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The dorsal medial prefrontal cortex (dmPFC) has been recognized as a key cortical area for nociceptive modulation. However, the underlying neural pathway and the function of specific cell types remain largely unclear. Here, we showed that lesions of the dmPFC induced an algesic and anxious state. By using multiple tracing methods including rabies-based transsynaptic tracing method, an excitatory descending neural pathway from the dmPFC to the ventrolateral periaqueductal gray (vlPAG) was outlined. Specific activation of the dmPFC-vlPAG neural pathway by an optogenetic manipulation, produced analgesic and anxiolytic effects in a chronic pain mice model. Inhibitory neurons in the dmPFC were specifically activated by using a chemogenetic approach, which logically produced an algesic and anxious state under both normal and chronic pain conditions. Antagonists of GABAAR or mGluR1 were applied to the dmPFC, which produced analgesic and anxiolytic effects. In summary, the present results suggest that the dmPFC-vlPAG neural pathway might participate in the maintenance of pain thresholds and anxiolytic behaviors under normal conditions, while silencing or suppressing the dmPFC-vlPAG pathway might be involved in the initial stages and maintenance of chronic pain and the emergence of anxiety-like behaviors.
Learn More >Sensory neurons are activated by physical and chemical stimuli, eliciting sensations such as temperature, touch, pain, and itch. From an evolutionary perspective, sensing danger is essential for organismal survival. Upon infection and injury, immune cells respond to pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), and produce inflammatory mediators that activate sensory neurons through neuro-immune interactions. Sensory neurons also express TLRs and other PRRs that directly sense danger signals after injury or during infection, leading to pain, itch, or analgesia. In addition to slow-acting canonical TLR signaling, TLRs function uniquely in sensory neurons through non-canonical coupling to ion channels, enabling rapid modulation of neuronal activity. We discuss how sensory neurons utilize TLRs and other PRR pathways to detect danger signals in their environment.
Learn More >Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy. The underlying mechanisms are not well understood. In this study, we investigated whether voltage-gated sodium channels are involved in the development of vincristine-induced neuropathy. We established a mouse model in which repeated systemic vincristine treatment results in the development of significant mechanical allodynia. Histological examinations did not reveal major structural changes at proximal sciatic nerve branches or distal toe nerve fascicles at the vincristine dose used in this study. Immunohistochemical studies and in vivo two-photon imaging confirmed that there is no significant change in density or morphology of intra-epidermal nerve terminals throughout the course of vincristine treatment. These observations suggest that nerve degeneration is not a prerequisite of vincristine-induced mechanical allodynia in this model. We also provided the first detailed characterization of tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) sodium currents in dorsal root ganglion neurons following vincristine treatment. Accompanying the behavioural hyperalgesia phenotype, voltage-clamp recordings of small and medium dorsal root ganglion neurons from vincristine-treated animals revealed a significant upregulation of TTX-S Na+ current in medium but not small neurons. The increase in TTX-S Na+ current density is likely mediated by Nav1.6, because in the absence of Nav1.6 channels, vincristine failed to alter TTX-S Na+ current density in medium dorsal root ganglion neurons and, importantly, mechanical allodynia was significantly attenuated in conditional Nav1.6 knockout mice. Our data show that TTX-S sodium channel Nav1.6 is involved in the functional changes of dorsal root ganglion neurons following vincristine treatment and it contributes to the maintenance of vincristine-induced mechanical allodynia.
Learn More >SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste and chemesthesis – loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, ACE2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors (SCARFs) are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free-nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.
Learn More >Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various and models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.
Learn More >The aim of the current study was to identify typical alterations in resting state connectivity within different stages of the migraine cycle and to thus explore task-free mechanisms of headache attack generation in migraineurs.
Learn More >Small fiber pathology is increasingly recognized as a potential contributor to neuropathic pain in different clinical syndromes, however, the underlying mechanisms leading to nociceptor sensitization and degeneration are unclear. With the diversity in clinical pain phenotypes and etiology of small fiber pathology, individual mechanisms are assumed, but are not yet fully understood. The thinly-myelinated Aδ- and unmyelinated C-nerve fibers are mainly affected and clinically require special small fiber test methods to capture functional, morphological, and electrophysiological alterations. Several methods have been established and implemented in clinical practice in the last years. In parallel, experimental and in vitro test systems have been developed allowing important insights into the molecular mechanisms underlying nociceptor sensitization and degeneration as main hallmarks of small fiber pathology. In our narrative review we focus on these methods and current knowledge, and provide a synopsis of the achievements made so far in this exciting field.
