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Neuropathic pain is an intractable medical condition with few or no options for effective treatment. Emerging evidence shows a strong structure-function relationship between dendritic spine dysgenesis and the presence of neuropathic pain. Post-mortem tissue analyses can only imply dynamic structural changes associated with injury-induced pain. Here, we profiled the dynamics of dendritic spines over time on the same superficial dorsal horn (lamina II) neurons before and after peripheral nerve injury-induced pain. We employed a two-photon, whole-animal imaging paradigm that permitted repeat imaging of the same dendritic branches of these neurons in C57/Bl6 Thy1-YFP male mice. Our study demonstrates for the first time the ongoing, steady-state changes in dendritic spine dynamics in the dorsal horn associated with peripheral nerve injury and pain. Ultimately, the relationship between altered dendritic spine dynamics and neuropathic pain may serve as a structure-based opportunity to investigate mechanisms of pain following injury and disease.This work is important because it demonstrates for the first time: a)The powerful utility of intravital study of dendritic spine dynamics in the superficial dorsal horn.b)That nerve injury-induced pain triggers changes in dendritic spine steady-state behavior in the spinal cord dorsal horn.c)This work opens the door to further investigations of spinal cord dendritic spine dynamics in the context of injury and disease.
Learn More >The evidence that action shapes perception has become widely accepted, for example, in the domain of vision. However, the manner in which action-relevant factors might influence the neural dynamics of acute pain processing has remained underexplored, particularly the functional roles of anterior insula (AI) and midanterior cingulate cortex (mid-ACC), which are frequently implicated in acute pain. To address this, we examined a unique group of heterozygous carriers of the rare R221W mutation on the nerve growth factor (NGF) gene. R221W carriers show a congenitally reduced density of C-nociceptor afferent nerves in the periphery, but can nonetheless distinguish between painful and nonpainful stimulations. Despite this, carriers display a tendency to underreact to acute pain behaviorally, thus exposing a potential functional gap in the pain-action relationship and allowing closer investigation of how the brain integrates pain and action information. Heterozygous R221W carriers and matched controls performed a functional magnetic resonance imaging (fMRI) task designed to dissociate stimulus type (painful or innocuous) from current behavioral relevance (relevant or irrelevant), by instructing participants to either press or refrain from pressing a button during thermal stimulation. Carriers' subjective pain thresholds did not differ from controls', but the carrier group showed decreased task accuracy. Hemodynamic activation in AI covaried with task performance, revealing a functional role in pain-action integration with increased responses for task-relevant painful stimulation ("signal," requiring button-press execution) over task-irrelevant stimulation ("noise," requiring button-press suppression). As predicted, mid-ACC activation was associated with action execution regardless of pain. Functional connectivity between AI and mid-ACC increased as a function of reported urge to withdraw from the stimulus, suggesting a joint role for these regions in motivated action during pain. The carrier group showed greater activation of primary sensorimotor cortices-but not the AI and mid-ACC regions-during pain and action, suggesting compensatory processing. These findings indicate a critical role for the AI-mid-ACC axis in supporting a flexible, adaptive action selection during pain, alongside the accompanying subjective experience of an urge to escape the pain.
Learn More >Vulvodynia is a condition that occurs in 8-10% of women of all ages and is characterized by pain at the vulva that is present during sexual and/or non-sexual situations. Diagnosis is established through careful medical history and pelvic examination, including the cotton-swab test. The onset and maintenance of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression and childhood maltreatment as well as cognitive-affective, behavioural and interpersonal factors. Given the absence of empirically supported treatment guidelines, a stepwise approach of pelvic floor physical therapy and cognitive behavioural therapy as well as medical management is suggested, with surgery as the last option. Vulvodynia has a negative effect on the quality of life of women and their partners, and imposes a profound personal and societal economic burden. In addition, women with vulvodynia are more likely to report other chronic pain conditions, which further alters their quality of life. Future efforts should aim to increase girls', women's and healthcare professionals' education and awareness of vulvodynia, phenotype different subgroups of women based on biopsychosocial characteristics among more diverse samples, conduct longitudinal studies and improve clinical trial designs.
Learn More >The mechanisms underlying depression-associated pain remain poorly understood. Using a mouse model of depression, the authors hypothesized that the central amygdala-periaqueductal gray circuitry is involved in pathologic nociception associated with depressive states.
Learn More >To evaluate the effectiveness of yoga as an adjuvant to conventional medical management on clinical outcomes in patients with migraine.
Learn More >Painful stimuli are detected by peripheral nociceptors, and the brain processes this nociceptive input into an unpleasant sensation. A new study identifies a brain circuit that integrates sensory and affective aspects of inflammatory and neuropathic pain.
Learn More >Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N=50) and a large sample of cLBP patients (N=102) with structural brain imaging (T1-weighted MRI for Voxel Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P=0.01) over the low back, but not finger (P=0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P<0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ=0.27, P=0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ=0.52, P=0.03) and increased S1-back adjacent white matter FA (ρ=-0.56, P=0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.
Learn More >Nerve-binding fluorophores with near-infrared (NIR; 650 to 900 nm) emission could reduce iatrogenic nerve injury rates by providing surgeons precise, real-time visualization of the peripheral nervous system. Unfortunately, current systemically administered nerve contrast agents predominantly emit at visible wavelengths and show nonspecific uptake in surrounding tissues such as adipose, muscle, and facia, thus limiting detection to surgically exposed surface-level nerves. Here, a focused NIR fluorophore library was synthesized and screened through multi-tiered optical and pharmacological assays to identify nerve-binding fluorophore candidates for clinical translation. NIR nerve probes enabled micrometer-scale nerve visualization at the greatest reported tissue depths (~2 to 3 mm), a feat unachievable with previous visibly emissive contrast agents. Laparoscopic fluorescent surgical navigation delineated deep lumbar and iliac nerves in swine, most of which were invisible in conventional white-light endoscopy. Critically, NIR oxazines generated contrast against all key surgical tissue classes (muscle, adipose, vasculature, and fascia) with nerve signal-to-background ratios ranging from ~2 (2- to 3-mm depth) to 25 (exposed nerve). Clinical translation of NIR nerve-specific agents will substantially reduce comorbidities associated with surgical nerve damage.
