthesia, spinal cord blood flow (SCBF) and local field potentials (LFP) evoked by electrical stimulation of the sciatic nerve were recorded simultaneously in the lumbar enlargement of the spinal cord, 14 or 28 days after the injections. Mechanical hypersensitivity was observed in CFA compared with CTL rats for the back (p<0.001) and hind paws (p<0.01). SCBF response amplitude and LFP amplitude were not significantly different between groups (day 14: p>0.5; day 28: p>0.6). However, the time course of SCBF responses was different between groups on day 14 (p<0.001) and day 28 (p<0.001). Nevertheless, neurovascular coupling was comparable between groups on days 14 and 28, whether NVC was calculated with the amplitude or the area under the curve of SCBF responses (all p>0.2). These results indicate that spinal hemodynamic changes reflect neuronal activity in this animal model, although the time course of SCBF responses is affected by chronic inflammatory back pain. This warrants careful use of spinal fMRI in animal models and patients with chronic back pain.
Learn More >A number of genes have been implicated in rare familial syndromes which have migraine as part of their phenotype but these genes have not previously been implicated in the common form of migraine.
Learn More >Alterations of empathy for others' pain among patients with chronic pain remained inconsistent. Here, applying a capsaicin-based ongoing pain model on healthy participants, this study investigated how ongoing first-hand pain influences empathic reactions to vicarious pain stimuli. Healthy participants were randomly treated with topical capsaicin cream (capsaicin group) or hand cream (control group) on the left forearm. Video clips showing limbs in painful and non-painful situations were used to induce empathic responses. The capsaicin group showed greater empathic neural responses in the right primary somatosensory cortex (S1) than the control group but smaller responses in the left anterior insula (AI) accompanied with smaller empathic pain-intensity ratings. Notably, the intensity of ongoing pain negatively correlated with empathy-related neural responses in the left AI. Inter-subject phase synchronization analysis was used to assess stimulus-dependent dynamic functional connectivity within or between brain regions engaged in pain empathy. The capsaicin group showed greater empathy-related neural synchronization within S1 and between S1 and AI, but less synchronization within AI and between AI and MCC. Behaviorally, the differential inter-subject pain-intensity rating alignment between painful and non-painful videos was more positive for the capsaicin group than for the control group, and this effect was partially mediated by the inter-subject neural synchronization between S1 and AI. These results suggest that ongoing first-hand pain facilitates neural activation and synchronization within brain regions associated with empathy-related somatosensory resonance at the cost of inhibiting activation and synchronization within brain regions engaged in empathy-related affective sharing.
Learn More >To date, little is known about the prevalence of itch in multiple sclerosis (MS) and its characteristics.
Learn More >Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels widely distributed in the central peripheral nervous system and muscles which participate in rapid synaptic transmission. The α9α10 nAChR is an acetylcholine receptor subtype and is involved in chronic pain. In the present study, a new A-superfamily conotoxin Bt14.12 cloned from was found to selectively inhibit α9α10 nAChRs with an IC of 62.3 nM. Unlike α-conotoxins and other A-superfamily conotoxins, Bt14.12 contains a four Cys (C-C-C-C) framework with a unique disulfide bond connection "C1-C4, C2-C3". The structure-activity studies of Bt14.12 demonstrate that all amino acid residues contribute to its potency. Interestingly, mutation experiments show that the deletion of Asp or the addition of three Arg residues at the N-terminus of Bt14.12 significantly enhances its inhibitory activity (IC is 21.9 nM or 12.7 nM, respectively) by 2- or 4-fold compared to the wild-type Bt14.12. The NMR structure of Bt14.12 shows that it contains α-helix- and β-turn-like elements, and further computational modelings of the interaction between Bt14.12 and the α9α10 nAChR demonstrate that Bt14.12 possesses a distinctive mode of action and displays a different structure-activity relationship from known α9α10 nAChR targeting α-conotoxins. Our findings provide a novel conotoxin that potently targets α9α10 nAChRs and a new motif for designing potent inhibitors against α9α10 nAChRs.
Learn More >Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review.
Learn More >Ginsenoside Rh2 is one of the major bioactive ginsenosides in Panax ginseng. Although Rh2 is known to enhance immune cells activity for treatment of cancer, its anti-inflammatory and neuroprotective effects have yet to be determined. In this study, we investigated the effects of Rh2 on spared nerve injury (SNI)-induced neuropathic pain and elucidated the potential mechanisms. We found that various doses of Rh2 intrathecal injection dose-dependently attenuated SNI-induced mechanical allodynia and thermal hyperalgesia. Rh2 also inhibited microglia and astrocyte activation in the spinal cord of a murine SNI model. Rh2 treatment inhibited SNI-induced increase of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1 and IL-6. Expression of miRNA-21, an endogenous ligand of Toll like receptor (TLR)8 was also decreased. Rh2 treatment blocked the mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting of phosphorylated extracellular signal-regulated kinase expression. Finally, intrathecal injection of TLR8 agonist VTX-2337 reversed the analgesic effect of Rh2. These results indicated that Rh2 relieved SNI-induced neuropathic pain via inhibiting the miRNA-21-TLR8-MAPK signaling pathway, thus providing a potential application of Rh2 in pain therapy.
Learn More >Spinal analgesia is recommended for intractable cancer pain. Morphine-clonidine and sufentanil-clonidine are often used in association in intrathecal drug delivery systems, injected by intraabdominal pumps. To refill these pumps and to limit patient transport, it may be necessary to ship the mixtures in polypropylene syringes to peripheral establishments located near patient homes. The purpose of this study is to determine the stability of morphine-clonidine and sufentanil-clonidine mixtures in polypropylene syringes to ensure the best and safest transport conditions and in implantable pumps for intrathecal use.
Learn More >The opioid tolerant patient requiring surgery is highly likely to be discharged on high Oral Morphine Equivalent Daily Dosages (OMEDDs), with concomitant risk of increased morbidity and mortality.
Learn More >Circadian rhythms and sleep are fundamental biological processes integral to human health. Their disruption is associated with detrimental physiological consequences, including cognitive, metabolic, cardiovascular and immunological dysfunctions. Yet many of the molecular underpinnings of sleep regulation in health and disease have remained elusive. Given the moderate heritability of circadian and sleep traits, genetics offers an opportunity that complements insights from model organism studies to advance our fundamental molecular understanding of human circadian and sleep physiology and linked chronic disease biology. Here, we review recent discoveries of the genetics of circadian and sleep physiology and disorders with a focus on those that reveal causal contributions to complex diseases.
Learn More >Migraine is a common and complex neurovascular disorder. Clinically, the diagnosis of migraine mainly relies on scales, but the degree of pain is too subjective to be a reliable indicator. It is even more difficult to diagnose the medication-overuse headache, which can only be evaluated by whether the symptom is improved after the medication adjustment. Therefore, an objective migraine classification system to assist doctors in making a more accurate diagnosis is needed. In this research, 13 healthy subjects (HC), 9 chronic migraine subjects (CM), and 12 medication-overuse headache subjects (MOH) were measured by functional near-infrared spectroscopy (fNIRS) to observe the change of the hemoglobin in the prefrontal cortex (PFC) during the mental arithmetic task (MAT). Our model shows the sensitivity and specificity of CM are 100% and 75%, and that of MOH is 75% and 100%.The results of the classification of the three groups prove that fNIRS combines with machine learning is feasible for the migraine classification.
Learn More >Heavy menstrual bleeding and pain are common reasons women discontinue intrauterine device (IUD) use. Copper IUD (Cu IUD) users tend to experience increased menstrual bleeding, whereas levonorgestrel IUD (LNG IUD) users tend to have irregular menstruation. Medical therapies used to reduce heavy menstrual bleeding or pain associated with Cu and LNG IUD use include non-steroidal anti-inflammatory drugs (NSAIDs), anti-fibrinolytics and paracetamol. We analysed treatment and prevention interventions separately because the expected outcomes for treatment and prevention interventions differ. We did not combine different drug classes in the analysis as they have different mechanisms of action. This is an update of a review originally on NSAIDs. The review scope has been widened to include all interventions for treatment or prevention of heavy menstrual bleeding or pain associated with IUD use.