Learn More >A hyperexcitable state and spontaneous activity of nociceptors have been suggested to play a critical role in the development of chronic neuropathic pain following spinal cord injury (SCI). In male rats, we employed the action potential clamp technique to determine the underlying ionic mechanisms responsible for driving SCI-nociceptors to a hyperexcitable state and for triggering their spontaneous activity. We found that the increased activity of low voltage activated T-type calcium channels induced by the injury sustains the bulk (∼60-70%) of the inward current active at subthreshold voltages during the interspike interval in SCI-nociceptors, with a modest contribution (∼10-15%) from tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels and HCN channels. In current clamp recordings, inhibition of T-type calcium channels with 1 μM TTA-P2 reduced both the spontaneous and the evoked firing in response to current injections in SCI-nociceptors to a level similar to sham-nociceptors. Electrophysiology was then combined with the conditioned place preference (CPP) paradigm to determine the relationship between the increased activity of T-type channels in SCI-nociceptors and chronic neuropathic pain following SCI. The size of the interspike T-type calcium current recorded from nociceptors isolated from SCI rats showing TTA-P2-induced CPP (responders) was ∼6 fold greater than the interspike T-type calcium current recorded from nociceptors isolated from SCI rats without TTA-P2-induced CPP (non-responders). Taken together, our data suggest that the increased activity of T-type calcium channels induced by the injury plays a primary role in driving SCI-nociceptors to a hyperexcitable state and contributes to chronic neuropathic pain following SCI.Chronic neuropathic pain is a major comorbidity of SCI, affecting up to 70-80% of patients. Anticonvulsant and tricyclic antidepressant drugs are first line analgesics used to treat SCI-induced neuropathic pain, but their efficacy is very limited. A hyperexcitable state and spontaneous activity of SCI-nociceptors have been proposed as a possible underlying cause for the development of chronic neuropathic pain following SCI. Here we show that the increased activity of T-type calcium channels induced by the injury plays a major role in driving SCI-nociceptors to a hyperexcitable state and for promoting their spontaneous activity, suggesting that T-type calcium channels may represent a pharmacological target to treat SCI-induced neuropathic pain.
Learn More >Diabetic polyneuropathy (DPN) is a common complication to diabetes and is often associated with neuropathic pain. The mechanisms underlying development and maintenance of painful DPN are largely unknown and quantification of intraepidermal nerve fiber density (IENFD) from skin biopsy, one of the neuropathological gold standard when diagnosing DPN, does not differentiate between patients with and without pain. Identification of possible pain pathophysiological biomarkers in patients with painful DPN may increase our knowledge of mechanisms behind neuropathic pain. Animal models of painful DPN have been shown to have an increased density of peptidergic nerve fibers (Substance P (SP) and Calcitonin-gene related peptide (CGRP)). In this study we performed a detailed skin biopsy analysis in a well-characterized group of DPN patients with primarily small fiber involvement, with and without pain and in healthy controls and test for correlation between skin biopsy findings and pain intensity and quantitative sensory testing (QST). We found that while there was no difference in IENFD using PGP 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing SP and CGRP compared to patients with painless DPN and healthy controls. Peptidergic nerve fiber density correlated with pain ratings in patients with pain (R=0.33; p=0.019) but not with QST results. Here we show, for the first time in humans, an increased density of dermal peptidergic fibers in painful DPN. These findings provide new insight in the pathophysiological mechanisms of pain in diabetes and opens the research towards new therapeutic targets.
Learn More >Deep brain stimulation (DBS) is a treatment alternative for refractory chronic Cluster headache (CCH). Despite several recent prospective case series reporting on good outcome, the effectiveness and the optimal stimulation target of DBS for CCH remain unclear. We aimed to obtain precise estimates and predictors of long-term pain relief in an individual patient data meta-analysis. Further, we aimed to construct a probabilistic stimulation map of effective DBS.
Learn More >This systematic review and meta-analysis aimed to evaluate the evidence pertaining to attentional bias for painful and non-painful somatosensory stimuli in individuals with chronic pain. Eligible studies were identified via searches of Medline, PsycINFO, CINAHL, Web of Science, Scopus, and Cochrane Library databases. Search terms were words and phrases organised into three concept blocks: pain condition, cognitive process and stimuli/paradigm. The search identified 29 eligible studies (reporting 32 eligible experiments), of which quantitative meta-analysis was possible for 16 studies (19 experiments). The meta-analysis found that chronic pain patients, excluding somatoform pain patients, showed significantly greater attentional bias to stimuli in the somatosensory modality than healthy controls (k = 9, g = 0.34). Additionally, meta-analysis of studies that used a temporal order judgement task found that patients with unilateral chronic pain showed a spatial attentional bias away from somatosensory stimuli (k = 7, effect estimate = 22.43 milliseconds) and visual stimuli (k = 2, effect estimate = 13.75 milliseconds) on or near the painful body side. Most studies of attentional bias to the somatosensory modality recruited samples of patients with fibromyalgia whereas most studies of spatial attentional bias assessed patients with complex regional pain syndrome. The extent to which these results generalise to other pain conditions is therefore unclear. We recommend future research test spatial and modality attentional biases across chronic pain conditions and examine the psychometric properties of attentional bias measurement paradigms for use with chronic pain populations. PROSPERO registration number CRD42019124510.