Learn More >Single cell sequencing has provided unprecedented information about the transcriptomic diversity of somatosensory systems. Here we describe a simple and versatile in situ hybridization (ISH) based approach for mapping this information back to the tissue. We illustrate the power of this approach by demonstrating that ISH localization with just eight probes is sufficient to distinguish all major classes of neurons in sections of the trigeminal ganglion. To further simplify the approach and make transcriptomic class assignment and cell segmentation automatic we developed a machine learning approach for analyzing images from multiprobe ISH experiments. We demonstrate the power of in situ class assignment by examining the expression patterns of voltage gated sodium channels that play roles in distinct somatosensory processes and pain. Specifically, this analysis resolves intrinsic problems with single cell sequencing related to the sparseness of data leading to ambiguity about gene expression patterns. We also used the multiplex in situ approach to study the projection fields of the different neuronal classes. Our results demonstrate that the surface of the eye and meninges are targeted by broad arrays of neural classes despite their very different sensory properties but exhibit idiotypic patterns of innervation at a quantitative level. Very surprisingly, itch related neurons extensively innervated the meninges, indicating that these transcriptomic cell classes are not simply labeled lines for triggering itch. Together, these results substantiate the importance of a sensory neuron's peripheral and central connections as well as its transcriptomic class in determining its role in sensation.
Learn More >Recent studies have drawn the attention to the link between Alcohol Use Disorder (AUD) and the presence of pain. Indeed, the correct management of pain in patients with a previous history of AUD has been reported to decrease the risk of relapse in alcohol drinking, suggesting that in this prone population, pain may increase the vulnerability to relapse. Previous data in male rats revealed that inflammatory pain desensitizes mu opioid receptors (MORs) in the ventral tegmental area (VTA) and increases intake of high doses of heroine. Due to the relevant role of MORs in alcohol effects, we hypothesize that pain may also alter alcohol reinforcing properties and therefore affect alcohol relapse in male rats. Our microdialysis studies show that the presence of inflammatory pain blunted the increase of extracellular dopamine levels in the Nucleus Accumbens induced by 1.5g/kg of ethanol (s.c.). Moreover, we also revealed that the administration of 52 nmol of ethanol into the VTA failed to induce place preference only in inflammatory pain-suffering animals, and a higher dose (70nmol) was necessary to reverse this effect. Finally, we evaluated the effect of inflammatory pain on the alcohol deprivation effect (ADE) in long-term ethanol-experienced male rats. After four cycles of free ethanol intake and abstinence periods, inflammatory pain induced ADE without affecting its magnitude. These intriguing data reveals the impact of pain on neurochemical and behavioral effects following alcohol administration but also underscore the necessity of finding an appropriate paradigm to determine the long-term behavioral consequences.
Learn More >Pharmacological tools for chronic visceral pain management are still limited and inadequate. A3 adenosine receptor (A3AR) agonists are effective in different models of persistent pain. Recently their activity has been related to the block of N-type voltage-gated Ca channels (Cav2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A3AR agonists in reducing post-inflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intra-colonic instillation of 2,4-dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 ml 50% EtOH). Visceral hypersensitivity was assessed by measuring the viscero-motor response and the abdominal withdrawal reflex to colorectal distension. The effects of A3AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Cav2.2 blocker PD173212, and the clinically used drug linaclotide. A3AR agonists significantly reduced DNBS-evoked visceral pain both in the post-inflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Cav2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A3AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A3AR agonists inhibited Cav2.2 in DRG neurons isolated from either control or DNBS-treated rats. The effect on Ca current was PD173212-sensitive and prevented by MRS1523. A3AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.
Learn More >Rheumatoid arthritis-associated pain is poorly managed, often persisting when joint inflammation is pharmacologically controlled. Comparably, in the mouse K/BxN serum-transfer model of inflammatory arthritis, hind-paw nociceptive hypersensitivity occurs with ankle joint swelling (5 days post-immunisation) persisting after swelling has resolved (25 days post-immunisation). In this study, lipid mediator profiling of lumbar dorsal root ganglia (DRG), the site of sensory neuron cell bodies innervating the ankle joints, 5 days and 25 days after serum transfer demonstrated a shift in specialised pro-resolving lipid mediator (SPM) profiles. Persistent nociception without joint swelling was associated with low concentrations of the SPM Maresin-1 (MaR1) and high macrophage numbers in DRG. MaR1 application to cultured DRG neurons inhibited both capsaicin-induced increase of intracellular calcium ions and release of calcitonin gene-related peptide (CGRP) in a dose-dependent manner. Furthermore, in peritoneal macrophages challenged with lipopolysaccharide, MaR1 reduced pro-inflammatory cytokine expression. Systemic MaR1 administration caused sustained reversal of nociceptive hypersensitivity and reduced inflammatory macrophage numbers in DRG. Unlike gabapentin, which was used as positive control, systemic MaR1 did not display acute anti-hyperalgesic action. Therefore, these data suggest that MaR1 effects observed following K/BxN serum transfer relate to modulation of macrophage recruitment, more likely than to direct actions on sensory neurons. Our study highlights that, in DRG, aberrant pro-resolution mechanisms play a key role in arthritis joint pain dissociated from joint swelling, opening novel approaches for RA pain treatment.
Learn More >High-threshold mechanosensitive and mechano-insensitive ("silent") nociceptors have similar electrical thresholds for transcutaneous sine wave stimulation at 4 Hz that selectively activates cutaneous C-nociceptors in human skin. Their fundamentally different functions particularly in chronic pain warrant differential stimulation protocols. We used transcutaneously delivered slow depolarizing stimuli (half-sine, 500 ms duration, 0.01 – 1 mA) in humans to assess intensity-response relations for the induction of pain psycho-physically and recorded activation of mechanosensitive and silent nociceptors in healthy volunteers by microneurography. Differential C-fiber activation was confirmed in single fiber recordings in pig allowing stimulation amplitudes up to 10 mA. Perception and pain thresholds to half-sine wave pulses were 0.06 ± 0.03 mA and 0.18 ± 0.1 mA, respectively, and caused pain in an amplitude-dependent manner (n=24). When matched for pain intensity, only sine wave stimulation induced an instant widespread axon reflex erythema (n=10). In human microneurography, half-sine stimulation activated mechanosensitive nociceptors (n=13), but only one of 11 silent nociceptors. In pig skin, the amplitude-dependent activation of mechanosensitive nociceptors was confirmed (0.2 – 1 mA, n=28) and activation thresholds for most silent nociceptors (n=13) were found above 10 mA. Non-nociceptive low threshold mechanosensitive C-fibers (n=14) displayed lower activation thresholds for half-sine wave stimuli with an amplitude-dependent discharge increase between 0.01 and 0.1 mA. We conclude that transcutaneous electrical stimulation with 500 ms half-sine wave pulses between 0.2 and 1 mA causes amplitude-dependent pain by preferential activation of mechanosensitive C-nociceptors.