Learn More >Migraine is a common and disabling neurological disorder, with several manifestations, of which pain is just one. Despite its worldwide prevalence, there remains a paucity of targeted and effective treatments for the condition, leaving many of those affected underserved by available treatments. Work over the last 30+ years has recently led to the emergence of the first targeted acute and preventive treatments in our practice since the triptan era in the early 1990s, which are changing the landscape of migraine treatment. These include the monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. Evolving work on novel therapeutic targets, as well as continuing to exploit drugs used in other disorders that may also have a therapeutic effect in migraine, is likely to lead to more and more treatments being able to be offered to migraineurs. Future work involves the development of agents that lack vasoconstrictive effects, such as lasmiditan, do not contribute to medication overuse, such as the gepants, and do not interact with other drugs that may be used for the disorder, as well as agents that can act both acutely and preventively, thereby utilising the quantum between acute and preventive drug effects which has been demonstrated with different migraine drugs before. Here we discuss the evolution of oral migraine treatments over the last 5 years, including those that have gained regulatory approval and reached clinical practice, those in development and potential other targets for the future.
Learn More >Despite the worldwide prevalence and severe complications of type 2 diabetes mellitus (T2DM), the pathophysiological mechanisms underlying the development of diabetic polyneuropathy (DPN) are poorly understood. Beyond strict control of glucose levels, clinical trials for reversing DPN have largely failed. Therefore, understanding the pathophysiological and molecular mechanisms underlying DPN is crucial. Accordingly, this study explored biochemical and neuropathological deficits in a rat model of T2DM induced through high-fat diet (HFD) feeding along with two low-dose streptozotocin (STZ) injections; the deficits were explored through serum lipid, neurobehavioral, neurophysiology, neuropathology, and immunohistochemistry examinations. Our HFD/STZ protocol induced (1) mechanical hyperalgesia and depression-like behaviors, (2) loss of intraepidermal nerve fibers (IENFs) and reduced axonal diameters in sural nerves, and (3) decreased compound muscle action potential. In addition to hyperglycemia, which was correlated with the degree of mechanical hyperalgesia and loss of IENFs, we observed that hypertriglyceridemia was the most dominant deficit in the lipid profiles of the diabetic rats. In particular, SEPT9, the fourth component of the cytoskeleton, increased in the satellite glial cells (SGCs) of the dorsal root ganglia (DRG) in the T2DM-like rats. The number of SEPT9(+) SGCs/DRG was correlated with serum glucose levels and mechanical thresholds. Our findings indicate the putative molecular mechanism underlying DPN, which presumably involves the interaction of SGCs and DRG neurons; nevertheless, further functional research is warranted to clarify the role of SEPT9 in DPN.
Learn More >Inflammatory bowel disease (IBD) is characterized by a chronic and relapsing inflammatory response in the gastrointestinal tract, resulting in severe symptoms such as abdominal pain, vomiting, diarrhea, bloody stools, and weight loss. Currently, there is no cure, and the pharmacological treatment includes drugs that induce and keep the patient in remission, not reversing the underlying pathogenic mechanism. These therapies, in the long term, may cause various side effects and complications, which has increased the need to investigate new, more effective, and safer pharmacological approaches. In preclinical studies, topiramate has demonstrated a potential anti-inflammatory effect by inhibiting the production of several pro-inflammatory cytokines. This study aimed to investigate the effect of topiramate in a chronic TNBS-induced colitis model in rodents. Experimental colitis was induced by four intrarectal administrations of 1% TNBS in female CD-1 mice. Topiramate 10 and 20 mg were administered intraperitoneally for 14 days. Several parameters were evaluated, such as bodyweight, alkaline phosphatase (ALP), fecal hemoglobin, fecal calprotectin, tumor necrosis factor (TNF)-α, and interleukin (IL)-10. Topiramate reduces TNBS-induced colonic damage in a model of chronic experimental colitis and normalizes the stool consistency and anus appearance. Additionally, topiramate significantly reduced the concentration of ALP, fecal hemoglobin, fecal calprotectin, TNF-α, and IL-10, demonstrating it to be a promising pharmacological approach for the treatment of IBD in the future.
Learn More >Obstructive sleep apnea (OSA) is a relatively common disease in the general population. Besides its interaction with many comorbidities, it can also interact with potentially painful conditions and modulate its course. The association between OSA and pain modulation has recently been a topic of concern for many scientists. The mechanism underlying OSA-related pain connection has been linked with different pathophysiological changes in OSA and various pain mechanisms. Furthermore, it may cause both chronic and acute pain aggravation as well as potentially influencing the antinociceptive mechanism. Characteristic changes in OSA such as nocturnal hypoxemia, sleep fragmentation, and systemic inflammation are considered to have a curtailing impact on pain perception. Hypoxemia in OSA has been proven to have a significant impact on increased expression of proinflammatory cytokines influencing the hyperalgesic priming of nociceptors. Moreover, hypoxia markers by themselves are hypothesized to modulate intracellular signal transduction in neurons and have an impact on nociceptive sensitization. Pain management in patients with OSA may create problems arousing from alterations in neuropeptide systems and overexpression of opioid receptors in hypoxia conditions, leading to intensification of side effects, e.g., respiratory depression and increased opioid sensitivity for analgesic effects. In this paper, we summarize the current knowledge regarding pain and pain treatment in OSA with a focus on molecular mechanisms leading to nociceptive modulation.
Learn More >Functional brain networks and the perception of pain can fluctuate over time. However, how the time-dependent reconfiguration of functional brain networks contributes to chronic pain remains largely unexplained. Here, we explored time-varying changes in brain network integration and segregation during pain over a disease-affected area (joint) compared to a neutral site (thumbnail) in 28 patients with rheumatoid arthritis (RA) in comparison with 22 healthy controls (HC). During functional magnetic resonance imaging, all subjects received individually calibrated pain pressures corresponding to visual analog scale 50 mm at joint and thumbnail. We implemented a novel approach to track changes of task-based network connectivity over time. Within this framework, we quantified measures of integration (participation coefficient, PC) and segregation (within-module degree -score). Using these network measures at multiple spatial scales, both at the level of single nodes (brain regions) and communities (clusters of nodes), we found that PC at the community level was generally higher in RA patients compared to HC during and after painful pressure over the inflamed joint and corresponding site in HC. This shows that all brain communities integrate more in RA patients than in HC for time points following painful stimulation to a disease-relevant body site. However, the elevated community-related integration seen in patients appeared to not pertain uniquely to painful stimulation at the inflamed joint, but also at the neutral thumbnail, as integration and segregation at the community level did not differ across body sites in patients. Moreover, there was no specific nodal contribution to brain network integration or segregation. Altogether, our findings indicate widespread and persistent changes in network interaction in RA patients compared to HC in response to painful stimulation.
Learn More >This proof-of-concept study explores the potential of developing objective pain identification based on the analysis of electroencephalography (EEG) signals. Data were collected from participants living with chronic fibromyalgia pain ( = 4) and from healthy volunteers ( = 7) submitted to experimental pain by the application of capsaicin cream (1%) on the right upper trapezius. This data collection was conducted in two parts: (1) baseline measures including pain intensity and EEG signals, with the participant at rest; (2) active measures collected under the execution of a visuo-motor task, including EEG signals and the task performance index. The main measure for the objective identification of the presence of pain was the coefficient of variation of the upper envelope (CVUE) of the EEG signal from left fronto-central (FC5) and left temporal (T7) electrodes, in alpha (8-12 Hz), beta (12-30 Hz) and gamma (30-43 Hz) frequency bands. The task performance index was also calculated. CVUE (%) was compared between groups: those with chronic fibromyalgia pain, healthy volunteers with "No pain" and healthy volunteers with experimentally-induced pain. The identification of the presence of pain was determined by an increased CVUE in beta (CVUE) from the EEG signals captured at the left FC5 electrode. More specifically, CVUE increased up to 20% in the pain condition at rest. In addition, no correlation was found between CVUE and pain intensity or the task performance index. These results support the objective identification of the presence of pain based on the quantification of the coefficient of variation of the upper envelope of the EEG signal.
Learn More >Urothelial cells of the urinary bladder play a critical role in the development and progression of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic and debilitating inflammatory disease. Given the lack of data on the exact phenotype and function of urothelial cells in an inflammatory setting (as in IC/BPS), we performed the first in-depth characterization of these cells using RNA sequencing, qPCR, ELISA, Western blot, and immunofluorescence. After TNFα stimulation, urothelial cells in the model of IC/BPS showed marked upregulation of several proinflammatory mediators, such as SAA, C3, IFNGR1, IL1α, IL1β, IL8, IL23A, IL32, CXCL1, CXCL5, CXCL10, CXCL11, TNFAIPR, TNFRSF1B, and BIRC3, involved in processes and pathways of innate immunity, including granulocyte migration and chemotaxis, inflammatory response, and complement activation, as well as TLR-, NOD-like receptor- and NFkB-signaling pathways, suggesting their active role in shaping the local immune response of the bladder. Our study demonstrates that the TNFα-stimulated urothelial cells recapitulate key observations found in the bladders of patients with IC/BPS, underpinning their utility as a suitable model for understanding IC/BPS mechanisms and confirming the role of TNFα signaling as an important component of the associated pathology. The present study also identifies novel upregulated gene targets of TNFα in urothelial cells, including genes encoding the acute phase protein SAA, complement component C3, and the cytokine receptor IFNGR1, which could be exploited as therapeutic targets of IC/BPS. Altogether, our study provides a reference database of the phenotype of urothelial cells in an inflammatory environment that will not only increase our knowledge of their role in IC/BPS, but also advance our understanding of how urothelial cells shape tissue immunity in the bladder.