Learn More >Chronic pain is a serious debilitating condition that affects ∼20% of the world's population. Currently available drugs fail to produce effective pain relief in many patients and have dose-limiting side effects. Several voltage-gated sodium (NaV) and calcium (CaV) channels are implicated in the etiology of chronic pain, particularly NaV1.1, NaV1.3, NaV1.7-NaV1.9, CaV2.2 and CaV3.2. Numerous NaV and CaV modulators have been described, but with few exceptions, they display poor potency and/or selectivity for pain-related channel subtypes. Here we report the discovery and characterization of two novel tarantula-venom peptides (Tap1a and Tap2a) isolated from Theraphosa apophysis venom that modulate the activity of both NaV and CaV3 channels. Tap1a and Tap2a inhibited on-target NaV and CaV3 channels at nanomolar to micromolar concentrations and displayed moderate off-target selectivity for NaV1.6 and weak affinity for NaV1.4 and NaV1.5. The most potent inhibitor, Tap1a, nearly ablated neuronal mechanosensitivity in afferent fibers innervating the colon and the bladder, with in vivo intracolonic administration reversing colonic mechanical hypersensitivity in a mouse model of irritable bowel syndrome. These findings suggest that targeting a specific combination of NaV and CaV3 subtypes provides a novel route for treatment of chronic visceral pain.
Learn More >Chronic pain (CP) was associated with impaired cognitive performance in several cross-sectional studies conducted in older adults; however, fewer longitudinal studies assessed this link which remains still debated. With a prospective design, the present analysis was aimed at evaluating the relationship between CP and the change in several tests assessing memory, attention, verbal fluency and processing speed. The study population was selected from the PAQUID study, a cohort of community dwellers aged 65 and over; 693 subjects receiving a pain assessment were included. CP was evaluated using a questionnaire administered at 3-year follow-up. Cognitive performances were assessed every 2-3 years between 3 and 15 years assessing general cognition (MMSE), verbal and visual memory (word paired associate test and Benton test) attention and speed processing (Wechsler DSST, Zazzo's cancellation task) language skills and executive functions (Isaacs set test). The link between CP and the change in cognitive function was assessed with latent process mixed models controlled for age, gender, education, comorbidities, depression and analgesic drugs. The association between CP and each of the cognitive scores was then tested with the same procedure. A significant relationship was observed between CP and poorer 15-year scores on global cognitive performance (p=0.004), and specifically DSST (p=0.002) associated with a higher slope of decline (p=0.02). CP is associated with higher cognitive decline, in particular in processing speed. This result reinforces the importance of actively treating CP with pharmacological and non-pharmacological strategies to prevent its consequences, including cognitive consequences.
Learn More >Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.
Learn More >Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (e.g. conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experiment sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. Additionally, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations and placebo response emphasizing the need to consider sex as a biological variable when placebo outcomes are parts of drug development trials and in pain management.
Learn More >Atogepant is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist under investigation for treatment of migraine. We aimed to examine a range of oral doses for safety, tolerability, and efficacy for the preventive treatment of migraine.
Learn More >Frequent exposure to patient distress is associated with higher prevalence of clinician distress and symptoms of burnout. Patients with chronic pain often present with high levels of emotional distress. The current study examined the prevalence of burnout symptoms among a multidisciplinary sample of pain clinicians in Australia, the relationship between clinician confidence managing emotions and symptoms of burnout, and clinicians' perspectives on sources of stress and wellbeing at work. One hundred and seventy-six clinicians from 58 multidisciplinary pain clinics across Australia completed a survey including the 22-item Maslach Burnout Inventory, a measure of clinician confidence managing patient emotions and their own emotions, and open-ended questions probing clinician perspectives on sources of stress and wellbeing at work. High levels of emotional exhaustion and depersonalisation were reported by 21.6% and 14.2% of respondents, respectively. These burnout symptoms were predicted by clinician confidence managing their own emotions. Low levels of personal accomplishment were reported by 18.8% of respondents and were predicted by clinician confidence managing patients' emotions. Consistent with these quantitative findings, qualitative data revealed that emotionally challenging patient encounters were common sources of stress. Working with a multidisciplinary team and supportive relationships with colleagues were commonly reported sources of clinician wellbeing. The results of this study are discussed in light of previous reports of burnout in pain medicine physicians. Implications for clinician training in pain management and the prevention of burnout in pain clinicians are discussed.
Learn More >Chronic pain is often comorbid with anxiety and depression, altering the level of perceived pain, which negatively affects therapeutic outcomes. The role of the endogenous mu-opioid receptor (MOP) system in pain-negative affect interactions and the influence of genetic background thereon is poorly understood. The inbred Wistar-Kyoto (WKY) rat, which mimics aspects of anxiety and depression, displays increased sensitivity (hyperalgesia) to noxious stimuli, compared to Sprague-Dawley (SD) rats. Here, we report that WKY rats are hyporesponsive to the antinociceptive effects of systemically administered MOP agonist morphine in the hot plate and formalin tests, compared to SD counterparts. Equivalent plasma morphine levels in the two rat strains suggested that these differences in morphine sensitivity were unlikely to be due to strain-related differences in morphine pharmacokinetics. Although MOP expression in the ventrolateral periaqueductal grey (vlPAG) did not differ between WKY and SD rats, the vlPAG was identified as a key locus for the hyporesponsivity to MOP agonism in WKY rats in the formalin test. Moreover, morphine-induced effects on c-Fos (a marker of neuronal activity) in regions downstream of vlPAG, namely the rostral ventromedial medulla and lumbar spinal dorsal horn, were blunted in the WKY rats. Together, these findings suggest that a deficit in MOP-induced recruitment of the descending inhibitory pain pathway may underlie hyperalgesia to noxious inflammatory pain in the WKY rat strain genetically predisposed to negative affect.