Learn More >The ongoing substance misuse epidemic in the United States is complex and dynamic and should be approached as such in the development and evaluation of policy. Drug overdose deaths (largely attributable to opioid misuse) in the United States have grown exponentially for almost four decades, but the mechanisms of this growth are poorly understood. From analysis of 661,565 overdose deaths from 1999 to 2017, we show that the age-specific drug overdose mortality curve for each birth-year cohort rises and falls according to a Gaussian-shaped curve. The ascending portion of each successive birth-year cohort mortality curve is accelerated compared with that of all preceding birth-year cohorts. This acceleration can be attributed to either of two distinct processes: a stable peak age, with an increasing amplitude of mortality rate curves from one birth-year cohort to the next; or a youthward shift in the peak age of the mortality rate curves. The overdose epidemic emerged and increased in amplitude among the 1945-1964 cohort (Baby Boomers), shifted youthward among the 1965-1980 cohort (Generation X), and then resumed the pattern of increasing amplitude in the 1981-1990 Millennials. These shifting age and generational patterns are likely to be driven by socioeconomic factors and drug availability, the understanding of which is important for the development of effective overdose prevention measures.
Learn More >Sleep disruption caused by obstructive sleep apnea (OSA) may be associated with hyperalgesia and may contribute to poor pain control and use of prescription opioids. However, the relationship between OSA and opioid prescription is not well described. We examine this association using cross-sectional data from a national cohort of veterans from recent wars enrolled from October 1, 2001 to October 7, 2014. The primary outcome was the relative risk ratio (RRR) of receiving opioid prescriptions for acute (<90 days/year) and chronic (≥90 days/year) durations compared to no opioid prescriptions. The primary exposure was a diagnosis of OSA. We used multinomial logistic regression to control for factors that may affect diagnosis of OSA or receipt of opioid prescriptions. Of the 1,149,874 patients (mean age 38.0±9.6 years) assessed, 88.1% had no opioid prescriptions, 9.4% had acute prescriptions, and 2.5% had chronic prescriptions. Ten percent had a diagnosis of OSA. Patients with OSA were more likely to be older, male, non-white, obese, current or former smokers, have higher pain intensity, and have medical and psychiatric comorbidities. Controlling for these differences, patients with OSA were more likely to receive acute (RRR 2.02 [95% CI 1.98, 2.06]) or chronic (RRR 2.15 [2.09, 2.22]) opioids. Further dividing opioid categories by high versus low dosage did not yield substantially different results. OSA is associated with a two-fold likelihood of being prescribed opioids for pain. Clinicians should consider incorporating OSA treatment into multi-modal pain management strategies; OSA as a target for pain management should be further studied.
Learn More >A growing body of literature shows that justice-related appraisals are significant determinants of pain-related outcomes and prolonged trajectories of recovery. We conducted a systematic review of the literature assessing the relationship between perceived injustice and pain-related outcomes in individuals with musculoskeletal pain.
Learn More >To evaluate the relationship between pain catastrophizing level, sensory processing patterns, and headache severity among adolescents with episodic migraine.
Learn More >One out of seven women will develop a state of chronic postoperative pain following robot-assisted hysterectomy for endometrial cancer. Recently, metabolic studies have indicated that circulating lipids and lipoproteins could act as nociceptive modulators and thereby influence the induction and perpetuation of pain. The objectives of this explorative study were (1) to examine the preoperative serologic variations in concentrations of lipids, lipoproteins, and various low-molecular metabolites in patients with and without chronic postoperative pain after robot-assisted hysterectomy and (2) to explore if any of these serological biomarkers were predictive for development of chronic postoperative pain.
Learn More >Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD.
Learn More >Pain is one of the most common reasons to seek medical attention and chronic pain is a worldwide epidemic. There are currently no relevant biomarkers for the diagnosis of chronic pain, and new therapeutic strategies for chronic pain treatment are desperately needed. The chronic constriction injury (CCI) of the sciatic nerve is a widely used preclinical model of pathological neuropathic pain. Over the past decade, investigators have come to appreciate the many contributions of noncoding RNA including microRNA (miRNA), and other long and short noncoding (nc) RNAs. The development and/or maintenance of chronic pain could be controlled epigenetically through ncRNAs. Here we seek to characterize CNS tissues in a mouse model of neuropathic pain as this may serve to elucidate potential biomarkers relevant to pathological pain in humans. Male C57BL6/J mice (6 CCI and 6 sham procedure) underwent surgery for sciatic nerve ligation with chromic gut sutures. Following 7 days, mechanical allodynia was quantified using the von Frey assay. Mice were then euthanized for collection of spinal cord and sciatic nerve. cDNA was synthesized to 627 unique mature miRNAs from the total RNA. In the CCI mice that displayed mechanical allodynia, 11 and 125 miRNAs were differentially expressed (i.e., greater than 1.5-fold increase or decrease; P < 0.05) in the spinal cord and sciatic nerve, respectively, as compared to sham controls. Among those differentially expressed miRNAs in the sciatic nerve of CCI mice, the following passed the more stringent Bonfferoni correction: miR-138-3p, miR-138-5p and miR-676-3p, reduced and miR-142-5p, increased. Our data support miRNAs as promising therapeutic targets for the treatment of pathological pain.
Learn More >Influential theoretical accounts take the position that classical conditioning can induce placebo effects through conscious expectancies. In the current study two different conditioning procedures (hidden and open) were used to separate expectancy from conditioning in order to reveal the role of expectancy in the formation of nocebo hyperalgesia. Eighty-seven healthy females were randomly assigned to three groups (hidden conditioning, open conditioning, and control). Participants were selected according to the Fear of Pain Questionnaire scores and assigned to two subgroups: high and low level of fear of pain (trait). They received electrocutaneous pain stimuli preceded by either an orange or blue color. During the conditioning phase, one color was paired with pain stimuli of moderate intensity (control stimuli) and the other color was paired with pain stimuli of high intensity (nocebo stimuli) in both hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association, however just before the testing phase the expectancy of hyperalgesia induced in this way was withdrawn. In the control group, both colors were followed by control pain stimuli. During the testing phase all participants received a series of stimuli of the same intensity, regardless of the preceding color. Participants rated pain intensity, expectancy of pain intensity and fear (state). We found that nocebo hyperalgesia was induced by hidden rather than open conditioning. The hidden conditioning procedure did not produce conscious expectancies related to pain. Nocebo hyperalgesia was induced in participants with low and high fear of pain and there was no difference in the magnitude of the nocebo effect between both groups. Nocebo hyperalgesia was not predicted by the fear of upcoming painful stimuli.
