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Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express , the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.
Learn More >Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aβ slowly adapting type 1 (SA1) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aβ SA1 LTMR action potentials that are transmitted to the central nervous system, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory, but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Utilizing a genetic Merkel cell knockout mouse model, we subsequently examined the importance of intact Merkel cell-Aβ complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-Aβ afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex dependent manner.Merkel discs or Merkel cell-Aβ afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-Aβ afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.
Learn More >Patients with a history of early life stress (ELS) exposure have an increased risk of developing chronic pain and mood disorders later in life. The severity of ELS in patients with urologic chronic pelvic pain syndrome (UCPPS) is directly correlated with symptom severity and increased comorbidity, and is inversely related to likelihood of improvement. Voluntary exercise improves chronic pain symptoms, and our group and others have shown that voluntary wheel running can improve outcomes in stress-induced UCPPS models, suggesting that exercise may negate some of the outcomes associated with ELS. Here, we provide further evidence that voluntary wheel running can attenuate increased perigenital mechanical sensitivity, bladder output, and mast cell degranulation in the bladder and prostate in male mice that underwent neonatal maternal separation (NMS). Sedentary male NMS mice had reduced serum corticosterone, which was not impacted by voluntary wheel running, although stress-related regulatory gene expression in the hypothalamus and hippocampus was significantly increased after exercise. Neurogenesis in the dentate gyrus of the hippocampus was diminished in sedentary NMS mice and significantly increased in both exercised naïve and NMS mice. Sucrose consumption increased in exercised naïve but not NMS mice, and anxiety behaviors measured on an elevated plus maze were increased after exercise. Together these data suggest that voluntary wheel running is sufficient to normalize many of the UCPPS-related outcomes resulting from NMS. Exercise also increased hippocampal neurogenesis and stress-related gene expression within the hypothalamic-pituitary-adrenal axis, further supporting exercise as a nonpharmacological intervention for attenuating outcomes related to ELS exposure.
Learn More >Understanding how neuronal circuits control nociceptive processing will advance the search for novel analgesics. We use functional imaging to demonstrate that lateral hypothalamic parvalbumin-positive (LH) glutamatergic neurons respond to acute thermal stimuli and a persistent inflammatory irritant. Moreover, their chemogenetic modulation alters both pain-related behavioral adaptations and the unpleasantness of a noxious stimulus. In two models of persistent pain, optogenetic activation of LH neurons or their ventrolateral periaqueductal gray area (vlPAG) axonal projections attenuates nociception, and neuroanatomical tracing reveals that LH neurons preferentially target glutamatergic over GABAergic neurons in the vlPAG. By contrast, LH projections to the lateral habenula regulate aversion but not nociception. Finally, we find that LH activation evokes additive to synergistic antinociceptive interactions with morphine and restores morphine antinociception following the development of morphine tolerance. Our findings identify LH neurons as a lateral hypothalamic cell type involved in nociception and demonstrate their potential as a target for analgesia.
Learn More >Itch is an unpleasant sensation that elicits robust scratching and aversive experience. However, the identity of the cells and neural circuits that organize this information remains elusive. Here we show the necessity and sufficiency of chloroquine-activated neurons in the central amygdala (CeA) for both itch sensation and associated aversion. Further, we show that chloroquine-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of chloroquine-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send projections to the ventral periaqueductal gray that are critical in modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice.
Learn More >A key clinical problem is identifying the endometriosis patient whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (e.g. hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cut-off in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes (CSS)) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18-50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0±7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (p's<.001) and with the CSI score (0-100) (r=.731, p<.001). ROC analysis indicated that a CSI cut-off of 40 had sensitivity 78% (95% CI: 72.7% – 84.6%) and specificity 80% (95% CI: 70.3% – 84.5%) for identifying an endometriosis patient with ≥ 3 CSS. In the group with CSI≥40, 18% retrospectively self-reported pain non-responsive to hormonal therapy and 40% self-reported daily pain, compared to 6% and 20% in the CSI<40 group (p=.003 and .002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify endometriosis patients with pain contributors related to central nervous system sensitization.
Learn More >Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels influence CPTP trajectories. 17β-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (β = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.
Learn More >To track the interplay between (micro-) structural changes along the trajectories of nociceptive pathways and its relation to the presence and intensity of neuropathic pain (NP) after spinal cord injury (SCI).
Learn More >Pain is among the most widespread chronic health condition confronting society today and our inability to manage chronic pain contributes to the opioid abuse epidemic in America. The immune system is known to contribute to acute and chronic pain, but only limited therapeutic treatments such as non-steroid anti-inflammatory drugs have resulted from this knowledge. The last decade has shed light on neuro-immune interactions mediating the development, maintenance, and resolution of chronic pain. Here, we do not aim to perform a comprehensive review of all immune mechanisms involved in chronic pain, but to briefly review the contribution of the main cytokines and immune cells (macrophages, microglia, mast cells and T cells) to chronic pain. Given the urgent need to address the Pain crisis, we provocatively propose to repurpose/reposition FDA-approved immunomodulatory drugs for their potential to alleviate chronic pain. Repositioning or repurposing offers an attractive way to accelerate the arrival of new analgesics.
Learn More >Migraine is a complex genetic brain disorder with an intricate pathogenesis and polymorphous clinical presentations, particularly in children. In this Perspective, we describe the different phenotypes of migraine in children, including conditions that have been referred to in the International Classification of Headache Disorders as "syndromes that may be related to migraine''. Evidence is presented for the integration of abdominal migraine, cyclical vomiting syndrome, benign paroxysmal vertigo, benign paroxysmal torticollis and infantile colic into the unified diagnosis of 'childhood migraine syndrome' on the basis of clinical and epidemiological characteristics, and shared inheritance. In our opinion, such integration will guide clinicians from specialities other than neurology to consider migraine in the assessment of children with these disorders, as well as stimulate research into the genetics, pathophysiology and clinical features of all disorders within the syndrome. A diagnosis of childhood migraine syndrome would also enable patients to benefit from inclusion in clinical trials of old and new migraine treatments, thus potentially increasing the number of treatment options available.