Learn More >The purpose of our work was to determine the role of non-opioid peptides derived from opioid prohormones in sensory hypersensitivity characteristics of neuropathic pain and to propose a pharmacological approach to restore the balance of these endogenous opioid systems. Non-opioid peptides may have a pronociceptive effect and therefore contribute to less effective opioid analgesia in neuropathic pain. In our study, we used unilateral chronic constriction injury (CCI) of the sciatic nerve as a neuropathic pain model in rats. We demonstrated the pronociceptive effects of proopiomelanocortin (POMC)- and proenkephalin (PENK)-derived non-opioid peptides assessed by von Frey and cold plate tests, 7-14 days after injury. The concentration of PENK-derived pronociceptive peptides was increased more robustly than that of Met-enkephalin in the ipsilateral lumbar spinal cord of CCI-exposed rats, as shown by mass spectrometry, and the pronociceptive effect of one of these peptides was blocked by an antagonist of the melanocortin 4 (MC4) receptor. The above results confirm our hypothesis regarding the possibility of creating an analgesic drug for neuropathic pain based on enhancing opioid activity and blocking the pronociceptive effect of non-opioid peptides. We designed and synthesized bifunctional hybrids composed of opioid (OP) receptor agonist and MC4 receptor antagonist (OP-linker-MC4). Moreover, we demonstrated that they have potent and long-lasting antinociceptive effects after a single administration and a delayed development of tolerance compared to morphine after repeated intrathecal administration to rats subjected to CCI. We conclude that the bifunctional hybrids OP-linker-MC4 we propose are important prototypes of drugs for use in neuropathic pain.
Learn More >Mutations in the genes encoding for voltage-gated sodium channels cause profound sensory disturbances and other symptoms dependent on the distribution of a particular channel subtype in different organs. Humans with the gain-of-function mutation p.Leu811Pro in SCN11A (encoding for the voltage-gated Nav1.9 channel) exhibit congenital insensitivity to pain, pruritus, self-inflicted injuries, slow healing wounds, muscle weakness, Charcot-like arthropathies, and intestinal dysmotility. As already shown, knock-in mice (Scn11a+/L799P) carrying the orthologous mutation p.Leu799Pro replicate reduced pain sensitivity and show frequent tissue lesions. In the present study we explored whether Scn11a+/L799P mice develop also pruritus, muscle weakness, and changes in gastrointestinal transit time. Furthermore, we analyzed morphological and functional differences in nerves, skeletal muscle, joints and small intestine from Scn11a+/L799P and Scn11a+/+ wild type mice. Compared to Scn11a+/+ mice, Scn11a+/L799P mice showed enhanced scratching bouts before skin lesions developed, indicating pruritus. Scn11a+/L799P mice exhibited reduced grip strength, but no disturbances in motor coordination. Skeletal muscle fiber types and joint architecture were unaltered in Scn11a+/L799P mice. Their gastrointestinal transit time was unaltered. The small intestine from Scn11a+/L799P showed a small shift towards less frequent peristaltic movements. Similar proportions of lumbar dorsal root ganglion neurons from Scn11a+/L799P and Scn11a+/+ mice were calcitonin gene-related peptide (CGRP-) positive, but isolated sciatic nerves from Scn11a+/L799P mice exhibited a significant reduction of the capsaicin-evoked release of CGRP indicating reduced neurogenic inflammation. These data indicate important Nav1.9 channel functions in several organs in both humans and mice. They support the pathophysiological relevance of increased basal activity of Nav1.9 channels for sensory abnormalities (pain and itch) and suggest resulting malfunctions of the motor system and of the gastrointestinal tract. Scn11a+/L799P mice are suitable to investigate the role of Nav1.9, and to explore the pathophysiological changes and mechanisms which develop as a consequence of Nav1.9 hyperactivity.
Learn More >Migraine treatment may mitigate migraine and associated pain in the perioperative period.
Learn More >Many diseases display unequal prevalence between sexes. The sex-specific immune response to both injury and persistent pain remains underexplored and would inform treatment paradigms. We utilized high-dimensional mass cytometry to perform a comprehensive analysis of phenotypic and functional immune system differences between male and female mice after orthopedic injury. Multivariate modeling of innate and adaptive immune cell responses after injury using an elastic net algorithm, a regularized regression method, revealed sex-specific divergence at 12 h and 7 days after injury with a stronger immune response to injury in females. At 12 h, females upregulated STAT3 signaling in neutrophils but downregulated STAT1 and STAT6 signals in T regulatory cells, suggesting a lack of engagement of immune suppression pathways by females. Furthermore, at 7 days females upregulated MAPK pathways (p38, ERK, NFkB) in CD4T memory cells, setting up a possible heightened immune memory of painful injury. Taken together, our findings provide the first comprehensive and functional analysis of sex-differences in the immune response to painful injury.
Learn More >The characteristics of the hypersensitivity to auditory stimuli during the interictal period in episodic migraine are discussed. The combined use of event-related potentials, time-frequency power and phase-synchronization can provide relevant information about the time-course of sensory-attentional processing in migraine and its underlying mechanisms.