Learn More >Background: Patients with chronic pain often have limited access to comprehensive care that includes behavioral pain management strategies. Virtual reality (VR) is an immersive technology and emerging digital behavioral pain therapeutic with analgesic efficacy for acute pain. We found no scientific literature on skills-based VR behavioral programs for chronic pain populations.
Learn More >Over the last 3 years and for the first time in 60 years, life expectancy in the United States has declined across all racial groups primarily because of drug overdoses, alcohol abuse, and suicide. A public health response to the opioid crisis must expand its focus to more broadly include children, adolescents, and young adults while increasing efforts toward preventing new cases of opioid addiction, early identification of individuals with opioid-abuse disorder, and ensuring access to effective opioid addiction treatment, while simultaneously continuing to safely meet the needs of patients experiencing pain.
Learn More >Chronic postsurgical pain (CPSP) is a debilitating chronic pain condition that has a substantial effect on quality of life. CPSP shows considerable clinical overlap with different chronic peripheral pain syndromes, suggesting a shared aetiology. This study aims to assess the genetic overlap between different chronic pain syndromes and CPSP, providing relevant biological context for potential chronic pain markers of CPSP. To analyse the genetic overlap between CPSP and chronic peripheral pain syndromes, recent GWAS studies were combined for polygenic risk scores (PRS) analysis, using a cohort of CPSP patients as starting point. Biological contextualisation of genetic marker, overlap between CPSP and chronic pain syndromes, was assessed through Gene Ontology (GO), using Pathway Scoring Algorithm (PASCAL) and REVIGO. PRS analyses suggest a significant genetic overlap between CPSP and 3 chronic pain disorders: chronic widespread pain (CWP, p value threshold = 0.003, R 0.06, p = 0.003), rheumatoid arthritis (RA, p value threshold = 0.0177, R = 0.04, p = 0.017) and possibly sciatica (p value threshold = 0.00025, R = 0.03, p = 0.045). Whereas no significant genetic overlap was found with cluster headache and migraine, the outcome for osteoarthritis (OA) was inconsistent between the cohorts. This is likely related to cohort composition, as repeated random reallocation of patients' nullified CPSP/OA outcome variation between the discovery and replication cohorts. GO analyses suggested an aetiological involvement of genetic markers that control neurological signalling (specifically sodium channels) and inflammatory response. The current study reaffirms the impact of sample size, cohort composition and open data accessibility on the unbiased identification of genetic overlap across disorders. In conclusion, this study is the first to report genetic overlap between regulatory processes implicated in CPSP and chronic peripheral pain syndromes. Interaction between neurological signalling and inflammatory response may explain the genetic overlap between CPSP, CWP and RA. Enhanced understanding of mechanisms underlying chronification of pain will aid the development of new therapeutic strategies for CPSP with sodium channel biochemistry as a potential candidate.
Learn More >Craniofacial muscle pain is highly prevalent in temporomandibular disorders but is difficult to treat. Enhanced understanding of neurobiology unique to craniofacial muscle pain should lead to the development of novel mechanism-based treatments. Herein, we review recent studies to summarize neural pathways of craniofacial muscle pain. Nociceptive afferents in craniofacial muscles are predominantly peptidergic afferents enriched with TRPV1. Signals from peripheral glutamate receptors converge onto TRPV1, leading to mechanical hyperalgesia. Further studies are needed to clarify whether hyperalgesic priming in nonpeptidergic afferents or repeated acid injections also affect craniofacial muscle pain. Within trigeminal ganglia, afferents innervating craniofacial muscles interact with surrounding satellite glia, which enhances the sensitivity of the inflamed neurons as well as nearby uninjured afferents, resulting in hyperalgesia and ectopic pain originating from adjacent orofacial tissues. Craniofacial muscle afferents project to a wide area within the trigeminal nucleus complex, and central sensitization of medullary dorsal horn neurons is a critical factor in muscle hyperalgesia related to ectopic pain and emotional stress. Second-order neurons project rostrally to pathways associated with affective pain, such as parabrachial nucleus and medial thalamic nucleus, as well as sensory-discriminative pain, such as ventral posteromedial thalamic nuclei. Abnormal endogenous pain modulation can also contribute to chronic muscle pain. Descending serotonergic circuits from the rostral ventromedial medulla facilitate activation of second-order neurons in the trigeminal nucleus complex, which leads to the maintenance of mechanical hyperalgesia of inflamed masseter muscle. Patients with temporomandibular disorders exhibit altered brain networks in widespread cortical and subcortical regions. Recent development of methods for neural circuit manipulation allows silencing of specific hyperactive neural circuits. Chemogenetic silencing of TRPV1-expressing afferents or rostral ventromedial medulla neurons attenuates hyperalgesia during masseter inflammation. It is likely, therefore, that further delineation of neural circuits mediating craniofacial muscle hyperalgesia potentially enhances treatment of chronic muscle pain conditions.
Learn More >The purpose of this study was to examine the changes in cold block of unmyelinated C-fibers in the tibial nerve by pre-conditioning with heating and to develop a safe method for thermal block of C-fiber conduction. In 7 cats under α-chloralose anesthesia, C-fiber evoked potentials elicited by electrical stimulation were recorded on the tibial nerve during block of axonal conduction induced by exposing a small segment (9 mm) of the nerve to cooling (from 35 °C to ≤5 °C) or heating (45 °C). Before heating partial, reproducible, and reversible cold block was first detected at a threshold cold block temperature of 15 °C and complete cold block occurred at a temperature of ≤5 °C. After heating the nerve at 45 °C for 5-35 minutes the threshold cold block temperature significantly (p<0.05) increased from 15° C to 25 °C and the complete cold block temperature significantly (p<0.05) increased from ≤5 °C to 15°C on average. The increased cold block temperatures persisted for the duration of the experiments (30-100 minutes) while the amplitude of the C-fiber evoked potential measured at 35 °C recovered significantly (p<0.05) to about 80% of control. This study discovered a novel thermal method to block mammalian C-fibers at an elevated temperature (15-25 °C), providing the opportunity to develop a thermal nerve block technology to suppress chronic pain of peripheral origin. The interaction between heating and cooling effects on C-fiber conduction indicates a possible interaction between different temperature sensitive channels known to be present in the mammalian C-fibers.
Learn More >Research supports a role for coping responses in adjustment to chronic pain. However, it is likely that some coping responses play a larger role in adjustment to pain for some individuals than others. The identification of the factors that moderate the association between coping responses and pain-related outcomes has important clinical implications. This study sought to determine if musculoskeletal pain diagnosis moderates the associations between eight pain-coping responses and both pain and function.