Learn More >Chronic pain in Veterans is a major problem compounded by comorbid posttraumatic stress disorder (PTSD) and depression. Adopting a transdiagnostic framework to understanding "shared territory" among these diagnoses has the potential to inform our understanding of the underlying cognitive processes and mechanisms that transverse diagnostic boundaries.
Learn More >Native Americans (NAs) experience higher rates of chronic pain than the general U.S. population, but the risk factors for this pain disparity are unknown. NAs also experience high rates of stressors and cardiovascular and metabolic health disparities (eg, diabetes, cardiovascular disease) consistent with allostatic load (stress-related wear-and-tear on homeostatic systems). Given that allostatic load is associated with chronic pain, then allostatic load may contribute to their pain disparity. Data from 302 healthy, pain-free men and women (153 NAs, 149 non-Hispanic Whites [NHW]) were analyzed using structural equation modeling to determine whether cardiometabolic allostatic load (body mass index, blood pressure, heart rate variability) mediated the relationship between NA ethnicity and experimental measures of pronociceptive processes: temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR), conditioned pain modulation of pain (CPM-pain) and NFR (CPM-NFR), and pain tolerance. Results indicated that NAs experienced greater cardiometabolic allostatic load that was related to enhanced TS-NFR and impaired CPM-NFR. Cardiometabolic allostatic load was unrelated to measures of pain perception (CPM-pain, TS-pain, pain sensitivity). This suggests cardiometabolic allostatic load may promote spinal sensitization in healthy NAs, that is not concomitant with pain sensitization, perhaps representing a unique pain risk phenotype in NAs. Perspective: Healthy, pain-free Native Americans experienced greater cardiometabolic allostatic load that was associated with a pronociceptive pain phenotype indicative of latent spinal sensitization (ie, spinal sensitization not associated with hyperalgesia). This latent spinal sensitization could represent a pain risk phenotype for this population.
Learn More >The current cross-sectional study investigates whether pain catastrophizing mediates the relationship between ethnicity/race and pain, disability and physical function in individuals with knee osteoarthritis. Furthermore, this study examined mediation at 2-year follow-up. Participants included 187 community-dwelling adults with unilateral or bilateral knee pain who screened positive for knee osteoarthritis. Participants completed several self-reported pain-related measures and pain catastrophizing subscale at baseline and 2-year follow-up. Non-Hispanic Black (NHB) adults reported greater pain, disability, and poorer functional performance compared to their non-Hispanic White (NHW) counterparts (ps<.05). NHB adults also reported greater catastrophizing compared to NHW adults. Mediation analyses revealed that catastrophizing mediated the relationship between ethnicity/race and pain outcome measures. Specifically, NHB individuals reported significantly greater pain and disability, and exhibited lower levels of physical function, compared to NHW individuals, and these differences were mediated by higher levels of catastrophizing among NHB persons. Catastrophizing was a significant predictor of pain and disability 2-years later in both ethnic/race groups. These results suggest that pain catastrophizing is an important variable to consider in efforts to reduce ethnic/race group disparities in chronic pain. The findings are discussed in light of structural/systemic factors that may contribute to greater self-reports of pain catastrophizing among NHB individuals. PERSPECTIVE: The current study examines whether pain catastrophizing mediates the relationship between ethnicity/race and OA-related pain, disability, and functional impairment at baseline and during a 2-year follow-up period in non-Hispanic Black and non-Hispanic White adults with knee pain. These results point to the need for interventions that target pain catastrophizing.
Learn More >Storytelling is a distinctive human characteristic that may have played a fundamental role in humans' ability to bond and navigate challenging social settings throughout our evolution. However, the potential impact of storytelling on regulating physiological and psychological functions has received little attention. We investigated whether listening to narratives from a storyteller can provide beneficial effects for children admitted to intensive care units. Biomarkers (oxytocin and cortisol), pain scores, and psycholinguistic associations were collected immediately before and after storytelling and an active control intervention (solving riddles that also involved social interaction but lacked the immersive narrative aspect). Compared with the control group, children in the storytelling group showed a marked increase in oxytocin combined with a decrease in cortisol in saliva after the 30-min intervention. They also reported less pain and used more positive lexical markers when describing their time in hospital. Our findings provide a psychophysiological basis for the short-term benefits of storytelling and suggest that a simple and inexpensive intervention may help alleviate the physical and psychological pain of hospitalized children on the day of the intervention.
Learn More >The present experiments determined the effects of the narrow-spectrum antibiotic vancomycin on inflammatory pain-stimulated and pain-depressed behaviors in rats. Persistent inflammatory pain was modeled using dilute formalin (0.5%). Two weeks of oral vancomycin administered in drinking water attenuated Phase II formalin pain-stimulated behavior, and prevented formalin pain-depressed wheel running. Fecal microbiota transplantation (FMT) produced a non-significant trend toward reversal of the vancomycin effect on pain-stimulated behavior. Vancomycin depleted Firmicutes and Bacteroidetes populations in the gut while having a partial sparing effect on Lactobacillus species and Clostridiales. The vancomycin treatment effect was associated with an altered profile in amino acid concentrations in the gut with increases in arginine, glycine, alanine, proline, valine, leucine, and decreases in tyrosine and methionine. These results indicate that vancomycin may have therapeutic effects against persistent inflammatory pain conditions that are distal to the gut. Perspective: The narrow-spectrum antibiotic vancomycin reduces pain-related behaviors in the formalin model of inflammatory pain. These data suggest that manipulation of the gut microbiome may be one method to attenuate inflammatory pain amplitude.
Learn More >Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention.