Learn More >Avoidance towards innocuous stimuli is a key characteristic across anxiety-related disorders and chronic pain. Insights into the relevant learning processes of avoidance are often gained via laboratory procedures, where individuals learn to avoid stimuli or movements that have been previously associated with an aversive stimulus. Typically, statistical analyses of data gathered with conditioned avoidance procedures include frequency data, for example, the number of times a participant has avoided an aversive stimulus. Here, we argue that further insights into the underlying processes of avoidance behavior could be unraveled using computational models of behavior. We then demonstrate how computational models could be used by reanalysing a previously published avoidance data set and interpreting the key findings. We conclude our article by listing some challenges in the direct application of computational modeling to avoidance data sets.
Learn More >Racial and ethnic minorities in the United States report higher levels of both clinical and experimental pain, yet frequently receive inadequate pain treatment. Although these disparities are well documented, their underlying causes remain largely unknown. Evidence from social psychological and health disparities research suggests that clinician-patient racial/ethnic concordance may improve minority patient health outcomes. Yet whether clinician-patient racial/ethnic concordance influences pain remains poorly understood.
Learn More >Interactions between central glial cells and neurons in the pain circuitry are critical contributors to the pathogenesis of chronic pain. In the central nervous system (CNS), two major glial cell types predominate: astrocytes and microglia. Injuries or pathological conditions which evoke pain are concurrently associated with the presence of a reactive microglia or astrocyte state, which is characterized by a variety of changes in the morphological, molecular, and functional properties of these cells. In this review, we highlight the changes that reactive microglia and astrocytes undergo following painful injuries and insults and discuss the critical and interactive role these two cell types play in the initiation and maintenance of chronic pain. Additionally, we focus on several crucial mechanisms by which microglia and astrocytes contribute to chronic pain and provide commentary on the therapeutic promise of targeting these pathways. In particular, we discuss how the inflammasome in activated microglia drives maturation and release of key pro-inflammatory cytokines, which drive pain through neuronal- and glial regulations. Moreover, we highlight several potentially-druggable hemichannels and proteases produced by reactive microglia and astrocytes in pain states and discuss how these pathways regulate distinct phases during pain pathogenesis. We also review two emerging areas in chronic pain research: 1) sexually dimorphic glial cell signaling and 2) the role of oligodendrocytes. Finally, we highlight important considerations for potential pain therapeutics targeting glial cell mediators as well as questions that remain in our conceptual understanding of glial cell activation in pain states.
Learn More >The present study was performed to determine neuronal loci and individual molecular mechanisms responsible for remifentanil-induced hyperalgesia. The effect of methylnaltrexone on remifentanil-induced behavioral hyperalgesia was assessed to distinguish contributions of the peripheral and/or central nervous system to remifentanil-induced hyperalgesia. Phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) in the dorsal root ganglion (DRG) neurons after remifentanil infusion, and the effect of a p38MAPK inhibitor on remifentanil-induced hyperalgesia were analyzed to investigate involvement of p38MAPK in the peripheral mechanisms of remifentanil-induced hyperalgesia. Spinal levels of prodynorphin mRNA after remifentanil infusion, and the effect of the BK2 bradykinin receptor antagonist on remifentanil-induced hyperalgesia were investigated to assess potential spinal mechanisms. The effects of methylnaltrexone and BK2 antagonists on remifentanil-induced exacerbation of post-incisional hyperalgesia were also investigated using behavioral analysis. Remifentanil infusion induced hyperalgesia in the early (4 hours to 2 days) and late (8 to 14 days) post-infusion periods. Methylnaltrexone inhibited hyperalgesia only during the early post-infusion period. p38MAPK phosphorylation was observed in the DRG neuron, and the p38MAPK inhibitor inhibited hyperalgesia during the early post-infusion period. Prodynorphin expression increased in the spinal cord, and a BK2 antagonist inhibited hyperalgesia during the late post-infusion period. Remifentanil-induced exacerbation of incisional hyperalgesia was inhibited by methylnaltrexone and the BK2 antagonist. The present study demonstrated that remifentanil activates peripheral and spinal neurons to promote chronologically distinctive hyperalgesia. p38MAPK phosphorylation in the DRG neuron leads to peripherally-driven hyperalgesia during the early post-infusion period, while spinal dynorphin-bradykinin signaling promotes hyperalgesia during the late post-infusion period.
Learn More >Clinical heterogeneity is a peculiarity of vestibular migraine, in contrast to other vestibular disorders that have a more stereotypical expression. Migraine presents a range of variability in symptoms depending on the age of the patient. Supposing that migraine headache and vestibular migraine share the same pathogenetic mechanisms, a multiparametric analysis was performed to verify the hypotheses of an age-related influence on the clinical features of vestibular migraine at the onset.
Learn More >To examine longitudinal associations between parent factors (parent headache frequency and disability, protective parenting behaviors, parent catastrophizing) with adolescent headache-related disability and headache frequency over 6 months.
Learn More >Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the mu opioid receptor triggers both the antinociceptive and adverse effects of opioids.