Learn More >This special issue highlights emerging research spanning from epidemiology to diagnostic workup, pathogenesis, and therapeutics for patients suffering from chronic pruritus. The special issue contains 13 articles reporting relevant epidemiologic and experimental data on chronic pruritus.
Learn More >To investigate sensory changes, physical function (pF), quality of life (QoL) and pain intensity of patients with osteoarthritis (OA) in the natural course of disease, and patients undergoing total joint replacement therapy (TJR) 31 (20 females, mean age 64.6 ± 10.4 years), patients with OA were investigated with questionnaires and quantitative sensory testing (QST) in the area of referred pain at the thigh at baseline and follow-up 22-49 weeks later; changes were analyzed separately for patients with ( = 13) and without TJR ( = 18). In patients without TJR pain intensity, pF, QoL did not improve, and increased pain sensitivity to cold and a stronger loss of detection were observed. In patients after TJR, however, a reduction in mechanical pain sensitivity and allodynia occurred in accordance with a reduction of pain intensity and improvement of functionality while QoL did not improve. Additionally, an increased sensitivity to heat pain and a more pronounced loss of mechanical detection could be observed in this group. TJR seems to stop peripheral pain input leading to a reduction of pain intensity and central sensitization, but surgery-induced sensory changes such as peripheral sensitization and loss of detection occur. Furthermore, TJR has favorable effects on pain intensity and functionality but not QoL.
Learn More >ALD403 is a genetically engineered, humanized immunoglobulin G1 monoclonal antibody that inhibits the action of human calcitonin gene-related peptide (CGRP). Clinical trial data indicate that ALD403 is effective as a preventive therapy for migraine and has an acceptable safety profile. For preclinical characterization of ALD403, rabbit antibodies targeting α-CGRP were humanized and modified to eliminate Fcγ-receptor (FcγR) and complement interactions. The ability of ALD403 to inhibit CGRP-induced cyclic adenosine monophosphate (cAMP) production was assessed using a cAMP bioassay (Meso Scale Discovery). The IC50 for inhibition of cAMP release was 434 and 288 pM with the rabbit-human chimera antibody and the humanized ALD403, respectively. ALD403 inhibited α-CGRP binding with an IC50 of 4.7 x 10-11 and 1.2 x 10-10 for the α-CGRP and AMY1 receptors, respectively. ALD403 did not induce antibody-dependent cellular cytotoxicity nor complement-dependent cytotoxicity and did not stably interact with any of the FcγR mediating these functions, exhibiting only weak binding to FcγRI. ALD403 significantly lowered capsaicin-induced blood flow responses in rodents at all time points starting at 5 minutes post-application in a dose-dependent manner. In conclusion, ALD403 is a potent functional ligand inhibitor of α-CGRP‒driven pharmacology. SIGNIFICANCE STATEMENT: α-CGRP blockade by ALD403 was assessed via radiolabeled ligand displacement, in vitro inhibition of cell signaling, and in vivo inhibition of capsaicin-induced vasodilation. Lack of engagement of Fc-mediated immune-effector functions by ALD403 was shown.
Learn More >The crosstalk between the immune and nervous system in the regulation of OA pain is increasingly becoming evident. GM-CSF signals in both systems and might be a new treatment target to control OA pain. Anti GM-CSF treatment has analgesic effects in OA without affecting synovitis scores, suggesting that treatment effects are not caused by local anti-inflammatory effects. We aimed to evaluate whether expression of GM-CSF and its receptor GM-CSFrα in synovial tissue is linked to synovial inflammation and/or knee pain in knee OA patients.
Learn More >Opioid analgesics remain the mainstay for managing intractable chronic pain, but their use is limited by detrimental side effects such as analgesic tolerance and hyperalgesia. Calcium-dependent synaptic plasticity is a key determinant in opiates tolerance and hyperalgesia. However, the exact substrates for this calcium-dependent synaptic plasticity in mediating these maladaptive processes are largely unknown. Canonical transient receptor potential 1, 4, and 5 (TRPC1, 4, 5) proteins assemble into heteromultimeric nonselective cation channels with high Ca permeability and influence various neuronal functions. However, whether and how TRPC1/4/5 channels contribute to the development of opiates tolerance and hyperalgesia remains elusive. Here, we show that TRPC1/4/5 channels contribute to the generation of morphine tolerance and hyperalgesia. Chronic morphine exposure leads to upregulation of TRPC1/4/5 channels in the spinal cord. Spinally expressed TRPC1, TPRC4, and TRPC5 are required for chronic morphine-induced synaptic long-term potentiation (LTP) as well as remodeling of synaptic spines in the dorsal horn, thereby orchestrating functional and structural plasticity during the course of morphine-induced hyperalgesia and tolerance. These effects are attributed to TRPC1/4/5-mediated Ca elevation in the spinal dorsal horn induced by chronic morphine treatment. This study identifies TRPC1/4/5 channels as a promising novel target to prevent the unwanted morphine tolerance and hyperalgesia.
Learn More >In an oversaturated market of publicly available mobile apps for psychosocial self-care and stress management, health care providers, patients, and consumers interested in mental health-related apps may wonder which, if any, are efficacious. Readily available metrics for consumers include user popularity and media buzz rather than scientific evidence.
Learn More >Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. We investigated self-reported cold extremities as a marker for vascular dysfunction in migraine. Secondly, we hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency.
Learn More >HIV-associated neuropathic pain (HNP) is a common complication for AIDS patients. The pathological mechanism governing HNP has not been elucidated, and HNP has no effective analgesic treatment. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic factor family related to the plasticity of the central nervous system. BDNF dysregulation is involved in many neurological diseases, including neuropathic pain. However, to the best of our knowledge, the role and mechanism of BDNF in HNP have not been elucidated. In this study, we explored this condition in an HNP mouse model induced by intrathecal injection of gp120. We found that Wnt3a and β-catenin expression levels increased in the spinal cord of HNP mice, consequently regulating the expression of BDNF and affecting hypersensitivity. In addition, the blockade of Wing-Int/β-catenin signaling, BDNF/TrkB or the BDNF/p75NTR pathway alleviated mechanical allodynia. BDNF immunoreactivity was colocalized with spinal microglial cells, which were activated in HNP mice. Inhibition of spinal microglial cell activation by minocycline relieved mechanical allodynia in HNP mice. This study helped to elucidate the role of the Wing-Int/β-catenin/BDNF signaling axis in HNP and may establish a foundation for further research investigating the Wing-Int/β-catenin/BDNF signaling axis as a target for HNP treatment.