Learn More >Patients with injury may be at high risk of long-term opioid use due to the specific features of injury (e.g., injury severity), as well as patient, treatment, and provider characteristics that may influence their injury-related pain management.
Learn More >Patients who have perioperatively benefited from regional anesthesia frequently report moderate to severe pain when the nerve block effects fade away. Over the past years, the term "rebound pain" has been introduced, suggesting a specific pathologic process. It is debated whether significant pain on block resolution reflects a separate and distinct pathologic mechanism potentially involving proinflammatory and neurotoxic effects of local anesthetics, or is simply caused by the recovery of sensory function at a timepoint when nociceptive stimuli are still intense, and moderate to severe pain should be anticipated. In that latter case, the phenomenon referred to as rebound pain could be considered a failure of pain management providers to devise an adequate analgesia plan. Whatever the ultimate designation, management of rebound pain should be proactive, by implementing multimodal analgesia, or tailoring the blockade to the expected trajectory of postoperative pain and managing patient expectations accordingly. Until we know more about the etiology and impact of this phenomenon, the authors suggest a more neutral designation such as "pain on block resolution."
Learn More >In chronic pain syndromes, acceptance of pain may be a better approach than pain control. So far, little data have been available on how pain and its acceptance affect illness intrusiveness among patients with low-back pain (LBP).
Learn More >This study examines changes in utilization and costs trends associated with migraine medications.
Learn More >Preclinical studies have indicated insulin-like growth factor 1 (IGF1) as a novel therapeutic target in the treatment of migraines. We aimed to investigate the causal effect of circulating IGF1 levels on migraine risk using the two-sample Mendelian randomization method.
Learn More >Theory of mind (ToM), the ability to understand other minds-that is, their beliefs, intentions (cognitive ToM), or emotions (affective ToM)-and its neuropsychological mechanisms in migraine have been poorly investigated. The aim of the study was to explore the deficit of cognitive and affective ToM and its possible associations with cognitive functioning in patients with chronic migraine (CM).
Learn More >The objective of this study was to explore patient preference for attributes of calcitonin gene-related peptide (CGRP) inhibitors for the preventive treatment of migraine and to describe differences in treatment preferences between patients.
Learn More >Sickle cell disease (SCD) is characterized by severe acute pain episodes as well as risk for chronic pain. Digital delivery of SCD pain self-management support may enhance pain self-management skills and accessibility for youth. However, little is known about how youth with SCD and their caregivers engage with digital health programs. iCanCope with pain is a digital pain self-management platform adapted for youth with SCD and caregivers through a user-centered design approach. The program was delivered via a website (separate versions for youth and caregiver) and mobile app (youth only).
Learn More >The application of antineoplastic chemotherapeutic agents causes a common side effect known as chemotherapy-induced peripheral neuropathy (CIPN) that leads to reducing the quality of patient's life. This research involves the performance of molecular docking and molecular dynamic (MD) simulation studies to explore the impact of terpenoids of Ginkgo biloba on the targets (CB-1, TLR4, FAAH-1, COX-1, COX-2) that can significantly affect the controlling of CIPN's symptoms. According to the in-vitro and in-vivo investigations, terpenoids, particularly ginkgolides B, A, and bilobalide, can cause significant effects on neuropathic pain. The molecular docking results disclosed the tendency of our ligands to interact with mainly CB1 and FAAH-1, as well as partly with TLR4, throughout their interactions with targets. Terpene trilactone can exhibit a lower rate of binding energy than CB1's inhibitor (7dy), while being precisely located in the CB1's active site and capable of inducing stable interactions by forming hydrogen bonds. The analyses of MD simulation proved that ginkgolide B was a more suitable activator and inhibitor for CB1 and TLR4, respectively, when compared to bilobalide and ginkgolide A. Moreover, bilobalide is capable of inhibiting FAAH-1 more effectively than the two other ligands. According to the analyses of ADME, every three ligands followed the Lipinski's rule of five. Considering these facts, the exertion of three ligands is recommended for their anti-inflammatory, neuroprotective, and anti-nociception influences caused by primarily activating CB1 and inhibiting FAAH-1 and TLR4; in this regard, these compounds can stand as potential candidates for the control and treatment of CIPN's symptoms.
Learn More >Depression is a common comorbid condition in individuals with chronic back pain (CBP), leading to poorer treatment outcomes and increased medical complications. Digital interventions have demonstrated efficacy in the prevention and treatment of depression; however, high dropout rates are a major challenge, particularly in clinical settings.
Learn More >In women with chronic pelvic pain (CPP), interstitial cystitis/bladder pain syndrome (IC/BPS) and endometriosis frequently coexist. The mechanism of these diseases coexisting is explained by cross-sensitization between endometriosis and IC/BPS. The overlapped symptoms may be related to cross-sensitization with transient receptor potential vanilloid 1 (TRPV1) and/or transient receptor potential ankyrin 1 (TRPA1) hyperexpression. This study was aimed at exploring whether bladder hypersensitivity is evoked in the surgically induced ectopic endometriosis rat and whether TRPV1 and/or TRPA1 play a vital role.
Learn More >The objective of this peripheral nerve stimulation consensus guideline is to add to the current family of consensus practice guidelines and incorporate a systematic review process. The published literature was searched from relevant electronic databases, including PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science from database inception to March 29, 2021. Inclusion criteria encompassed studies that described peripheral nerve stimulation in patients in terms of clinical outcomes for various pain conditions, physiological mechanism of action, surgical technique, technique of placement, and adverse events. Twenty randomized controlled trials and 33 prospective observational studies were included in the systematic review process. There is Level I evidence supporting the efficacy of PNS for treatment of chronic migraine headaches via occipital nerve stimulation; chronic hemiplegic shoulder pain via stimulation of nerves innervating the trapezius, supraspinatus, and deltoid muscles; failed back surgery syndrome via subcutaneous peripheral field stimulation; and lower extremity neuropathic and lower extremity post-amputation pain. Evidence from current Level I studies combined with newer technologies facilitating less invasive and easier electrode placement make peripheral nerve stimulation an attractive alternative for managing patients with complex pain disorders. Peripheral nerve stimulation should be used judiciously as an adjunct for chronic and acute postoperative pain following adequate patient screening and positive diagnostic nerve block or stimulation trial.
Learn More >We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies.
Learn More >Migraine is the second leading cause of disability worldwide. Although many preventive treatments reduce migraine frequency and severity, it is unclear whether these treatments reduce migraine-related disability in a clinically meaningful way. This pooled analysis evaluated the ability of fremanezumab to reduce migraine-related disability, based on responses and shifts in severity in patient-reported disability outcomes.
Learn More >Alterations in white matter microstructure and functional activity have been demonstrated to be involved in the central nervous system mechanism of classic trigeminal neuralgia (CTN). However, the rich-club organization and related topological alterations in the CTN brain networks remain unclear.
Learn More >Although patient-controlled epidural analgesia (PCEA) is an effective form of regional analgesia for abdominal surgery, some patients experience significant rebound pain after the discontinuation of PCEA. However, risk factors for rebound pain associated with PCEA in major abdominal surgery remain unknown. This study evaluated the incidence of rebound pain related to PCEA and explored potential associated risk factors.
Learn More >Chronic pain affects 20% of adults and is one of the leading causes of disability worldwide. Women and girls are disproportionally affected by chronic pain. About half of chronic pain conditions are more common in women, with only 20% having a higher prevalence in men. There are also sex and gender differences in acute pain sensitivity. Pain is a subjective experience made up of sensory, cognitive, and emotional components. Consequently, there are multiple dimensions through which sex and gender can influence the pain experience. Historically, most preclinical pain research was conducted exclusively in male animals. However, recent studies that included females have revealed significant sex differences in the physiological mechanisms underlying pain, including sex specific involvement of different genes and proteins as well as distinct interactions between hormones and the immune system that influence the transmission of pain signals. Human neuroimaging has revealed sex and gender differences in the neural circuitry associated with pain, including sex specific brain alterations in chronic pain conditions. Clinical pain research suggests that gender can affect how an individual contextualizes and copes with pain. Gender may also influence the susceptibility to develop chronic pain. Sex and gender biases can impact how pain is perceived and treated clinically. Furthermore, the efficacy and side effects associated with different pain treatments can vary according to sex and gender. Therefore, preclinical and clinical research must include sex and gender analyses to understand basic mechanisms of pain and its relief, and to develop personalized pain treatment.