Learn More >To assess the efficacy of erenumab at the ≥50%, ≥75%, and 100% reduction in monthly migraine days (MMD) response thresholds, using data from the 6-month double-blind treatment phase (DBTP) of the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention (STRIVE) pivotal clinical trial.
Learn More >Pain remains a prevalent symptom for rheumatoid arthritis (RA) patients despite a wide therapeutic choice. The objective of this study was to provide a multidimensional evaluation of pain.
Learn More >Preclinical data implicate large conductance calcium-activated potassium (BK) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BK channels would cause headache and vascular effects in healthy volunteers.
Learn More >The aim of this systematic review is to indirectly compare the efficacy of any intervention, administered perioperatively, on acute and persistent pain after breast surgery.
Learn More >Calcitonin gene-related peptide plays a key role in cluster headache pathophysiology. It is released from the trigeminal nerve, which also innervates the eye. In this study, we tested if tear fluid calcitonin gene-related peptide measurement detects elevated calcitonin gene-related peptide levels in cluster headache patients compared to controls.
Learn More >Pain is comprised of both sensory and affective components. The anterior cingulate cortex (ACC) is a key brain region involved in the emotional processing of pain. Specifically, glutamatergic transmission within the ACC has been shown to modulate pain-related aversion. In the present study, we use optogenetics to activate or silence, using channelrhodopsin (ChR2) and archaerhodopsin (ArchT) respectively, calmodulin-kinase IIα (CaMKIIα)-expressing excitatory glutamatergic neurons of the ACC during a formalin-induced conditioned place aversion (F-CPA) behavioral paradigm in both female and male adult Sprague-Dawley rats. Expression of c-Fos, a marker of neuronal activity, was assessed within the ACC using immunohistochemistry. Optogenetic inhibition of glutamatergic neurons of the ACC abolished F-CPA without affecting formalin-induced nociceptive behavior during conditioning. In male rats, optogenetic activation of ACC glutamatergic neurons decreased formalin-induced nociceptive behavior during conditioning without affecting F-CPA. Interestingly, the opposite effect was seen in females, where optogenetic activation of glutamatergic neurons of the ACC increased formalin-induced nociceptive behavior during conditioning. The abolition of F-CPA following optogenetic inhibition of glutamatergic neurons of the ACC was associated with a reduction in c-Fos immunoreactivity in the ACC in male rats, but not female rats. These results suggest that excitatory glutamatergic neurons of the ACC play differential and sex-dependent roles in the aversion learning and acute sensory components of pain.
Learn More >A literature review was conducted to compare placebo responses in a recent trial-which implemented an Accurate Pain Reporting (APR) and Placebo Response Reduction (PRR) training program-to placebo responses in similar previous trials in chronic lower back pain (CLBP) which did not use such training.
Learn More >Myofascial pain syndrome (MPS) has a high global prevalence and is associated with myofascial trigger points (MTrPs) in taut bands or nodules. Little is known about the aetiology. The current study assessed the pathophysiological characteristics of MTrPs in MPS patients.
Learn More >Overuse of diagnostic imaging for patients with low back pain remains common. The underlying beliefs about diagnostic imaging that could drive overuse remain unclear. We synthesised qualitative research that has explored clinician, patient or general public beliefs about diagnostic imaging for low back pain.
Learn More >The incidence of herpes zoster (HZ) has been increasing in recent decades. Although two vaccines for HZ are available, there have been few studies on the incidence rates of HZ and post-herpetic neuralgia (PHN) since their introduction. This study examined the incidence rates of HZ and PHN from 1994-2018 in the United States to determine if they have continued to increase since introduction of the herpes zoster vaccines.
Learn More >The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.
Learn More >Migraine has consistently been connected with rosacea. Commonalities in epidemiology, trigger factors and associated neuropeptides support shared aetiology and pathophysiological pathways, though underlying mechanisms remain unclear. We established two cohorts of patients diagnosed with either migraine and/or rosacea. All patients were phenotyped in regard to migraine and rosacea. In this article, we describe the baseline parameters of the cohorts. In the future, we expect that these cohorts will help uncover potential disease overlaps and allow for prolonged follow-up through national Danish health registers.
Learn More >A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G activator with minimal β-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates.
Learn More >The Headache Disability Inventory assesses the dimensions of headache disability, but it is not available in Brazilian Portuguese yet. We aimed to translate the Headache Disability Inventory into Brazilian Portuguese and analyze its measurement properties.
Learn More >Chronic pain manifests in multiple disorders and is highly debilitating. While its pathophysiology is not fully understood, the involvement of the mesocorticolimbic monoaminergic systems have been shown to play a critical role in chronic pain emergence and/or maintenance. In this study, we analyzed the levels of monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in mesocorticolimbic areas – medial prefrontal cortex, orbitofrontal cortex, striatum, nucleus accumbens and amygdala – 1 month after a neuropathic lesion, Spared Nerve Injury (SNI). In SNI animals, were observed a marginal decrease of DA and 5-HT in the striatum and a rightward shift in the levels of NA in the nucleus accumbens. While mesocorticolimbic monoamines might be relevant for chronic pain pathophysiology its content appears to be relatively unaffected in our experimental conditions.