Learn More >Family members are cited as a common source of prescription opioids used for nonmedical reasons. However, the overdose risk associated with exposure to opioids prescribed to family members among adolescents and young adults is not well established.
Learn More >Chronic pain, unrelated to the burn itself, can manifest as a long-term complication in patients sustaining burn injuries. The purpose of this study was to determine the prevalence of chronic neuropathic pain (CNP) and compare burn characteristics between patients who developed CNP and patients without CNP who were treated at a burn center.
Learn More >Neck pain commonly accompanies recurrent headaches such as migraine, tension-type and cervicogenic headache. Neck pain may be part of the headache symptom complex or a local source. Patients commonly seek neck treatment to alleviate headache, but this is only indicated when cervical musculoskeletal dysfunction is the source of pain. Clinical presentation of reduced cervical extension, painful cervical joint dysfunction and impaired muscle function collectively has been shown to identify cervicogenic headache among patients with recurrent headaches. The pattern's validity has not been tested against the 'gold standard' of controlled diagnostic blocks. This study assessed the validity of this pattern of cervical musculoskeletal signs to identify a cervical source of headache and neck pain, against controlled diagnostic blocks, in patients with headache and neck pain.
Learn More >Migraine is a severe and disabling brain disorder, and the exact neurological mechanisms remain unclear. Migraineurs have altered pain perception, and headache attacks disrupt their sensory information processing and sensorimotor integration. The altered functional connectivity of sub-regions of sensorimotor brain areas with other brain cortex associated with migraine needs further investigation.
Learn More >Primary stabbing headache (PSH) is a transient and localized headache disorder. Facial variants of this rare pain syndrome have not been previously described. Four patients (n = 2 female, 2 male) presented themselves to our headache and facial pain outpatient clinic. They suffered daily from several dozen to several hundred short-lasting stabbing pain paroxysms primarily in the second and third trigeminal branches (V2 and V3) without lateral predominance. These non-neuralgic pain paroxysms did not strictly follow dermatomes, were not accompanied by trigeminal autonomic features and could not be triggered but occurred exclusively spontaneously. They did not fulfill any existing ICHD-3 criteria but appeared clinically to have similarities to primary stabbing headache syndromes. Indomethacin showed no efficacy. Exclusive facial variants of stabbing pain paroxysms should be classified as separate entities and tentatively be called stabbing facial pain.
Learn More >Pain is a growing public health problem associated with significant health and functional implications. Limited data exist for Aboriginal Australians.
Learn More >Urologic chronic pelvic pain syndrome (UCPPS) is a chronic, noncyclic pain condition which can lead to significant patient morbidity and disability. It is defined by pain in the pelvic region, lasting for greater than 3 to 6 months, with no readily identifiable disease process. The aim of this review is to provide a comprehensive update of diagnosis and treatment of UCPPS.
Learn More >High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, facilitates pain signals as well as inflammation. Intraplantar or intraspinal application of HMGB1 elicits hyperalgesia/allodynia in rodents by activating the advanced glycosylation end-product specific receptor (receptor for advanced glycation end-products; RAGE) or Toll-like receptor 4 (TLR4). Endogenous HMGB1 derived from neurons, perineuronal cells or immune cells accumulating in the dorsal root ganglion or sensory nerves participates in somatic and visceral pain consisting of neuropathic and/or inflammatory components. Endothelial thrombomodulin (TM) and recombinant human soluble TM, TMα, dramatically promote thrombin-dependent degradation of HMGB1, and systemic administration of TMα prevents and reverses various HMGB1-dependent pathological pain. Small molecules that directly inactivate HMGB1 or antagonize HMGB1-targeted receptors would be useful to reduce various intractable pain. Thus, HMGB1 and its receptors are considered to serve as promising targets in developing novel agents to prevent or treat pathological pain.
Learn More >Migraine is associated with debilitating symptoms that can affect daily functioning. "My Migraine Voice" was a large, cross-sectional, multi-country online survey aimed at understanding disease burden directly from people with migraine.
Learn More >Voltage gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic SAR studies carried out to identify novel sulfonamide derivatives as potent, selective and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5 and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43 and 51 have shown favorable PK profile across different species and robust efficacy in veratridine and formalin induced inflammatory pain models in mice. Compound 51 has also shown significant effect in CCI induced neuropathic pain model. Profile of 51 has indicated that it has the potential for further evaluation as a therapeutic for pain.
Learn More >Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder that is characterized by persistent and widespread pain. FMS has been associated with sleep disturbance, mood disorders and depression. Racial/ethnic minorities are less likely to receive a diagnosis of FMS than White individuals. Although mood disorders and depression are prevalent among racial/ethnic minority groups, researchers have not examined whether there are differences between racial/ethnic minorities and White individuals with FMS.
Learn More >The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT) receptor agonism, to 'reset' areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.
Learn More >Fully illuminating mechanisms relating parent behaviors to child pain require examining both verbal and nonverbal communication. We conducted a multimethod investigation into parent nonverbal communication and physiology, and investigated the psychometric properties of the Scheme for Understanding Parent Emotive Responses Scale to assess parent nonverbals accompanying reassurance and distraction. 23 children (7-12 years) completed the cold pressor task with their parent (predominately mothers). Parent heart rate and heart rate variability were monitored and assessed. The Scheme for Understanding Parent Emotive Responses Scale coding of parent nonverbal behaviors (i.e., vocal cues, facial expressions, posture) was used to detect levels of fear, warmth, disengagement and humor. : Preliminary evidence for the psychometric properties of the scale are offered. Parent reassurance was associated with more fear, less warmth and less humor compared with distraction.
Learn More >After decades of increased opioid pain reliever prescribing, providers are rapidly reducing prescribing. We hypothesized that reduced access to prescribed opioid pain relievers among patients previously reliant upon opioid pain relievers would result in increased illicit opioid use.
Learn More >Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here a drug-design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II-VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CA II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.
Learn More >Opioids are commonly used for postoperative pain management in spine surgery. However, few guidelines exist for appropriate prescribing in the acute postoperative phase of care. We identify risk factors for inpatient (IP) opioid use and examine relationships between IP requirements and discharge (DC) opioid prescriptions.