Learn More >Effective communication skills are essential for optimally managing chronic pain and opioids. This exploratory sequential mixed methods study tested the effect of a novel framework designed to improve pain-related communication and outcomes.
Learn More >The spinal N-methyl-D-aspartate receptor (NMDAR), particularly their subtypes NR2A and NR2B, plays pivotal roles in neuropathic and inflammatory pain. However, the roles of NR2A and NR2B in orofacial pain and the exact molecular and cellular mechanisms mediating nervous system sensitization are still poorly understood. Here, we exhaustively assessed the regulatory effect of NMDAR in mediating peripheral and central sensitization in orofacial neuropathic pain. Von-Frey filament tests showed that the inferior alveolar nerve (IANX) induced ectopic allodynia behavior in the whisker pad of mice. Interestingly, mechanical allodynia was reversed in mice lacking NR2A and NR2B. IANX also promoted the production of peripheral sensitization-related molecules, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, brain-derived neurotrophic factor (BDNF), and chemokine upregulation (C-C motif) ligand 2 (CCL2), and decreased the inward potassium channel (Kir) 4.1 on glial cells in the trigeminal ganglion, but NR2A conditional knockout (CKO) mice prevented these alterations. In contrast, NR2B CKO only blocked the changes in Kir4.1, IL-1β, and TNF-α and further promoted the production of CCL2. Central sensitization-related c-fos, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were promoted and Kir4.1 was reduced in the spinal trigeminal caudate nucleus by IANX. Differential actions of NR2A and NR2B in mediating central sensitization were also observed. Silencing of NR2B was effective in reducing c-fos, GFAP, and Iba-1 but did not affect Kir4.1. In contrast, NR2A CKO only altered Iba-1 and Kir4.1 and further increased c-fos and GFAP. Gain-of-function and loss-of-function approaches provided insight into the differential roles of NR2A and NR2B in mediating peripheral and central nociceptive sensitization induced by IANX, which may be a fundamental basis for advancing knowledge of the neural mechanisms' reaction to nerve injury.
Learn More >Surgery is a major risk factor for chronic opioid use among patients who had not recently been prescribed opioids. This study identifies the rate of, and risk factors for, persistent opioid use following laparoscopic cholecystectomy and open inguinal hernia repair in patients not recently prescribed opioids.
Learn More >Although cognitive-behavioural treatments for chronic pain are delivered in groups, there is little research investigating group effects in these treatments.
Learn More >Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation. In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. , intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with simulations that CBDV binding increased the flexibility of the internal loop of MD2. Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.
Learn More >Chronic itch is a complex psychophysiological sensation, which can severely affect the quality of life in patients with atopic dermatitis and psoriasis. Itch depends on the irritation of receptors in the skin and the processing of sensory information in the central nervous system. Severe itch leads to activation and later on to disruption of the stress response, resulting in disorders of skin repair, functional and microstructural changes in the areas of the central nervous system that are responsible for the perception of itch. Psychosocial stress can be an essential factor, activating neurohumoral mechanisms which lead to increased itch and scratch, exacerbating skin damage. Patients with chronic itch often have sleep disorders, increased irritability, and depletion of the nervous system. They are characterized by disrupting social relationships, high incidence of anxiety, depressive disorders, and suicidal tendencies. Psychological methods of intervention can effectively influence various mechanisms in the pathogenesis of itch and scratch and improve social functioning in patients with chronic dermatological itch. In this mini-review, we discuss family constellation seminars as an effective method of psychological intervention that can reduce the intensity of itch, and improve sleep and performance in patients with atopic dermatitis and psoriasis. This method is insufficiently described in previous reviews of psychological interventions in atopic dermatitis and psoriasis patients. The positive impact of family constellations seminars in patients with chronic dermatological itch may be related to reducing stress by improving understanding of the family situation, appropriate management of family secrets, and enhancing interactions with the social environment.
Learn More >Spinal cord stimulation (SCS) is an effective method of treatment for chronic pain. We previously showed that programming using accelerometry was advantageous for paresthesia-based stimulation. However, programming can be labor intensive.
Learn More >Chronic joint pain is common in patients with osteoarthritis (OA). Non-steroidal anti-inflammatory drugs and opioids are used to relieve OA pain, but they are often inadequately effective. Dorsal root ganglion field stimulation (GFS) is a clinically used neuromodulation approach, although it is not commonly employed for patients with OA pain. GFS showed analgesic effectiveness in our previous study using the monosodium iodoacetate (MIA) – induced OA rat pain model. This study was to evaluate the mechanism of GFS analgesia in this model.
Learn More >Music-imaginative Pain Treatment (MIPT) is a form of music therapy addressing pain experience and affective attitudes toward pain. It includes two self-composed music pieces: one dedicated to the pain experience (pain music, PM) and the other to healing imagination (healing music, HM). Our non-experimental study addresses patients with chronic somatoform pain disorders participating in MIPT. The goal is to gain insight into the direct effect mechanisms of MIPT by combining outcome measures on both the objective physiological and subjective perception levels. The research questions are directed toward changes in pain experience and heart rate variability and their correlations. Thirty-seven hospitalized patients with chronic or somatoform pain disorders receiving MIPT participated in this study. Demographic data and psychometric measures (Symptom Check List SCL90, Childhood Trauma Questionnaire CTQ) were collected to characterize the sample. Subjective pain experience was measured by McGill Pain Questionnaire (SF-MPQ), and Heart Rate Variability by 24 h-ECG. Data analysis shows a reduction of reported pain from M = 19.1 (SD = 7.3) to M = 10.6 (SD = 8.0) in all dimensions of the SF-MPQ. HRV analyses shows a reduced absolute power during PM and HM, while a relative shift in the autonomic system toward higher vagal activity appears during HM. Significant correlations between HRV and MPQ could not be calculated. Findings are interpreted as a physiological correlate to the psychological processes of the patients. Future studies with more participants, a control-group design, and the integration of medium- and long-term effects are recommended.
Learn More >This study aimed to evaluate the inflammatory response, hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2), and voltage-gated potassium (Kv) 9.1 channel expression in rats with paclitaxel-induced neuropathic pain-like behavior.
Learn More >Central post-stroke pain (CPSP) is an intractable neuropathic pain, which can be caused by primary lesion of central somatosensory system. It is also a common sequelae of the thalamic hemorrhagic stroke (THS). So far, the underlying mechanisms of CPSP remain largely unknown. Our previous studies have demonstrated that SDF1-CXCR4 signaling in the hemorrhagic region contributes to the maintenance of the THS pain hypersensitivity mediation of the thalamic neuroinflammation. But whether the spinal dorsal horn, an initial point of spinothalamic tract (STT), suffers from retrograde axonal degeneration from the THS region is still unknown. In this study, neuronal degeneration and loss in the spinal dorsal horn were detected 7 days after the THS caused by intra-thalamic collagenase (ITC) injection by immunohistochemistry, TUNEL staining, electron microscopy, and extracellular multi-electrode array (MEA) recordings, suggesting the occurrence of secondary apoptosis and death of the STT projecting neuronal cell bodies following primary THS retrograde axonal degeneration. This retrograde degeneration was accompanied by secondary neuroinflammation characterized by an activation of microglial and astrocytic cells and upregulation of SDF1-CXCR4 signaling in the spinal dorsal horn. As a consequence, central sensitization was detected by extracellular MEA recordings of the spinal dorsal horn neurons, characterized by hyperexcitability of both wide dynamic range and nociceptive specific neurons to suprathreshold mechanical stimuli. Finally, it was shown that suppression of spinal neuroinflammation by intrathecal administration of inhibitors of microglia (minocycline) and astrocytes (fluorocitrate) and antagonist of CXCR4 (AMD3100) could block the increase in expression levels of Iba-1, GFAP, SDF1, and CXCR4 proteins in the dorsal spinal cord and ameliorate the THS-induced bilateral mechanical pain hypersensitivity, implicating that, besides the primary damage at the thalamus, spinal secondary damage and neuroinflammation also play the important roles in maintaining the central post-THS pain hypersensitivity. In conclusion, secondary neuronal death and neuroinflammation in the spinal dorsal horn can be induced by primary thalamic neural damage retrograde axonal degeneration process. SDF1-CXCR4 signaling is involved in the mediation of secondary spinal neuroinflammation and THS pain hypersensitivity. This finding would provide a new therapeutic target for treatment of CPSP at the spinal level.