Learn More >Provoked vestibulodynia is the most common subtype of chronic vulvar pain. This highly prevalent and debilitating condition is characterized by acute recurrent pain located at the entry of the vagina in response to pressure application or attempted vaginal penetration. Physical therapy is advocated as a first-line treatment for provoked vestibulodynia but evidence supporting its efficacy is scarce.
Learn More >Neuroimmune-related sex differences contribute to the complexity of neurological disorders, such as drug abuse, depression, and chronic pain. The collection of articles presented in this issue add to our understanding of sex as a critical biological variable in the study of psychiatric and neurological diseases. Consideration of sex in the design and interpretation of study results is critical. Sex differences may warrant different treatment approaches for diseases in which sex or gender influences disease outcomes. The studies and reviews presented here examine the contribution of sexual dimorphism in the physiological responses and pharmacological treatments of neurological and psychiatric disorders.
Learn More >Objectives Chronic postoperative pain is prevalent after robot-assisted laparoscopic hysterectomy for endometrial cancer. Preoperative Quantitative Sensory Testing (QST) has been utilized to identify patients at risk of developing chronic postoperative pain after a range of surgical procedures. The aim of this prospective, observational study was to (1) determine the prevalence of chronic postoperative pain, (2) assess selected preoperative risk factors for chronic postoperative pain, and (3) evaluate if preoperative QST profiling could predict the development of chronic postoperative pain following robot-assisted laparoscopic hysterectomy for endometrial cancer. Methods One-hundred and sixty consecutive patients were included and handheld pressure algometry, cuff pressure algometry, temporal summation of pain, conditioned pain modulation, and heat pain thresholds were assessed prior to surgery. Patients were asked to fill out a questionnaire concerning pain in the pre- and post-operative time period six months after surgery. Chronic postoperative pain was defined as persistent, moderate to severe pain (mean visual analogue scale (VAS)≥3) on a daily basis six months after surgery. Results The prevalence of chronic postoperative pain after robot-assisted laparoscopic hysterectomy for endometrial cancer was of 13.6% (95% CI 8.4-20.4%). Patients that would develop chronic postoperative pain had a lower BMI (p=0.032), a higher prevalence of preoperative pelvic pain (p<0.001), preoperative heat pain hyperalgesia (p=0.043) and a higher level of acute postoperative pain (p<0.001) when compared to patients that would not develop chronic postoperative pain. A logistic regression model demonstrated that the presence of preoperative pelvic pain was a significant, independent predictive risk factor for development of chronic postoperative pain (OR=6.62, 95% CI 2.26-19.44), whereas none of the QST parameters could predict postoperative pain. Conclusions Preoperative QST assessment could not predict the development of chronic postoperative pain despite preoperative heat pain hyperalgesia in patients that would develop chronic postoperative pain.
Learn More >Greater acceptance of chronic pain is associated with lesser levels of pain-related distress and disability and better overall functioning. Pain acceptance is most often assessed using the Chronic Pain Acceptance Questionnaire (CPAQ), which includes both an eight-item short form (CPAQ-8) and a twenty item parent measure (CPAQ-20). This study derived a two-item CPAQ for use in busy clinical settings and for repeated measurement during treatment, the CPAQ-2. An Item Response Theory approach was used to identify the strongest items from the CPAQ-20, one from each of its two subscales. Next, regression analyses were conducted to evaluate the utility of the CPAQ-2 by examining variance accounted for in the CPAQ-8, CPAQ-20, and in measures of depression, pain-related fear, physical disability, and psychosocial disability. Four clinical databases were combined (N = 1776) for the analyses. Items 9 and 14 were identified as the strongest CPAQ-20 items in the IRT analyses. The sum score of these two items accounted for over 60% of the variance in the CPAQ-8 and CPAQ-20. Furthermore, this score accounted for significant variance in measures of depression, pain-related fear, physical disability, and psychosocial disability after controlling for data collection method (i.e., in clinic or online), participant age, education, pain duration, and usual pain. Finally, the amount of variance accounted for by the CPAQ-2 was comparable to that accounted for by both the CPAQ-8 and CPAQ-20. These results provide initial support for the CPAQ-2 and suggest that it is well suited as a brief assessment of chronic pain acceptance.
Learn More >Improvements in pain management might be achieved by matching treatment to underlying mechanisms for pain persistence. Many authors argue for a mechanism-based classification of pain, but the field is challenged by the wide variation in the proposed terminology, definitions, and typical characteristics. This study aimed to (1) systematically review mechanism-based classifications of pain experienced in the musculoskeletal system; (2) synthesize and thematically analyze classifications, using the International Association for the Study of Pain categories of nociceptive, neuropathic, and nociplastic as an initial foundation; and (3) identify convergence and divergence between categories, terminology, and descriptions of each mechanism-based pain classification.