Learn More >Most studies investigating the course of recent-onset low back pain (LBP) included patients from primary care. We aimed to describe the prognosis in people with recent-onset LBP presenting to emergency departments (EDs) and to identify prognostic factors for non-recovery. This inception cohort study with a one-year follow-up recruited 600 consecutive acute LBP patients presenting to four EDs. The outcomes measured the days to recover from pain, recover from disability, return to previous work hours and duties, and complete recovery. Within 12 months, 73% of participants (95% CI=69 to 77) recovered from pain, 86% (95% CI=82 to 90) recovered from disability, 75% (95% CI=67 to 82) returned to previous work hours and duties, and 68% (95% CI=64 to 72) completely recovered. The median recovery times were 67 days (95% CI=54 to 80) to recover from pain, 37 days (95% CI=31 to 43) to recover from disability, 37 days (95% CI=25 to 49) to return to previous work hours and duties, and 71 days (95% CI=56 to 85) to recover completely. Higher pain levels, a higher perceived risk of persistent LBP, more days of reduced activity due to LBP, more pain sites, and higher duration of LBP were associated with complete non-recovery within six months. Perspective: This information relates to prognosis and to likely recovery times for patients with recent-onset LBP in EDs. The findings also confirm previous factors associated with poor outcomes in patients with recent-onset LBP.
Learn More >Explore predictors of improvement in headache days and migraine-related disability through a secondary analysis of the cognitive-behavioral therapy plus amitriptyline trial in children and adolescents (Clinical Trials Registration Number: NCT00389038). Participants were 135 youth aged 10-17 years old diagnosed with chronic migraine. Predictor variables included group assignment (treatment or control), baseline scores from depression and quality of life measures, and demographic variables. Criterion variables included headache days and migraine-related disability. Higher baseline depression scores were indicative of more days with headache post-treatment regardless of group assignment. Family income at the higher-end of the low-income range was significantly associated with less migraine-related disability regardless of group assignment (Household Income: HINC-01 in The United States Census Bureau. Bureau, U, 2020). Results from this secondary analysis identify depression symptoms and family income as predictors that can impact headache frequency and migraine-related disability. Self-reported symptoms of depression and family income are important factors to consider as part of the biopsychosocial model of care.
Learn More >Chronic pain and post-traumatic stress disorder (PTSD) frequently co-occur, and research suggests that these two conditions exacerbate one another producing greater impact on normal functioning in combination than separately. The influence of traumatic experiences on both pain and PTSD have been shown, but the nature of this interplay remains unclear. Although Criterion A trauma is required for the diagnosis of PTSD, whether the association between PTSD and chronic pain is dependent on Criterion A is underexplored. In this observational cohort study, we examined the association between pain and PTSD-like symptoms in the context of Criterion A trauma in 5791 men from the Vietnam Era Twin Registry. Correlations and mixed-effects regression models were used to evaluate the relationship between PTSD Checklist-Civilian Version symptoms and multiple indicators of pain from the Short Form McGill Pain Questionnaire across trauma history and chronic pain conditions. 53.21% of the participants experienced trauma consistent with DSM-IV Criterion A for PTSD. The associations between pain indicators and PTSD-like symptoms was stronger for individuals with a history of trauma but remained robust for individuals without trauma history. Small but significant interactions between past trauma and pain indicators and PTSD-like symptoms were observed. Findings were similar in a subsample of participants with history of chronic pain conditions. The relationship between PTSD-like symptoms and indicators of pain were largely independent of trauma consistent with Criterion A, highlighting the need to better understand and address stressful life events in chronic pain patients and pain concerns in individuals reporting trauma. Perspective: This article demonstrates that the relationship between PTSD-like symptoms and indicators of pain is largely independent of trauma consistent with Criterion A. This finding highlights the need to better understand and address stressful life events in chronic pain patients and pain concerns in individuals reporting trauma.
Learn More >Optimizing long-term outcomes of exposure for chronic primary pain from the lens of learning theory.
Exposure in vivo is a theory-driven and widely used treatment to tackle functional disability in people with chronic primary pain. Exposure is quite effective; yet, in line with exposure outcomes for anxiety disorders, a number of patients may not profit from it, or relapse. In this focus article, we critically reflect on the current exposure protocols in chronic primary pain, and provide recommendations on how to optimize them. We propose several adaptations that are expected to strengthen inhibitory learning and/or retrieval of the extinction memory, thus likely decreasing relapse. We summarise the limited, but emerging experimental data in the pain domain, and draw parallels with experimental evidence in the anxiety literature. Our reflections and suggestions pertain to the use of the fear hierarchy, reassurance, positive psychology interventions, exposure with a range of stimuli and within different contexts, and the use of safety behaviours during treatment, as well as associating the fear-inducing stimuli with novel outcomes. In addition, we reflect on the importance of specifically tackling (the return of) pain-related avoidance behaviour with techniques such as disentangling fear from avoidance and reinforcing approach behaviours. Finally, we discuss challenges in the clinical application of exposure to improve functioning in chronic primary pain and possible avenues for future research. Perspectives: Inspired by recent advances in learning theory and its applications on the treatment of anxiety disorders, we reflect on the delivery of exposure treatment for chronic primary pain and propose strategies to improve its long-term outcomes.