Learn More >Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days ), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity.
Learn More >Neuropathic pain (NP) in head and neck cancer (HNC) patients represents a treatment challenge. Most studies investigating drugs against NP are conducted in patients suffering with diabetic neuropathy or postherpetic neuralgia, while data are limited in cancer pain management. Additionally, regarding cancer therapy-related NP, most of the studies do not focus on HNC patients. The aim of this review is to identify the studies on systematically administered medication for NP management that included HNC patients under radiotherapy.
Learn More >Rheumatoid arthritis (RA) is a common chronic inflammatory disease affecting primarily peripheral joints, which is only partially controlled with current treatments. RA leads to pain, disability, deformities, and life expectancy shortening. Its pathogenesis is complex involving multiple cell types and signaling pathways that we incompletely understand. One of the pathways we have elucidated starts with WNT5A signaling and contributes to the aggressive phenotype of the RA synoviocytes through RYK-RhoA/ROCK signaling. Now, we have explored the contribution of ROCK to arthritis , using the K/BxN serum-transfer arthritis model; and to osteoclastogenesis, using the arthritis model and cells from patients with inflammatory arthritis. The mice and cells were treated with the ROCK inhibitor Y-27632 that caused a significant improvement of arthritis and reduction of osteoclastogenesis. The improvement in mouse arthritis was observed in the clinical evaluation and, histologically, in synovial inflammation, cartilage damage, bone erosion, and the abundance of multinucleated TRAP+ cells. Expression of inflammatory mediators in the arthritic joints, as assessed by real-time PCR, was also significantly reduced. The effect on bone was confirmed with assays using bone marrow precursors of arthritic mice and peripheral blood monocytes of patients with inflammatory arthritis. These assays showed dramatically reduced osteoclastogenesis and bone resorption. Overall, our findings suggest that ROCK inhibition could be part of a therapeutic strategy for RA by its dual action on inflammation and bone erosion.
Learn More >Fibromyalgia (FM) is considered a stress-related disorder characterized mainly by chronic widespread pain. Its pathogenesis is unknown, but cumulative evidence points at dysfunctional transmitter systems and inflammatory biomarkers that may underlie the major symptoms of the condition. This study aimed to evaluate pain scores (primary outcome), quality of life, inflammatory biomarkers and neurotransmitter systems in women with FM (secondary outcomes) subjected to gentle touch therapy (GTT) or placebo.
Learn More >In the context of giving risk information for obtaining informed consent, it is not easy to comply with the ethical principle of "primum nihil nocere." Carelessness, ignorance of nocebo effects and a misunderstood striving for legal certainty can lead doctors to comprehensive and brutal risk information. It is known that talking about risks and side effects can even trigger those and result in distress and nonadherence to medication or therapy.
Learn More >Neuropathic pain is a chronic intractable disease characterized by allodynia and hyperalgesia. Effective treatments are unavailable because of the complicated mechanisms of neuropathic pain. Transient receptor potential canonical 6 (TRPC6) is a nonselective calcium (Ca)-channel protein related to hyperalgesia. Dexmedetomidine (Dex) is an alpha-2 (α2) adrenoreceptor agonist that mediates intracellular Ca levels to alleviate pain. However, the relationship between TRPC6 and Dex is currently unclear. We speculated that the α2 receptor agonist would be closely linked to the TRPC6 channel. We aimed to investigate whether Dex relieves neuropathic pain by the TRPC6 pathway in the dorsal root ganglia (DRG).
Learn More >Trigeminal neuralgia, considered by many the worst pain that humankind can experience, has been called "the suicide disease." Neuroablative procedures are good options when conservative treatment fails to promote pain relief or in those whose side effects are unbearable. The objective was to compare the effectiveness and safety of trigeminal percutaneous radiofrequency ablation in classical refractory trigeminal neuralgia in a prospective, randomized, double-blind, sham-controlled clinical trial. We included 30 consecutive patients with classical trigeminal neuralgia who had failed to respond to drug treatment. The patients were randomly assigned into 2 groups, a thermal radiofrequency and a sham group. The thermal radiofrequency group were submitted to a 75 °C lesion for 60 seconds after proper sensory and motor stimulation. All steps were carried out in the sham group except the thermal lesion. Patients were evaluated using the Numerical Rating Scale, the 36-Item Short-Form Health Survey questionnaire, and anticonvulsant dose. After one month, the mean NRS score decreased from 9.2 to 0.7 in the radiofrequency group and from 8.9 to 5.8 in the sham group. This significant reduction was measurable starting at day one after the procedure and remained significant throughout the first month. Changing groups was allowed after one month, after which the pain reduction was similar between the two groups. Percutaneous trigeminal radiofrequency ablation results in statistically and clinically significant greater pain relief than the sham procedure after one month of follow-up. These results support using radiofrequency nerve ablation as a treatment for refractory trigeminal neuralgia.
Learn More >(1) Background: Vestibular migraine (VM) and Meniere's disease (MD) share multiple features in terms of clinical presentations and auditory-vestibular dysfunctions, e.g., vertigo, hearing loss, and headache. Therefore, differentiation between VM and MD is of great significance. (2) Methods: We retrospectively analyzed the medical records of 110 patients with VM and 110 patients with MD. We at first established a regression equation by using logistic regression analysis. Furthermore, sensitivity, specificity, accuracy, positive predicted value (PV), and negative PV of screened parameters were assessed and intuitively displayed by receiver operating characteristic curve (ROC curve). Then, two visualization tools, i.e., nomograph and applet, were established for convenience of clinicians. Furthermore, other patients with VM or MD were recruited to validate the power of the equation by ROC curve and the Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (GiViTI) calibration belt. (3) Results: The clinical manifestations and auditory-vestibular functions could help differentiate VM from MD, including attack frequency (X5), phonophobia (X13), electrocochleogram (ECochG) (X18), head-shaking test (HST) (X23), ocular vestibular evoked myogenic potential (o-VEMP) (X27), and horizontal gain of vestibular autorotation test (VAT) (X30). On the basis of statistically significant parameters screened by Chi-square test and multivariable double logistic regression analysis, we established a regression equation: P = 1/[1 + e] (P, predictive value; e, natural logarithm). Nomographs and applets were used to visualize our result. After validation, the prediction model showed good discriminative power and calibrating power. (4) Conclusions: Our study suggested that a diagnostic algorithm based on available clinical features and an auditory-vestibular function regression equation is clinically effective and feasible as a differentiating tool and could improve the differential diagnosis between VM and MD.
Learn More >Low back pain (LBP) is a global and disabling problem. A considerable number of systematic reviews published over the past decade have reported a range of factors that increase the risk of chronicity due to LBP. This study summarizes up-to-date and high-level research evidence on the biopsychosocial prognostic factors of outcomes in adults with non-specific low back pain at follow-up. An umbrella review was carried out. PubMed, the Cochrane Database of Systematic Reviews, Web of Science, PsycINFO, CINAHL Plus and PEDro were searched for studies published between 1 January 2008 and 20 March 2020. Two reviewers independently screened abstracts and full texts, extracted data and assessed review quality. Fifteen systematic reviews met the eligibility criteria; all were deemed reliable according to our criteria. There were five prognostic factors with consistent evidence of association with poor acute-subacute LBP outcomes in the long term (high levels of pain intensity and disability, high emotional distress, negative recovery expectations and high physical demands at work), as well as one factor with consistent evidence of no association (low education levels). For mixed-duration LBP, there was one predictor consistently associated with poor outcomes in the long term (high pain catastrophism). We observed insufficient evidence to synthesize social factors as well as to fully assess predictors in the chronic phase of LBP. This study provides consistent evidence of the predictive value of biological and psychological factors for LBP outcomes in the long term. The identified prognostic factors should be considered for inclusion into low back pain explanatory models.