Learn More >There is evidence regarding the presence of alterations in both the stress response and the endogenous pain modulation systems of people with fibromyalgia (FM). However, research on pain modulation under induced stress on FM patients is scarce and contradictory. The present study analyzes stress-induced changes in pain and intolerance thresholds among FM patients, examining the possible existence of differences linked to PTSD comorbidity and gaining insights into the role of cardiovascular reactivity. Eighteen women diagnosed with FM and comorbid PTSD (FM + PTSD), 18 women diagnosed with FM and no PTSD (FM-PTSD), and 38 healthy women (HC) were exposed to the Social Stress Test task. Pressure pain thresholds and intolerance thresholds were measured before and during stress induction, and after a recovery period, while systolic blood pressure and heart rate were simultaneously recorded. Overall, while pain thresholds decreased during stress and recovery for HC, no significant changes were observed for women with FM. The intolerance threshold decreased for HC during stress, but was maintained at basal level during recovery. FM-PTSD women exhibited a delayed response, with a drop at recovery. For FM + PTSD, tolerance levels remained unchanged. In addition, cardiovascular reactivity did not seem to explain these results. This performance of the pain modulation system seems to follow the same pattern of hypoactive responsiveness under stressors that has previously been observed in FM patients on the autonomic and neuroendocrine axes. Such a hypoactive pattern may involve a non-adaptive response that may contribute to the development and maintenance of chronic pain.
Learn More >Burning mouth syndrome is a chronic oral pain disorder that is characterized by a generalized or localized burning sensation without the presence of any specific mucosal lesions. It remains unclear, however, whether burning mouth syndrome is associated with the development of psychoneurological conditions among patients with the syndrome.
Learn More >Chronic pain (CP) may increase the risk for major adverse cardiac and cerebrovascular events (MACCEs); however, this issue is still unclear in the Asian population. We conducted this study to delineate it.
Learn More >To estimate the effects of excess body mass and leisure time physical activity on the incidence and persistence of chronic pain.
Learn More >We estimated the use of prescribed analgesics and adjuvants among nursing home residents without cancer who reported pain at their admission assessment, in relation to resident-reported pain severity.
Learn More >Telerehabilitation can facilitate multidisciplinary management for people with nonspecific chronic low back pain (NCLBP). It provides access to health care to individuals who are physically and economically disadvantaged.
Learn More >We previously reported that interleukin (IL)-6 in the red nucleus (RN) is involved in the maintenance of neuropathic pain induced by spared nerve injury (SNI), and exerts a facilitatory effect via Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and extracellular signal-regulated kinase (ERK) signal transduction pathways. The present study aimed at investigating the roles of tumor necrosis factor-α (TNF-α) and IL-1β in RN IL-6-mediated maintenance of neuropathic pain and related signal transduction pathways. Being similar to the elevation of RN IL-6 three weeks after SNI, increased protein levels of both TNF-α and IL-1β were also observed in the contralateral RN three weeks after the nerve injury. The upregulations of TNF-α and IL-1β were closely correlative with IL-6 and suppressed by intrarubral injection of a neutralizing antibody against IL-6. Administration of either the JAK2 antagonist AG490 or the ERK antagonist PD98059 to the RN of rats with SNI remarkably increased the paw withdrawal threshold (PWT) and inhibited the up-regulations of local TNF-α and IL-1β. Further experiments indicated that intrarubral injection of exogenous IL-6 in naive rats apparently lowered the PWT of the contralateral hindpaw and boosted the local expressions of TNF-α and IL-1β. Pretreatment with AG490 could block IL-6-induced tactile hypersensitivity and suppress the up-regulations of both TNF-α and IL-1β. However, injection of PD98059 in advance only inhibited the upregulation of IL-1β, but not TNF-α. These findings indicate that RN IL-6 mediates the maintenance of neuropathic pain by inducing the productions of TNF-α and IL-1β. IL-6 induces the expression of TNF-α through the JAK2/STAT3 pathway, and the production of IL-1β through the JAK2/STAT3 and ERK pathways.
Learn More >: To examine rates and correlates of dual cannabis and prescription pain reliever (PPNR) use and misuse among U.S. individuals aged 50+ who reported past-year cannabis use.: Using the 2015-2018 National Survey of Drug Use and Health, we examined cannabis nonuse/use and PPNR nonuse/use/misuse among all 35,229 respondents, and then focused on 2,632 past-year cannabis users to examine the risk of PPNR use but no misuse and the risk of PPNR misuse, compared to PPNR nonuse.: More than one-half of older cannabis users used PPNR in the past year. Multinomial logistic regression results show that the risks of PPNR use/no misuse and PPNR misuse were higher among those who had more chronic medical conditions and a major depressive episode. The risk of PPNR use/no misuse was also associated with high frequency and medical cannabis use. The risk of PPNR misuse was also associated with younger cannabis initiation age and cannabis and other illicit drug use disorders.: Correlates of dual cannabis and PPNR use/misuse among older adults are poor physical and mental health problems and problematic cannabis use.: Older adults with cannabis and PPNR misuse need access to evidence-based treatment, including medication-assisted treatment when needed.
Learn More >The Pain Stages of Change Questionnaire (PSOCQ) measures patients' willingness to engage in active self-management of their pain. The present study aimed to create validated German short versions of the PSOCQ for adolescents (PSOCQ-A) and their parents (PSOCQ-P). Additionally, an investigation of stages of change regarding pain characteristics and treatment outcomes was undertaken. In Study 1, the data of adolescents aged 11 to 18 years and their parents were collected prior to intake ( = 501) and at admission ( = 240) to specialist inpatient pain treatment. Confirmatory factor analyses indicated a poor fit of the full PSOCQ measures prior to intake, but an acceptable fit at admission. Short PSOCQ-A and PSOCQ-P versions were identified. In Study 2, these results were cross-validated with data from an additional = 150 patients and their parents, collected during and 3 months after interdisciplinary inpatient pain treatment. Model fits for both short versions were acceptable, although low internal consistency for the PSOCQ-A Precontemplation and Contemplation subscales was identified. During treatment, both patients' and their parents' readiness to change increased. Stage of change at discharge did not predict treatment non-response 3 months later. This study indicates that the PSOCQ is neither meaningful prior to admission nor predictive of non-response to treatment. While some value may exist in monitoring treatment progress, based on the results of this study, it is not recommended that the PSOCQ-A and PSOCQ-P be used as a measure of stage of change in German pediatric pain populations.
Learn More >Central sensitization (CS) has been recently identified as a significant risk factor for persistent pain and patient dissatisfaction following total knee arthroplasty (TKA). However, it remains unclear as to whether the preoperative CS persists after the elimination of a nociceptive pain source by TKA, or how CS affects the quality of life after TKA.