Learn More >Early life surgery produces peripheral nociceptive activation, inflammation, and stress. Early life nociceptive input and inflammation have been shown to produce long-term processing changes that are not restricted to the dermatome of injury. Additionally stress has shown long-term effects on anxiety, depression, learning, and maladaptive behaviors including substance abuse disorder and we hypothesized that early life surgery would have long-term effects on theses complex behaviors in later life. In this study surgery in the rat hindpaw was performed to determine if there are long-term effects on anxiety, depression, audiovisual attention, and opioid reward behaviors. Male animals received paw incision surgery and anesthesia or anesthesia alone (sham) at postnatal day 6. At 10 weeks after surgery, open field center zone entries were decreased, a measure of anxiety ( = 20) ( = 0.03) (effect size, Cohen's = 0.80). No difference was found in the tail suspension test as a measure of depression. At 16-20 weeks, attentional performance in an operant task was similar between groups at baseline and decreased with audiovisual distraction in both groups ( < 0.001) (effect size, η = 0.25), but distraction revealed a persistent impairment in performance in the surgery group ( = 8) ( = 0.04) (effect size, η = 0.13). Opioid reward was measured using heroin self-administration at 16-24 weeks. Heroin intake increased over time in both groups during 24-h free access ( < 0.001), but was greater in the surgery group ( = 0.045), with a significant interaction between time and treatment ( < 0.001) (effect size, Cohen = 0.36). These results demonstrate long-term disruptions in complex behaviors from surgical incision under anesthesia. Future studies to explore sex differences in early life surgery and the attendant peripheral neuronal input, stress, and inflammation will be valuable to understand emerging learning deficits, anxiety, attentional dysfunction, and opioid reward and their mechanisms. This will be valuable to develop optimal approaches to mitigate the long-term effects of surgery in early life.
Learn More >How people choose between options with differing outcomes (explore-exploit) is a central question to understanding human behaviour. However, the standard explore-exploit paradigm relies on gamified tasks with low-stake outcomes. Consequently, little is known about decision making for biologically-relevant stimuli. Here, we combined placebo and explore-exploit paradigms to examine detection and selection of the most effective treatment in a pain model. During conditioning, where 'optimal' and 'suboptimal' sham-treatments were paired with a reduction in electrical pain stimulation, participants learnt which treatment most successfully reduced pain. Modelling participant responses revealed three important findings. First, participants' choices reflected both directed and random exploration. Second, expectancy modulated pain – indicative of recursive placebo effects. Third, individual differences in terms of expectancy during conditioning predicted placebo effects during a subsequent test phase. These findings reveal directed and random exploration when the outcome is biologically-relevant. Moreover, this research shows how placebo and explore-exploit literatures can be unified.
Learn More >Cognitive impairment associated with chronic pain remains relatively poorly understood. Use of analgesic drugs and often present co-morbidities in patients can preclude conclusions of causative relationships between chronic pain and cognitive deficits. Here, the impact of pain resulting from spinal nerve ligation (SNL) injury in rats on short and long-term memory was assessed in the novel object recognition (NOR) task. To understand if chronic pain seizes the limited cognitive resources that are available at any given time, task difficulty was varied by using either very different (i.e., easy task) or similar (i.e., difficult task) pairs of objects. Nerve-injured, male rats exhibited no short or long-term memory deficits under easy task conditions. However, unlike sham-operated controls, injured rats showed deficits in both short and long-term memory by failing to differentiate similar objects in the difficult task version. In SNL rats, duloxetine produced anti-allodynic effects and ameliorated long-term memory deficits in the difficult task suggesting benefits of pain relief possibly complemented by noradrenergic mediated cognitive enhancement. Together these data suggest chronic pain reversibly takes up a significant amount of limited cognitive resources, leaving sufficient available for easy, but not difficult, tasks. PERSPECTIVE: Memory deficits in a rat model of chronic pain were only seen when the cognitive load was high, i.e., in a difficult task. Acute treatment with duloxetine was sufficient to relieve memory deficits, suggesting chronic pain induces memory deficits by seizing limited cognitive resources to the detriment of task-related stimuli.
Learn More >Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options.
Learn More >It has been hypothesised that attentional bias to environmental threats can contribute to persistent pain. It is unclear whether people with acute low back pain (LBP) have an attentional bias to environmental threats. We investigated if attentional bias of threat related words is different in people with acute LBP and pain-free controls.
Learn More >Cocaine- and Amphetamine-Regulated Transcript encodes an eponymous peptide, CARTp, which exerts diverse pharmacologic actions in the central and peripheral nervous systems, as well as in several endocrine organs, including pancreas. Here we review those diverse actions, the physiological relevance of which had remained unestablished until recently. With the identification of a CARTp receptor, GPR160, the physiologic importance and therapeutic potential of CARTp or analogs are being revealed. Not only is the CARTp-GPR160 interaction essential for the circadian regulation of appetite and thirst, but also for the transmission of nerve injury-induced pain. Molecular approaches now are uncovering additional, physiologically relevant actions and the development of acute, tissue-specific gene compromise approaches may reveal even more, physiologically relevant actions of this pluripotent ligand/receptor pair.
Learn More >Clinically, the chemotherapeutic agent oxaliplatin can cause peripheral neuropathy, impaired balance, and muscle wastage. Using a preclinical model, we investigated whether exercise intervention improved these adverse conditions.
Learn More >While there is a vast array of etiologies that may lead to chronic pruritus, recent data suggests that many of these conditions share similar interactions between keratinocytes, nerves, and the immune system. Specifically, the type 2 immune response, including Th2 T-Cells and their related cytokines, has been noted to play a major role in the development of pruritus in a variety of itchy conditions. To date, atopic dermatitis is the most striking example of this pathogenesis. However, the body of literature supporting its role in many other itchy conditions, including other inflammatory, bullous, as well as systemic diseases, continues to grow. In addition, new treatments targeting this type 2 immune system continue to be developed and investigated. In the current review, we present the current body of literature supporting the role of the type 2 immune response in itchy conditions beyond atopic dermatitis as well as potential therapeutic options that target this pathway for chronic itch.
Learn More >The molecular mechanism behind pain in degenerative disc disease (DDD) and chronic low back pain (LBP) patients is largely unknown. This present study examines the association of LBP and disability to mediators of the inflammatory cascade, as indexed by mRNA gene expression of pro-inflammatory cytokine markers in the intervertebral disc (IVD).
Learn More >Characterization of a novel human placental tissue-derived biologic, PTP-001, which is in development as a candidate therapeutic for the treatment of osteoarthritis symptoms and pathophysiology.
Learn More >Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2‒immune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.
Learn More >Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, and tyrosine kinase 2. We aimed to assess the efficacy and safety of upadacitinib compared with placebo for the treatment of moderate-to-severe atopic dermatitis.