Learn More >Although opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs used in persistent pain treatment; they have shown many side effects. The development of new analgesics endowed with mu opioid receptor/delta opioid receptor (MOR/DOR) activity represents a promising alternative to MOR-selective compounds. Moreover, new mechanisms, such as sigma-1 receptor (σR) antagonism, could be an opioid adjuvant strategy. The in vitro σR and σR profiles of previous synthesized MOR/DOR agonists (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () were assayed. To investigate the pivotal role of -normetazocine stereochemistry, we also synthesized the (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () compounds. (-)-2/-LP2 (), (-)-2-LP2 (), and (-)-2-LP2 () compounds have Ki values for σ1R ranging between 112.72 and 182.81 nM, showing a multitarget opioid/σ1R profile. Instead, (+)-2/-LP2 (), (+)-2-LP2 (), and (+)-2-LP2 () isomers displayed a nanomolar affinity for σ1R, with significative selectivity vs. σ2R and opioid receptors. All isomers were evaluated using an in vivo formalin test. (-)-2-LP2, at 0.7 mg/kg i.p., showed a significative and naloxone-reversed analgesic effect. The σ1R selective compound (+)-2/-LP2 (), at 5.0 mg/kg i.p., decreased the second phase of the formalin test, showing an antagonist σ1R profile. The multitarget or single target profile of assayed -normetazocine derivatives could represent a promising pharmacological strategy to enhance opioid potency and/or increase the safety margin.
Learn More >Neuropathic pain (NP) arises as a direct consequence of traumatic spinal cord injury (SCI), which leads to devastating consequences for people suffering from this condition since no specific treatment has been defined. One relevant mechanism in generating painful stimuli involves the direct participation of reactive oxygen species (ROS) at the cellular and subcellular levels. Cannabidiol (CBD) is one of the two most crucial cannabinoid components of the cannabis plant and has been proposed as a potential treatment for NP. Its antioxidant, neuroprotective and anti-inflammatory properties have been documented. However, there is insufficient evidence regarding CBD as treatment of NP induced by SCI or the mechanisms that underlie this effect. In this study, we evaluated the antinociceptive effect of CBD as an acute treatment after the nociceptive behaviors characteristic of NP were established (hypersensitivity threshold and hypersensitivity response). Furthermore, the participation of oxidative stress was determined by lipid peroxidation (LP) and glutathione concentration (GSH) in female Wistar rats with SCI. Acute treatment with CBD (2.5-20 mg/kg, i.p.) decreased nociceptive behaviors in a dose-dependent manner, decreased LP, and increased GSH concentration in injured tissue 15 days after injury. The findings of this study suggest that the antinociceptive effect induced by CBD is regulated by reducing oxidative stress by decreasing the LP and increasing the concentration of antioxidant (GSH) defenses.
Learn More >Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6 to 9 days after surgery). Treatment with morphine (2 and 4mg/kg) or CBD (30mg/kg) induced a significant antinociceptive effect on evoked pain. The combination of CBD (30mg/kg) and morphine (1mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1mg/Kg). Treatment with morphine (1 and 2mg/kg) or CBD (30mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30mg/kg) and morphine (1mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance. In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.
Learn More >Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and the presence of restricted, repetitive behaviors. Additionally, difficulties in sensory processing commonly occur in ASD. Sensory abnormalities include heightened or reduced sensitivity to pain, but the mechanism underlying sensory phenotypes in ASD remain unknown. Emerging evidence suggests that microglia play an important role in forming and refining neuronal circuitry, and thus contribute to neuronal plasticity and nociceptive signaling. In the present study, we investigated the age-dependent tactile sensitivity in an animal model of ASD induced by prenatal exposure to valproic acid (VPA) and subsequently assessed the involvement of microglia in the spinal cord in pain processing. Pregnant ICR (CD1) mice were intraperitoneally injected with either saline or VPA (500 mg/kg) on embryonic day 12.5. Male offspring of VPA-treated mothers showed mechanical allodynia at both 4 and 8 weeks of age. In the spinal cord dorsal horn in prenatally VPA-treated mice, the numbers and staining intensities of ionized calcium-binding adapter molecule 1-positive cells were increased and the cell bodies became enlarged, indicating microglial activation. Treatment with PLX3397, a colony-stimulating factor 1 receptor inhibitor, for 10 days resulted in a decreased number of spinal microglia and attenuated mechanical allodynia in adult mice prenatally exposed to VPA. Additionally, intrathecal injection of Mac-1-saporin, a saporin-conjugated anti-CD11b antibody to deplete microglia, abolished mechanical allodynia. These findings suggest that prenatal VPA treatment causes allodynia and that spinal microglia contribute to the increased nociceptive responses.
Learn More >Endometriosis is an estrogen dependent, chronic inflammatory disease characterized by the growth of endometrial lining outside of the uterus. Mast cells have emerged as key players in regulating not only allergic responses but also other mechanisms such as angiogenesis, fibrosis, and pain. The influence of estrogen on mast cell function has also been recognized as a potential factor driving disease pathophysiology in number of allergic and chronic inflammatory conditions. However, precise information is lacking on the cross talk between endocrine and immune factors within the endometriotic lesions and whether that contributes to the involvement of mast cells with disease pathophysiology. In this study, we observed a significant increase in mast cell numbers within endometriotic lesions compared to matched eutopic endometrium from the same patients. Compared to eutopic endometrium, endometriotic lesions had significantly higher levels of stem cell factor (SCF), a potent growth factor critical for mast cell expansion, differentiation, and survival for tissue resident mast cells. Targeted mRNA Q-PCR array revealed that the endometriotic lesions harbour microenvironment (upregulation of CPA3, VCAM1, CCL2, CMA1, CCR1, and KITLG) that is conducive to mast cells recruitment and subsequent differentiation. To examine cross-talk of mast cells within the endometriotic lesion microenvironment, endometriotic epithelial cells (12Z) and endometrial stromal cells (hESC) incubated with mast cell-conditioned media showed significantly increased production of pro-inflammatory and chemokinetic cytokines. To further understand the impact of estrogen on mast cells in endometriosis, we induced endometriosis in C57BL/6 mice. Mature mast cells were significantly higher in peritoneal fluid of estrogen-treated mice compared to untreated mice within the sham operated groups. Mouse endometriotic lesion tissue revealed several genes (qRT-PCR) relevant in mast cell biology significantly upregulated in the estrogen treated, endometriosis-induced group compared to control endometrium. The endometriotic lesions from estrogen treated mice also had significantly higher density of Alcian blue stained mast cells compared to untreated lesions or control endometrium. Collectively, these findings suggest that endometriotic lesions provide a microenvironment necessary for recruitment and differentiation of mast cells. In turn, mast cells potentially release pro-inflammatory mediators that contribute to chronic pelvic pain and endometriosis disease progression.
Learn More >The descending pain modulatory pathway exerts important bidirectional control of nociceptive inputs to dampen and/or facilitate the perception of pain. The ventrolateral periaqueductal gray (vlPAG) integrates inputs from many regions associated with the processing of nociceptive, cognitive, and affective components of pain perception, and is a key brain area for opioid action. Opioid receptors are expressed on a subset of vlPAG neurons, as well as on both GABAergic and glutamatergic presynaptic terminals that impinge on vlPAG neurons. Microinjection of opioids into the vlPAG produces analgesia and microinjection of the opioid receptor antagonist naloxone blocks stimulation-mediated analgesia, highlighting the role of endogenous opioid release within this region in the modulation of nociception. Endogenous opioid effects within the vlPAG are complex and likely dependent on specific neuronal circuits activated by acute and chronic pain stimuli. This review is focused on the cellular heterogeneity within vlPAG circuits and highlights gaps in our understanding of endogenous opioid regulation of the descending pain modulatory circuits.
Learn More >Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post-hoc analysis of two phase III studies in patients with PsA treated with tofacitinib assessed dactylitis by location, and the impact on patient-reported outcomes (PROs).
Learn More >Local neuroinflammation secondary to spinal nerve compression in lumbar disk herniation (LDH) is a key driver contributing to neuropathic pain. Manual therapy (MT), a widely used nonsurgical therapy, can relieve LDH-mediated pain by reducing inflammation. MT has attracted extensive attention; however, its mechanism remains poorly understood. MicroRNAs (miRNAs) are important regulators of pain signaling transduction, but are rarely reported in the chronic compression of dorsal root ganglia (CCD) model, and further investigation is needed to decipher whether they mediate anti-inflammatory and analgesic effects of MT.
Learn More >To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women.
Learn More >This narrative review is an updated summary of the value of regional anesthesia and analgesia for trauma and the special considerations when optimizing pain management and utilizing regional analgesia for acute traumatic pain.
Learn More >The objective of the study was to find out the effectiveness of Kinesio taping (KT) and conventional physical therapy (CPT) such as transcutaneous electrical nerve stimulation and supervised exercise therapy and CPT alone in chronic low back pain (CLBP) patients.
Learn More >The McGill Quality of Life Questionnaire-Revised (MQoL-R) is the gold standard for assessing QoL in end-of-life, chronic patients; however, an Italian standardization is lacking.