Learn More >Objectives The link between social support and physical activity has primarily been examined cross-sectionally, with a focus on the direct association between the two variables. In a distinct body of work, there has been growing interest in the role of social support in reducing pain (emotional and physical). We examined the relationship between social support and physical activity over time. We further examined whether reduced pain mediates the relationship between social support and physical activity. Design Data were drawn from Waves 15, 16, and 17 of the Household Income and Labour Dynamics in Australia survey. Methods Mediation models were used to test our hypotheses in (a) a representative sample of 12,517 people residing in Australia, and (b) a subsample of 927 people with a condition that causes chronic or recurring pain. Results Social support was a weak predictor of subsequent physical activity in both the full sample and the subsample of people with a condition that causes chronic or recurring pain. However, in both samples, mediation analyses demonstrated a significant indirect effect of social support on physical activity through reduced pain. Conclusions One pathway through which social support impacts physical activity is by reducing peoples' pain. Increasing and strengthening peoples' social support networks may confer benefits for their physical activity levels, including among those whose physical activity is limited by pain. Statement of contribution What is already known on this subject? Social support can have a positive effect on health behaviours, including physical activity. There is somewhat inconsistent evidence for a positive direct relationship between social support and physical activity. Pain can be a barrier to physical activity, but may be attenuated by social support. What does this study add? Social support affected physical activity indirectly by reducing peoples' pain. This was true for both the general population and a subsample with a chronic pain condition. Improving peoples' social support networks may confer benefits for their physical activity.
Learn More >Increasing evidence suggests that activation of satellite glia cells (SGCs) in sensory ganglia play important roles in the development of neuropathic pain. The present study aimed to investigate the involvement of SGC activation in a novel model of motor nerve injury induced pain hypersensitivity. The neuropathic pain model was established by cervical 8 ventral root avulsion (C8VA). Glial fibrillary acidic protein (GFAP) was used as a marker of SGC activation. Unilateral C8VA resulted in mechanical allodynia, but not thermal hyperalgesia in bilateral paws. Expectedly, SGCs were robustly activated on as early as 1 day and persisted for at least 7 days in the ipsilateral and contralateral dorsal root ganglia (DRG) of C6, C7 and C8 after C8VA. Double immunofluorescence showed that almost all the activated SGCs enveloped neurofilament 200 (NF200) positive myelinated neurons in DRG. Local application of fluorocitrate (FC), a glial metabolism inhibitor, significantly decreased the number of activated SGCs and alleviated bilateral mechanical allodynia. These results suggest that SGC activation contributed to ipsilateral and mirror-image pain hypersensitivity after C8VA. Inhibition of SGC activation represented a promising therapeutic strategy for the management of neuropathic pain following brachial plexus root avulsion.
Learn More >Patients with neuropathic pain have altered proteomic and neuropeptide constituents in cerebrospinal fluid (CSF) compared to controls. Tonic spinal cord stimulation (SCS) has demonstrated differential expression of neuropeptides in CSF before and after treatment suggesting potential mechanisms of action. Burst-SCS is an evidence-based paraesthesia free waveform utilised for neuropathic pain with a potentially different mechanistic action to tonic SCS. This study examines the dynamic biological changes of CSF at a cellular and proteome level after Burst-SCS.
Learn More >The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure-activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2',6'-dimethyl-L-Tyr) moiety of [Dmt]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand-MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.
Learn More >People with type 2 diabetes (T2D) have a greater prevalence of musculoskeletal and neuropathic pain. This exploratory analysis investigated whether exercise of different intensities leads to changes in self-reported musculoskeletal pain or symptoms of diabetic neuropathy in inactive individuals with type 2 diabetes.
Learn More >Alcohol use has been associated with opioid misuse and dependence among adults with chronic pain. Yet, mechanisms underlying the relation between alcohol use problems and opioid misuse and dependence have yet to be fully explored among this population. Distress tolerance, reflecting the perceived ability to withstand negative emotional states, has demonstrated independent associations with alcohol use problems and opioid misuse, but these associations have not been explored among persons with chronic pain. The present study examined the moderating role of distress tolerance in terms of the association between alcohol use problems with opioid misuse and severity of opioid dependence. Participants included 424 adults (74.1% female; = 38.3, = 11.1) reporting current chronic pain and opioid medication use. Results indicated that alcohol use problems were significantly associated with current opioid misuse ( = 0.54, < .001) and severity of opioid dependence ( = 0.08, = .002) only for those with lower distress tolerance. These findings suggest that among individuals with chronic pain, the association between alcohol use problems and opioid misuse as well as opioid dependence severity is amplified among those with lower perceived distress tolerance. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Monoclonal antibodies (mABs) against calcitonin gene-related peptide (CGRP) or its receptor have emerged as effective and well-tolerated preventive medications for migraine. The key role played by CGRP has been recently demonstrated also in the pathophysiology of cluster headache (CH), paving the way for studies aimed to investigate the effectiveness of mABs targeting CGRP also in CH. However, no trials have been conducted so far to test the efficacy and tolerability of erenumab as CH preventive treatment.
Learn More >Chronic migraine is a neurological disorder characterized by 15 or more headache days per month of which at least 8 days show typical migraine features. The process that describes the development from episodic migraine into chronic migraine is commonly referred to as migraine transformation or chronification. Ample studies have attempted to identify factors associated with migraine transformation from different perspectives. Understanding CM as a pathological brain state with trigeminovascular participation where biological changes occur, we have completed a comprehensive review on the clinical, epidemiological, genetic, molecular, structural, functional, physiological and preclinical evidence available.
Learn More >African-American older adults, particularly those who live in economically deprived areas, are less likely to receive pain and psychotropic medications, compared to Whites. This study explored the link between social, behavioral, and health correlates of pain and psychotropic medication use in a sample of economically disadvantaged African-American older adults. This community-based study recruited 740 African-American older adults who were 55+ yeas-old in economically disadvantaged areas of South Los Angeles. Opioid-based and psychotropic medications were the outcome variables. Gender, age, living arrangement, socioeconomic status (educational attainment and financial strain), continuity of medical care, health management organization membership, sleeping disorder/insomnia, arthritis, back pain, pain severity, self-rated health, depressive symptoms, and major chronic conditions were the explanatory variables. Logistic regression was used for data analyses. Arthritis, back pain, severe pain, and poor self-rated health were associated with opioid-based medications. Pain severity and depressive symptoms were correlated with psychotropic medication. Among African-American older adults, arthritis, back pain, poor self-rated health, and severe pain increase the chance of opioid-based and psychotropic medication. Future research should test factors that can reduce inappropriate and appropriate use and prescription of opioid-based and psychotropic medication among economically disadvantaged African-American older adults.
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