Learn More >Headache attributed to Temporomandibular Disorder (HATMD) is a secondary headache that may have features resulting in diagnostic overlap with primary headaches, namely, tension-type (TTH) or migraine. This cross-sectional study of people with both chronic myogenous TMD and primary headaches evaluated characteristics associated with HATMD.
Learn More >Pain is a prevalent issue for elderly individuals. Unfortunately, it remains unclear how acute and chronic pain differs as a function of age, and surprisingly, there is even disagreement on how the sensory and affective dimensions of pain change with age. Therefore, the current investigation evaluated such age differences with behavioral methodology using a preclinical model of arthritis. The primary factors of interest were age and chronicity of pain using behavioral assessments designed to measure sensory and affective dimensions of pain processing. Mechanical and thermal paw withdrawal thresholds demonstrated unique outcomes associated with sensory processing across age. The processing of pain affect measured by the Place Escape/Avoidance Paradigm (PEAP testing) also demonstrated age related effects. Overall, younger animals appeared more sensitive to nociceptive stimuli than older animals. However, the results from the current study suggest that chronicity of pain can be impactful for how older animals process pain related affect and avoidance. The finding of unique patterns of pain across age and duration of pain highlights the clinical literature. Future research should aim to elucidate mechanisms for affective processing of chronic pain in older subjects.
Learn More >The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine.
Learn More >The literature on conditioned pain modulation (CPM) is inconclusive in relation to low-back pain and it is unclear how CPM affects temporal summation as a proxy of central pain integration. The aim of this study was to examine whether the CPM effect would be different on pain induced by temporal summation than single stimuli in a group of low back pain patients.
Learn More >In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects.
Learn More >Complex regional pain syndrome (CRPS) is a rare and severe chronic pain condition, with effective treatment options not established for many patients. The underlying pathophysiology remains unclear, but there is a growing appreciation for the role of central mechanisms which have formed the basis for brain-based therapies such as transcranial magnetic stimulation and mirror visual feedback (MVF). MVF has been deployed in the treatment of CRPS using both conventional mirrors and virtual reality (VR).
Learn More >: Erenumab, a monoclonal antibody targeting the receptor of calcitonin gene related peptide (CGRP), is the first disease-specific and mechanism-based treatment approved for the prevention of migraine. Although the safety and tolerability data from randomized trials are clear, the physiological effects of CGRP rise reasonable concerns. We aimed to evaluate the current evidence for safety and tolerability related to erenumab use in migraine.: This review outlines the severe adverse events (AEs), common AEs, AEs leading to treatment discontinuation and AEs of special interest, reported in all phase 2, phase 3, open label and observational studies with erenumab in migraine. Individual safety reports were also included in the systematic review of evidence.: No safety and tolerability flags were detected in this review. The most common AE are local skin reactions and constipation. No severe AEs, or frequent AEs leading to treatment discontinuation were detected. Treatment is well tolerated. The only AE of interest that may play a role in decision making and treatment monitoring is constipation. These findings are in line with previous safety reports, further highlighting the substantial tolerability and safety profile of the modern anti-CGRP monoclonal antibodies for the prevention of migraine.
Learn More >Peripheral neuropathies in HIV-infected patients are highly debilitating because of neuropathic pain and physical disabilities. We defined prevalence and associated predictive variables for peripheral neuropathy subtypes in a cohort of persons living with HIV (PWH).
Learn More >Kinesins are the motor proteins that transport excitatory receptors to the synaptic membrane by forming a complex with receptor cargo leading to central sensitization causing neuropathic pain. Many regulatory proteins govern the transit of receptors by activating kinesin, and Aurora kinases are one of them. In this study, we have performed in silico molecular dynamics simulation to delineate the dynamic interaction of Aurora kinase A with its pharmacological inhibitor, tozasertib. The results from the molecular dynamics study shows that tozasertib-Aurora kinase A complex is stabilized through hydrogen bonding, polar interactions, and water bridges. Findings from the studies suggest that tozasertib treatment significantly attenuates lipopolysaccharide (LPS)-induced increase in oxidonitrosative stress and kif11 overexpression in C6 glial cell lines. Further, we investigated the regulation of kif11 and its modulation by tozasertib in an animal model of neuropathic pain. Two weeks post-CCI surgery we observed a significant increase in pain hypersensitivity and kif11 overexpression in DRG and spinal cord of nerve-injured rats. Tozasertib treatment significantly attenuates enhanced pain hypersensitivity along with the restoration of kif11 expression in DRG and spinal cord and oxidonitrosative stress in the sciatic nerve of injured rats. Our findings demonstrate the potential role of tozasertib for the management of neuropathic pain.
Learn More >Long-term potentiation (LTP) is an important molecular mechanism for chronic pain in the anterior cingulate cortex (ACC), a key cortical region for pain perception and emotional regulation. Inhibiting ACC LTP via various manipulations or pharmacological treatments blocks chronic pain. Long-term depression (LTD) is another form of synaptic plasticity in the ACC, which is also proved to be involved in the mechanisms of chronic pain. However, less is known about the interactive relationship between LTP and LTD in the ACC. Whether the synaptic depression could be induced after synaptic LTP in the ACC is not clear. In the present study, we used multi-channel field potential recording systems to study synaptic depression after LTP in the ACC of adult mice. We found that low frequency stimulus (LFS: 1 Hz, 15 min) inhibited theta burst stimulation (TBS)-induced LTP at 30 min after the induction of LTP. However, LFS failed to induce depression at 90 min after the induction of LTP. Furthermore, NMDA receptor antagonist AP-5 blocked the induction of synaptic depression after potentiation. The GluN2B-selective antagonist Ro25-6981 also inhibited the phenomenon in the ACC, while the GluN2A-selective antagonist NVP-AAM077 and the GluN2C/D-selective antagonist PPDA and UBP145 had no any significant effect. These results suggest that synaptic LTP can be depressed by LTD in a time dependent manner, and GluN2B-containing NMDA receptors play important roles in this form of synaptic depression.