Learn More >Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch via TRP channels signaling are poorly understood. Herein, we show that genetic deletion or pharmacological antagonism of TRP vanilloid 4 (TRPV4) attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several miRNAs, including the miR-203b-3p, which induced a Ca response in rodent dorsal root ganglion neurons and scratching behavior in mice via serotonin receptor 2B (5-HTR2B) activation and the protein kinase C-dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch, targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular miRNA that can behave as an itch promoter via 5-HTR2B and TRPV4.
Learn More >Diabetic neuropathy is considered as the most common and alarming microvascular complication of diabetes worldwide. Despite the recent major advances, there remains a dearth in literature on effective treatment options that appropriately target the natural history of painful diabetic neuropathy.
Learn More >Pain is a common symptom in patients with advanced, metastatic, or terminal cancer. Neuropathic pain and psycho-emotional suffering are factors that increase the difficulty of pain management. Pain control in patients with cancer remains a challenge for medical professionals.
Learn More >The purpose of this study was to identify the prevalence of severe headache or migraine and the association between dietary thiamine and riboflavin intake with headache history using a large, nationally representative population sample.
Learn More >We investigated whether lidocaine can increase the pain threshold of rats with trigeminal neuralgia by affecting the expression of P2X7, p-p38 and IL-Iβ proteins in the thalamus. Thirty-three male Sprague-Dawley (SD) rats were randomly divided into three groups ( = 11): Sham group, Ion-CCI (infraorbital nerve chronic constriction injury) group and Ion-CCI+L group(Ion-CCI+lidocaine 10 mg/kg/day, i.p.). The mechanical pain threshold of rats was measured preoperatively and at 1, 3, 5, 7, 9, 11 and 14days after operation with the von Frey filament sensor tester. Fourteen days after operation, the rats were dissected to collect their whole brain, thalamus and trigeminal ganglion to detect IL-1β, P2X7, p38, and p-p38 protein expression. The pain threshold of rats in Ion-CCI+L group was lower than that in Sham group ( < 0.01) and higher than that in Ion-CCI group ( < 0.01).ELISA showed that IL-1β in the thalamus and trigeminal ganglion in Ion-CCI+L group were lower than those in ion-CCI group ( < 0.05) but higher than those in Sham group ( < 0.05). Western blot showed that the expression levels of P2X7 and p-p38 in the thalamus of rats in Ion-CCI+L group were lower than those in Ion-CCI group ( < 0.01) and higher than thaose in Sham group ( < 0.01),while the expression levels of IL-1β in the thalamus in Ion-CCI+L group were lower than those in Ion-CCI group ( < 0.05) and higher than those in Sham group ( < 0.01). Immunofluorescence showed that p-p38 in the thalamus in Ion-CCI+L group was lower than that in Ion-CCI group ( < 0.05) and higher than that in Sham group ( < 0.05). Lidocaine can reduce the inflammatory response of the central nervous system and increase the pain threshold of trigeminal neuralgia rats by inhibiting p2x7-p38-IL-1β signaling pathway.This pathway play an important role in the pathogenesis of trigeminal neuralgia, and it may be one of the targets for the treatment of trigeminal neuralgia.
Learn More >Veterans Health Administration implemented the Opioid Safety Initiative (OSI) in 2013 to promote safe/rational opioid prescribing. West Palm Beach VA Healthcare System (WPBVAHCS) has been an outlier for the percentage of Veterans with chronic non-cancer pain receiving ≥90 mg Morphine Equivalent Daily Dosing (MEDD) in Veterans Integrated Service Networks (VISN) 8 since the 2016 fiscal year. The purpose was to determine the utility of a Pain Clinical Pharmacist Practitioner (CPP) identifying, reviewing, and approaching Veterans utilizing high-dose opioids for dose reevaluation and the impact on OSI metric post-opioid reevaluation. Pain CPP opioid education resulted in 28% (11/39) of Veterans undergoing an average 17.7 mg MEDD opioid dose reduction. For Veterans evaluated by Pain CPP, 83% (15/18) reported no change or improvement in average pain and PEG score. Pain CPP's implemented 48 interventions outside of opioid dose reduction, the most common related to naloxone. No documented opioid overdose events, hospitalizations for uncontrolled pain or mental health, suicide attempts or pain-related crisis interventions were reported. Pain CPP's are equipped to provide opioid education, address risk mitigation strategies, reassess pain regimens, and refer for non-pharmacologic modalities. Utilization of Pain CPP resources helps improve OSI metrics while providing safe comprehensive medication management (CMM) for chronic pain.
Learn More >Connective tissue injuries are prevalent in active and aging populations, leading to chronic pain and decreased function. Turnover of this tissue is not well understood, especially as it relates to aging and injury. Supplementation of collagen peptides has been shown to improve connective tissue recovery and pain through increased collagen production.
Learn More >Chemotherapy-induced peripheral neuropathy is a debilitating pain syndrome produced as a side effect of antineoplastic drugs like paclitaxel. Despite efforts, the currently available therapeutics suffer from serious drawbacks like unwanted side effects, poor efficacy and provide only symptomatic relief. Hence, there is a need to find new therapeutic alternatives for the treatment of Chemotherapy-induced peripheral neuropathy.
Learn More >Chronic pain in adolescence is associated with diminished outcomes, lower socioeconomic status in later life, and decreased family well-being. Approximately one third of adolescents with chronic pain have obesity compared to the general population. In obesity, lipid signals regulate insulin sensitivity, satiety, and pain sensation. We determined whether there is a distinct lipid signature associated with chronic pain and its co-occurrence with obesity in adolescents.
Learn More >Non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are analgesics used for moderate to severe pain in many animals, including reptiles. However, reptilian dosing regimens are often extrapolated from other animal species. This is not ideal as inter- and intra-species variability in physiology may result in varied drug disposition. Therefore, this critical review aims to collate data from pharmacological studies of selected NSAIDs and opioids performed in reptile and provide an analysis and discussion on the existing pharmacodynamic knowledge and pharmacokinetic data of NSAIDs and opioids use in reptiles. Additionally, key pharmacokinetic trends that may aid dosing of NSAIDs and opioids in reptiles will also be highlighted. Most of the existing reports of NSAID used in reptiles did not observe any adverse effects directly associated to the respective NSAID used, with meloxicam being the most well-studied. Despite the current absence of analgesic efficacy studies for NSAIDs in reptiles, most reports observed behavioural improvements in reptiles after NSAID treatment. Fentanyl and morphine were studied in the greatest number of reptile species with analgesic effects observed with the doses used, while adverse effects such as sedation were observed most with butorphanol use. While pharmacokinetic trends were drug- and species-specific, it was observed that clearance (CL) of drugs tended to be higher in squamates compared to chelonians. The half-life (t) of meloxicam also appeared to be longer when dosed orally compared to other routes of drug administration. This could have been due to absorption-rate limited disposition. Although current data provided beneficial information, there is an urgent need for future research on NSAID and opioid pharmacology to ensure the safe and effective use of opioids in reptiles.
Learn More >While inflammation may not be the cause of disease, it is well known that it contributes to disease pathogenesis across a multitude of peripheral and central nervous system disorders. Chronic and overactive inflammation due to an effector T cell-mediated aberrant immune response ultimately leads to tissue damage and neuronal cell death. To counteract peripheral and neuroinflammatory responses, research is being focused on regulatory T cell enhancement as a therapeutic target. Regulatory T cells are an immunosuppressive subpopulation of CD4+ T helper cells essential for maintaining immune homeostasis. The cells play pivotal roles in suppressing immune responses to maintain immune tolerance. In so doing, they control T cell proliferation and pro-inflammatory cytokine production curtailing autoimmunity and inflammation. For nervous system pathologies, Treg are known to affect the onset and tempo of neural injuries. To this end, we review recent findings supporting Treg's role in disease, as well as serving as therapeutic agents in multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome, Parkinson's and Alzheimer's diseases, and amyotrophic lateral sclerosis. An ever-broader role for Treg in control of neurologic disease has been shown for traumatic brain injury, stroke, neurotrophic pain, epilepsy, and psychiatric disorders. To such ends, this review serves to examine the role played by Tregs in nervous system diseases with a focus on harnessing their functional therapeutic role(s).
Learn More >Ectoine is a widespread osmolyte enabling halophilic bacteria to withstand high osmotic stress that has many potential applications ranging from cosmetics to its use as a therapeutic agent.
Learn More >To investigate the association between sleep disturbance and clinical features of chronic whiplash-associated disorders. We also aimed to use a bootstrapped mediation analysis approach to systematically examine both direct and indirect pathways by which sleep disturbance may affect chronic pain and functional status.