Learn More >Rimegepant is an orally administered small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, with demonstrated efficacy in the acute treatment of migraine. Recent estimates from a single-arm trial (BHV3000-201) have also shown evidence of long-term preventive effects in monthly migraine days (MMDs) and health-related quality of life (HRQoL). This study aimed to compare MMDs and HRQoL data for oral rimegepant to those obtained in placebo-controlled trials for injectable anti-CGRP monoclonal antibodies (mAbs) galcanezumab and erenumab.
Learn More >Physiotherapy informed by Acceptance and Commitment Therapy (PACT) is a novel intervention that is related to improved disability and functioning in people with chronic lowback pain. This study explored physiotherapists experiences over time of the PACT training programme and intervention delivery.
Learn More >Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KEY MESSAGES: • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain.
Learn More >This study aimed to explore whether preoperative angiotensin II type 2 receptor (ATR) level in knee osteoarthritis (OA) patients was an independent risk factor for chronic post-surgical pain (CPSP) after total knee arthroplasty (TKA).
Learn More >The Pain Catastrophizing Scale (PCS), a widely used tool to assess catastrophizing related to spinal disorders, shows valid psychometric properties in general but the minimal important change (MIC) is still not determined.
Learn More >Central sensitization (CS) is defined as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS has been proposed as an underlying mechanism of chronic pain in musculoskeletal disorders including low back pain (LBP). A Central Sensitization Inventory (CSI) has recently been developed for screening participants with CS. However, the association of CS with chronic LBP (cLBP) in the general population remains unknown. The purpose of this study was to investigate the association of CS with cLBP using the CSI in a population-based cohort of a Japanese mountain village.
Learn More >In a previous proof-of-concept study we have demonstrated that visual exposure to specific colors results in pruritic or antipruritic effects.
Learn More >Postoperative pain has a major influence on older adults' rehabilitation. There is a lack of knowledge regarding how older adults return to daily living after discharge.
Learn More >Evaluate the Impact Stratification Score (ISS) measure of low back pain impact that assesses physical function, pain interference, and pain intensity.
Learn More >We sought to investigate the patient experience of telemedicine for headache care during the coronavirus disease 2019 (COVID-19) pandemic.
Learn More >Purpose Chronic musculoskeletal pain can have a major impact on ability to work. The work ability score is a commonly used single-item question to assess work ability but has not been fully validated yet. The aim of the present study was to evaluate test-retest reliability, agreement, construct validity, and responsiveness of the work ability score among sick-listed workers with chronic musculoskeletal pain. Methods Data of sick-listed workers with chronic musculoskeletal pain was routinely collected at seven rehabilitation centres in the Netherlands. Assessments included a set of questionnaires, administered at admission and discharge from a fifteen-week vocational rehabilitation program. Test-retest reliability was determined with the intraclass correlation coefficient. For agreement, the standard error of measurement and smallest detectable changes were calculated. Construct validity was assessed by testing hypotheses regarding Spearman rank correlation coefficient. Area under the curve obtained from the receiver operating characteristic curve and minimal clinically important change were determined for the total sample and work ability score baseline tertile groups to assess responsiveness. Results In total, 34 workers were analyzed for reliability and agreement, 1291 workers for construct validity, and 590 responded to the responsiveness questionnaire. Reliability reached an intraclass correlation coefficient of 0.89; 95% CI 0.77-0.94, a standard error of measurement of 0.69 points, and the smallest detectable change of 1.92 points. For construct validity, six of the seven predefined hypotheses were not refuted. The area under the curve was 0.76 (95% CI 0.71-0.81) allowing for discrimination between stable and improved workers, with a minimal clinically important change of 2.0 points for the total sample. Conclusion The work ability score showed good measurement properties among sick-listed workers with chronic musculoskeletal pain.
Learn More >Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.
Learn More >Surgery is a risk factor for chronic pain and long-term opioid use. As perioperative pain management continues to evolve, treatment modalities traditionally used for chronic pain therapy may provide additional benefit to patients undergoing surgery. Interventions such as radiofrequency ablation, cryoneurolysis, and neuromodulation may potentially be used in conjunction with acute pain procedures such as nerve blocks and multimodal analgesia. Pharmacological agents associated with chronic pain medicine, including gabapentinoids, ketamine, and selective serotonin reuptake inhibitors, may be useful adjuncts in perioperative pain management when indicated. There may also be a role for acupuncture, music therapy, and other integrative medicine therapies. A transitional pain service can help coordinate outpatient care with inpatient perioperative pain management and promote a more personalized and comprehensive approach that can improve postoperative outcomes.
Learn More >Post-traumatic trigeminal neuropathy (PTN) can have a substantial effect on patient well-being. However, the relation between the neuropathic symptoms and their effect on psychosocial functioning remains a matter of debate. The purpose of this study was to evaluate the association between objective and subjective assessments of neurosensory function in PTN and predict neurosensory outcome using baseline measurements.
Learn More >Opioids play an important role in pain relief, but repeated exposure results in tolerance and dependence. To make opioids more effective and useful, research in the field has focused on reducing the tolerance and dependence for chronic pain relief. Here, we showed the effect of ABIN-1 in modulating morphine function. We used hotplate tests and CPP tests to show that overexpression of ABIN-1 in the mice brain attenuated morphine dependence. These effects of ABIN-1 are most likely mediated through the formation of ABIN-1-β-arrestin2 complexes, which accelerate β-arrestin2 degradation by ubiquitination. With the degradation of β-arrestin2, ABIN-1 overexpression also decreased MOR phosphorylation and internalization following opioid treatment, affecting the β-arrestin2-dependent signaling pathway to regulate morphine tolerance. Importantly, the effect of ABIN-1 on morphine tolerance was abolished in β-arrestin2 knockout mice. Taken together, these results suggest that the interaction between ABIN-1 and β-arrestin2 inhibits MOR internalization to attenuate morphine tolerance, revealing a novel mechanism for MOR regulation. Hence, ABIN-1 may be a therapeutic target to regulate MOR internalization, thus providing a foundation for a novel treatment strategy for alleviating morphine tolerance and dependence. ABIN-1 overexpression in mice brain attenuated morphine tolerance and dependence. The mechanism may be that ABIN-1-β-arrestin-2 complex formation facilitated β-arrestin-2 degradation by ubiquitination. ABIN-1 targeted β-arrestin2 to regulate morphine tolerance Therefore, inhibiting of ABIN-1 is an important strategy to prevent morphine tolerance and dependence.