Learn More >Implantable devices for localized and controlled drug release are important, e.g., for therapies of cancer and chronic pain. However, most of the existing active implants are limited by the usage of nonbiodegradable materials; thus, surgery is needed to extract them after the treatment, which leads to secondary damage. Here, we show a fully biodegradable composite membrane made from silk fibroin and magnetic nanoparticles (MNPs). The membrane porosity can be remotely modified by an alternating magnetic field, which opens nanopores by local heating of MNPs in the composite allowing a liquid to diffuse through them. The stability of the silk membrane in water can be prolonged up to several months by increasing its β-sheet content through ethanol annealing. We present the following original findings. (a) Nanopores can be generated inside the silk/MNP composite membrane by exposing it to an external alternating magnetic field. (b) A longer exposure time results in more nanopore sites. (c) The controllable release of rhodamine B dye is achieved by tuning the period of exposure to the magnetic field. The obtained results demonstrate the suitability of the investigated silk/MNP composite membrane as a potential functional material for implantable drug delivery.
Learn More >The aim of the present study was (1) to validate the method of guilt-induction by means of a written auto-biographical essay and (2) to test whether experimental pain is apt to alleviate the mental burden of guilt, a concept receiving support from both empirical research and clinical observation.
Learn More >Central control of the bladder is a complex process. With the development of functional imaging technology and analysis methods, research on brain-bladder control has become more in-depth. Here, we review previous functional imaging studies and combine our latest findings to discuss brain regions related to bladder control, interactions between these regions, and brain networks, as well as changes in brain function in diseases such as urgency urinary incontinence, idiopathic overactive bladder, interstitial cystitis/bladder pain syndrome, urologic chronic pain syndrome, neurogenic overactive bladder, and nocturnal enuresis. Implicated brain regions include the pons, periaqueductal grey, thalamus, insula, prefrontal cortex, cingulate cortex, supplementary motor area, cerebellum, hypothalamus, basal ganglia, amygdala, and hippocampus. Because the brain is a complex information transmission and processing system, these regions do not work in isolation but through functional connections to form a number of subnetworks to achieve bladder control. In summarizing previous studies, we found changes in the brain functional connectivity networks related to bladder control in healthy subjects and patients involving the attentional network, central executive network or frontoparietal network, salience network, interoceptive network, default mode network, sensorimotor network, visual network, basal ganglia network, subcortical network, cerebella, and brainstem. We extend the working model proposed by Griffiths et al. from the brain network level, providing insights for current and future bladder-control research.
Learn More >Medical child abuse (MCA), previously referred to as Munchausen by proxy, can present as chronic pain. We report the presentation of five children seeking treatment for chronic pain who we identified as victims of MCA. The index case had essentially not eaten for the 6 years of her life due to alleged allergies to all foods, developed severe pain, used a wheelchair for ambulation beyond a few blocks, and was alleged to have dysautonomia requiring oxygen monitoring at night. Other cases posed as arthritis that resulted in foot amputation and total body pain, fibromyalgia with alleged mutation negative Stickler syndrome who had symptoms only in her mother's presence, severe incapacitating intermittent pains along with abdominal pain that resulted in appendectomy, cholecystectomy, and pancreatectomy, and alleged disabling hypermobile Ehlers-Danlos in a non-hypermobile child for which the mother sought a power wheelchair. The unusual pattern to the pain, the presence of multiple additional, atypical symptoms and diagnoses, and a generally well appearing child are characteristic. The perpetrator is typically over-invested in the symptoms, derives tangible and intangible secondary gain from the child's alleged illnesses, and is able to present the child in such a fashion to enlist the physician to aid in perpetuating the abuse. These children are highly over-medicalized and suffer significant morbidity. Multiple barriers exist to identifying and reporting these children to Child Protective Services, which need to be recognized and overcome in order to protect these vulnerable children.
Learn More >Osteoarthritis is one of the foremost disabling disorders in the world. There is no definitive treatment to prevent the progression of osteoarthritis. Hence, palliative treatment aims at minimizing pain, disability and improving function, performance and quality of life. Oral administration of nonsteroidal anti-inflammatory drug is associated with number of adverse effects and reduced therapeutic efficacy. Intra-articular injection has been the preferred route of drug administration. However, the clearance of drug from the arthritic site, risk of infections, cost and the pain associated with frequent injections make this route highly non-compliant to patients. Since osteoarthritis is a chronic condition which requires treatment for prolonged duration, there is an urgent need for another administration route which circumvents the hindrances linked with intra-articular route. Transdermal route across the skin locally at the osteoarthritis site could help in surpassing the disadvantages associated with intra-articular route. However, traversing skin barrier and reaching the chondrocytes with sufficient amount of the drug is extremely difficult. Nanocarrier-based approaches could hold an answer to the said shortcomings owing to their reduced size, targeting tunability and site specificity. In this article, we discuss the pathophysiology of osteoarthritis, molecular targets, and utilization of nanocarrier-based approaches to strategize the treatment of osteoarthritis in a new direction, i.e. topical delivery of nanocarriers in osteoarthritis.
Learn More >Triterpenes such as euphol and pristimerin, which are plant secondary metabolites, were the first to be characterized as monoacylglycerol lipase (MAGL) inhibitors. MAGL inhibitors alleviate chemotherapy-induced neuropathic pain (CINP) in rodent models. Pristimerin has been shown to have additive anticancer activity with paclitaxel, a chemotherapeutic drug. However, the activity of pristimerin on CINP has not been evaluated. The aims of this study were to evaluate whether various triterpenes had activity against recombinant human MAGL and MAGL activity in mouse tissues, and whether pristimerin could prevent development of paclitaxel-induced mechanical allodynia. The effects of four triterpenes betulinic acid, cucurbitacin B, euphol, and pristimerin on the activity human recombinant MAGL and MAGL activity of mice brain and paw skin tissues were evaluated using MAGL inhibitor screening and MAGL activity assay kits. The effects of treatment of female BALB/c mice with pristimerin intraperitoneally on the development of paclitaxel-induced mechanical allodynia were assessed using the dynamic plantar aesthesiometer and on nuclear factor-2 erythroid related factor-2 () gene expression in the paw skin were evaluated by real time polymerase chain reaction. Pristimerin inhibited the human recombinant MAGL activity in a concentration-dependent manner like JZL-195, a MAGL inhibitor. Betulinic acid, cucurbitacin B and euphol inhibited human recombinant MAGL activity but their effects were not concentration dependent and were less to that of pristimerin. Pristimerin inhibited both mouse brain and paw skin MAGL activity in a concentration-dependent manner. Paclitaxel induced mechanical allodynia and increase in MAGL activity in the paw skin. Treatment with pristimerin prevented the development of paclitaxel-induced mechanical allodynia and the paclitaxel-induced increase in MAGL activity. Pristimerin significantly upregulated mRNA expression of a regulator of endogenous antioxidant defense. These results indicate that triterpenes inhibit human recombinant MAGL activity with varying degrees. Pristimerin inhibits both mouse brain and paw skin MAGL activity in a concentration-dependent manner, prevents both the development of paclitaxel-induced mechanical allodynia and the associated increase in MAGL activity in the paw skin, and might protect against paclitaxel-induced oxidative stress. Co-treatment with pristimerin and paclitaxel could be useful in the treatment of cancer and prevention of CINP.
Learn More >Some 30-50% of the global population and almost 20% of the European population actually suffer from chronic pain, which presents a tremendous burden to society when this pain turns into a disability and hospitalization. Palmitoylethanolamide (PEA) has been demonstrated to improve pain in preclinical contexts, but an appraisal of clinical evidence is still lacking. The present study aimed at addressing the working hypothesis for the efficacy of PEA for nociceptive musculoskeletal and neuropathic pain in the clinical setting. The systematic search, selection and analysis were performed in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 recommendations. The primary outcome was pain reduction, as measured by a pain assessment scale. The secondary outcome was improvement in quality of life and/or of parameters of function. The results obtained for a total of 933 patients demonstrate the efficacy of PEA over the control ( < 0.00001), in particular in six studies apart from the two randomized, double-blind clinical trials included. However, the results are downgraded due to the high heterogeneity of the studies (I = 99%), and the funnel plot suggests publication bias. Efficacy in achieving a reduction in the need for rescue medications and improvement in functioning, neuropathic symptoms and quality of life are reported. Therefore, adequately powered randomized, double-blind clinical trials are needed to deepen the domains of efficacy of add-on therapy with PEA for chronic pain. PROSPERO registration: CRD42022314395.
Learn More >