Learn More >Despite several hundred previous randomised controlled trials (RCTs), the key treatment targets of exercise for persistent non-specific low back pain (NSLBP) remain unclear. This study aimed to generate consensus about the key treatment targets of exercise interventions for patients with NSLBP.
Learn More >Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells of mesodermal origin. Due to their capacity for self-renewal and differentiation into several cell types, MSCs have been extensively studied in experimental biology and regenerative medicine in recent years. Moreover, MSCs release extracellular vesicles (EVs), which might be partially responsible for their regenerative properties. MSCs regulate several processes in target cells via paracrine signalling, such as immunomodulation, antiapoptotic signalling, tissue remodelling, angiogenesis, and antifibrotic signalling. The aim of this review is to provide a detailed description of the functional properties of MSCs and EVs and their potential clinical applications, with a special focus on pain treatment. The analgesic, anti-inflammatory and regenerative properties of MSCs and EVs will be discussed for several diseases, such as neuropathic pain, osteoarthritis and spinal cord injury.
Learn More >Atopic dermatitis (AD) is among the most frequent inflammatory skin diseases in humans, affecting up to 20% of children and 10% of adults in higher income countries. Chronic pruritus is a disease-defining symptom of AD, representing the most burdensome symptom for patients. Severe chronic pruritus causes significant sleep disturbances and impaired quality of life, as well as increased anxiety, depression and suicidal behavior. Until recently, skin care, topical corticosteroids, and calcineurin-inhibitors were primarily used to treat mild to moderate AD, while phototherapy and immunosuppressive agents such as corticosteroids, cyclosporine, and methotrexate were used to treat patients with moderate to severe AD. The potential short- and long-term adverse events associated with these treatments or their insufficient therapeutic efficacy limited their use in controlling pruritus and eczema in AD patients over longer periods of time. As our understanding of AD pathophysiology has improved and new systemic and topical treatments have appeared on the market, targeting specific cytokines, receptors, or their intracellular signaling, a new era in atopic dermatitis and pruritus therapy has begun. This review highlights new developments in AD treatment, placing a specific focus on their anti-pruritic effects.
Learn More >Individuals with chronic pain often experience co-existing sleep problems and depression-related states. Chronic pain, sleep problems, and depression interrelate, and have been shown to exacerbate one another, which negatively impacts quality of life. This study explored the relationships between pain severity, pain interference, sleep quality, and depression among individuals with chronic pain. Secondly, we tested whether sleep quality may moderate the relationship between pain and depression. A cross-sectional survey was completed by 1,059 adults with non-malignant chronic pain conditions ( 43 years, 88% identified as women) and collected measures related to pain severity, pain interference, sleep quality, and depression. Multiple regression analyses found that pain severity, pain interference, and sleep quality are all significantly associated with depression. Secondly, moderated regression analyses revealed that sleep quality moderates the relationship between pain interference and depression among individuals with chronic pain such that good sleep quality attenuates the effect of pain interference on depression, and poor sleep quality amplifies the effect of pain interference on depression. These findings suggest that sleep quality may be a relevant therapeutic target for individuals with chronic pain and co-existing depression.
Learn More >Changes in inflammatory cytokine levels contribute to the induction and maintenance of neuropathic pain. We have shown that external low intensity focused ultrasound (liFUS) reduces allodynia in a common peroneal nerve injury (CPNI). Here, we investigate an underlying mechanism of action for this treatment and measure the effect of liFUS on inflammatory markers.
Learn More >A novel computational technique for the quantification of temporal summation in healthy individuals.
The pathophysiology of chronic musculoskeletal pain is linked to the neurophysiologic condition known as central sensitization. Developing reliable, sensitive and clinically feasible techniques for quantifying central sensitization is a timely priority for advancing the field of chronic pain diagnosis and management.
Learn More >In rheumatology, chronic pain most often sets in after a musculoskeletal injury. Its persistence is not always due to the progression of the initial injury, but in some cases to the onset of central sensitization. Much scientific data suggests that this central sensitization is caused by multiple complex interactions between the nervous system and immune system. Afferent nerve fibers carrying pain information are responsible for peripheral sensitization partly linked to inflammation molecules. These afferent fibers release neurotransmitters in the dorsal root ganglion and dorsal horn of the spinal cord, capable of activating microglia, which are the local immune cells. The activated microglia will produce pro-inflammatory cytokines, chemokines and neuropeptides capable of interacting with the second-order neuron, but also segmental and descending inhibitory neurons. This is referred to as neuroinflammation, which will amplify the hypersensitivity of second-order neurons, otherwise called central sensitization. This neuroinflammation will be able to reach the higher brain structures, which are involved in pain modulation and the emotional and cognitive aspects of pain. The aim of this update is to describe the pathophysiology of chronic pain, incorporating the latest scientific data on neuroplasticity and neuroinflammation.
Learn More >The current study introduces a new paradigm for exploring cognitive factors in pain. Interacting with virtual objects via embodied avatar hands increased the illusion of "being there" in the virtual world, increased VR analgesia for acute pain, and reduced accuracy on an attention demanding task. Twenty-four healthy volunteer college students participated in this within-subject randomized crossover design study. During Phase 1, each participant received brief thermal pain stimuli during interactive embodied avatar VR vs. passive VR (no avatar and no interactivity), VR treatment order randomized. After each pain stimulus, participants provided subjective 0-10 ratings of pain. Compared to the passive VR condition, during the interactive avatar VR, participants reported significant reductions in (1) worst pain, (2) pain unpleasantness, (3) time thinking about pain and (4). they had significantly more fun during the pain stimulus (p = .000 for each). During Phase 2, participants performed a divided attention task in each of the two VR conditions. Participants made significantly more errors on the divided attention task during the interactive avatar VR condition, compared to passive VR, implicating an attention mechanism for how virtual reality reduces pain and helping understand how VR influences pain perception.Trial registration: NCT04245475. Date of registration: 29/01/2020.
Learn More >Migraine is a common neurological disease that is often accompanied by psychiatric comorbidities. However, the relationship between abnormal brain function and psychiatric comorbidities in migraine patients remains largely unclear. Therefore, the present study sought to explore the correlations between the resting-state functional deficits and psychiatric comorbidities in migraine without aura (MwoA) patients.
Learn More >Application of spatially interlaced innocuous warm and cool stimuli to the skin elicits illusory pain, known as the thermal grill illusion (TGI). This study aimed to discriminate the underlying mechanisms of central and peripheral neuropathic pain focusing on pain quality, which is considered to indicate the underlying mechanism(s) of pain. We compared pain qualities in central and peripheral neuropathic pain with reference to pain qualities of TGI-induced pain.
Learn More >σ-1 receptors (σR) modulate nociceptive signaling, driving the search for selective antagonists to take advantage of this promising target to treat pain. In this study, a new series of benzylpiperazinyl derivatives has been designed, synthesized, and characterized for their affinities toward σR and selectivity over the σ-2 receptor (σR). Notably, 3-cyclohexyl-1-{4-[(4-methoxyphenyl)methyl]piperazin-1-yl}propan-1-one () showed the highest σR receptor affinity ( σ = 1.6 nM) among the series with a significant improvement of the σR selectivity ( σ/ σ 886) compared to the lead compound ( σ/ σ 432). Compound was further tested in a mouse formalin assay of inflammatory pain and chronic nerve constriction injury (CCI) of neuropathic pain, where it produced dose-dependent (3-60 mg/kg, i.p.) antinociception and anti-allodynic effects. Moreover, compound demonstrated no significant effects in a rotarod assay, suggesting that this σR antagonist did not produce sedation or impair locomotor responses. Overall, these results encourage the further development of our benzylpiperazine-based σR antagonists as potential therapeutics for chronic pain.
Learn More >Novel antibodies to trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3) have been recently described in otherwise cryptogenic small fiber neuropathy (SFN) cases. Our goal was to further describe clinical features in such cases and to analyze treatment responses.
Learn More >This report investigates the impact of a remote physical activity intervention on self-efficacy, satisfaction with functioning, and health-related quality of life (HRQOL) as assessed by the SF-36 in obese older adults with chronic pain. The intervention was group-mediated in nature and based in social cognitive theory and mindfulness-based relapse prevention.
Learn More >The anterior cingulate cortex (ACC) has been extensively implicated in the functional brain network underlying chronic pain. Electrical stimulation of the ACC has been proposed as a therapy for refractory chronic pain, although, mechanisms of therapeutic action are still unclear. As stimulation of the ACC has been reported to produce many different behavioral and perceptual responses, this region likely plays a varied role in sensory and emotional integration as well as modulating internally generated perceptual states. In this case series, we report the emergence of subjective musical hallucinations (MH) after electrical stimulation of the ACC in two patients with refractory chronic pain. In an N-of-1 analysis from one patient, we identified neural activity (local field potentials) that distinguish MH from both the non-MH condition and during a task involving music listening. Music hallucinations were associated with reduced alpha band activity and increased gamma band activity in the ACC. Listening to similar music was associated with different changes in ACC alpha and gamma power, extending prior results that internally generated perceptual phenomena are supported by circuits in the ACC. We discuss these findings in the context of phantom perceptual phenomena and posit a framework whereby chronic pain may be interpreted as a persistent internally generated percept.
Learn More >The purpose of this study was to determine predictors of pain severity among older United States (US) adults with pain.This cross-sectional, retrospective study utilized 2017 Medical Expenditure Panel Survey data. Eligible participants were alive for the calendar year, aged ≥50 years, and reported pain in the past 4 weeks. Hierarchical logistic regression models, adjusting for the survey design, were used to identify significant predictors of pain severity (i.e., extreme/quite a bit or moderate/little pain).An estimated 14,250,534 adults aged ≥50 with pain reported extreme/quite a bit of pain. Many variables were associated with extreme/quite a bit of pain, including: age 50 to 64 vs ≥65 years (adjusted odds ratio [AOR] = 1.49, 95% confidence interval [95% CI] = 1.22-1.82); males vs females (AOR = 0.80, 95% CI = 0.67-0.95); white race vs others (AOR = 0.75, 95% CI = 0.61-0.92); married vs other marital status (AOR = 1.31, 95% CI = 1.08-1.57); income <200% vs ≥200% federal poverty level (AOR = 1.30, 95% CI = 1.06-1.60); employed vs unemployed (AOR = 0.47, 95% CI = 0.37-0.60); limitation vs no limitation (AOR = 2.64, 95% CI = 2.09-3.33); 0, 1, 3, or 4 vs ≥5 chronic conditions (AOR ranged from 0.39 for 0 conditions to 0.77 for 4 conditions); excellent/very good or good vs fair/poor perceived physical health status (AOR ranged from 0.28 for excellent/very good to 0.40 for good); smokers vs non-smokers (AOR = 1.56, 95% CI = 1.27-1.93); exercise versus no exercise (AOR = 0.74, 95% CI = 0.62-0.88); and South vs West census region (AOR = 1.34, 95% CI = 1.04-1.74).This study found several characteristics could predict pain severity among older US adults who reported extreme/quite a bit of pain. These characteristics may guide specific areas of focus to improve patients' pain management.
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