Learn More >Clinical and preclinical studies have revealed that local administration of opioid agonists into peripheral tissue attenuates inflammatory pain. However, few studies have examined whether peripherally restricted opioids are effective in reducing mechanical allodynia and hyperalgesia that usually follows nerve injury. The aim of the present study was to determine whether the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic pain conditions is depressed by direct activation of delta opioid receptors (DORs) on their peripheral terminals. A murine model of peripheral neuropathic pain was induced with a spared nerve (tibial) injury, in which mice survived 7 or 28 days after surgery before electrophysiological testing began. Control groups comprised naïve and sham-operated animals. An ex vivo preparation of mouse plantar skin with attached tibial nerve was used to examine electrophysiologically the effects of the selective DOR agonist, deltorphin II, on the response properties of individual cutaneous C-fiber nociceptors. In contrast to naïve and sham-operated animals, deltorphin II induced an inhibition of the mechanical responsiveness of C-fiber mechanical nociceptors innervating skin under neuropathic conditions. The effects of deltorphin II were concentration-dependent and prevented by pretreatment with naltrindole indicating DOR-mediated inhibitory effects of deltorphin II. Our results provide the first direct evidence for expression of functional DORs on mechanical nociceptors innervating skin in an animal model of neuropathic pain.
Learn More >Neuropathic pain is one of the key features of the classical phenotype of Fabry disease (FD). Acid sensing ion channels (ASICs) are H-gated cation channels, which belong to the epithelial sodium channel/DeGenerin superfamily, sensitive to the diuretic drug Amiloride. Molecular cloning has identified several distinct ASIC subunits. In particular the ASIC1a subunit has been associated to pain and its upregulation has been documented in animal models of pain. We analyzed the expression of ASIC1a channels in cellular models that mimic the accumulation of glycosphingolipids in FD (FD-GLs) like Gb3, and LysoGb3. We used mouse primary neurons from brain cortex and hippocampus -supraspinal structures that accumulate FD-GLs-, as well as HEK293 cells. Incubation with Gb3, lysoGb3 and the inhibitor (1-deoxy-galactonojirymicin, DJG) of the enzyme α-galactosidase A (Gla) lead to the upregulation of ASIC1a channels. In addition, activation of ASIC1a results in the activation of the MAPK ERK pathway, a signaling pathway associated with pain. Moreover, accumulation of glycosphingolipids results in activation of ERK, an effect that was prevented by blocking ASIC1a channels with the specific blocker Psalmotoxin. Our results suggest that FD-GLs accumulation and triggering of the ERK pathway via ASIC channels might be involved in the mechanism responsible for pain in FD, thus providing a new therapeutic target for pain relief treatment.
Learn More >Objectives Complex regional pain syndrome (CRPS) is a rare chronic pain condition for which no curative treatment exists. Patients in tertiary centres are often required to make decisions about treatment options. This study was conducted to explore how prior attendance of a pain management program might alter patients' decision making processes. Methods This qualitative study uses focus groups to gather patient views on an immunosuppressant drug treatment (mycophenolate) for the management of CRPS. Participants were allocated to one of three focus groups based on their treatment journey; Group 1 (n=3) were involved in a recent mycophenolate drug trial; Group 2 (n=5) were neither involved in the trial nor attended a Pain Management Programme (PMP); Group 3 (n=6) were not involved in the trial but had attended a PMP. Outcomes were considered within the framework of Leventhal's Common Sense Model (CSM) in relation to the decision making process. Results Thematic analysis identified differing themes for each group. Group 1: (1) Medication as a positive form of treatment, (2) The trial/drug and (3) Pacing. Group 2: (1) Medication as form of treatment, (2) Other forms of support/treatment and (3) Side effects of mycophenolate. Group 3: (1) Varied view of medication, (2) Consideration of other forms of support and (3) Side effects. Conclusions Attendance on a PMP might provide patients with skills to better manage uncertainty when faced with various treatment options. Leventhal's model goes some way to explaining this. The specific importance of, and benefit from understanding pacing when commencing an effective drug treatment for chronic pain became apparent.
Learn More >Chronic pain management during the coronavirus disease 2019 (COVID-19) pandemic is a challenging process, especially with growing evidence that COVID-19 infection is associated with myalgias, referred pain, and widespread hyperalgesia. In light of the limited data available for COVID-19-related impact on chronic pain patients, this review explores the changes in the healthcare delivery system due to social distancing and safety precautions to provide the appropriate management of chronic pain patients during the COVID-19 pandemic. Understanding both the general problems facing chronic pain patients as well as specific problems in the COVID-19 era including deconditioning, increased mental health concerns, financial burdens, and potential for medication-induced immune-suppression is vital in the appropriate management of patients. Telemedicine, the practice of caring for patients remotely when the provider and patient are not physically present with each other, is becoming increasingly used and recognized as a valuable tool to both health care providers and patients. This paper concentrates on the proper utilization of the available resources to help patients with the most severe conditions as well as the most vulnerable group. COVID-19 may be associated with a profound effect on both the health care system and patients with chronic pain. As a result, delaying, or stopping, treatment for chronic pain patients will have negative consequences, and strong pain evaluations must be administered to triage patients appropriately. Recent recommendations for the safe use of non-opioid analgesics, opioid analgesics, and interventional pain management procedures are vital to know and understand specifically during the pandemic era. Further researches are needed to identify the advance planning and rapid responses to reduce the impact of the pandemic.
Learn More >To examine the peripheral nervous system (PNS) in spinal cord injured (SCI) patients using two novel methods: (1) MScanFit MUNE; a motor unit number estimation method detecting motor unit loss and (2) muscle velocity recovery cycles (MVRCs) measuring muscle membrane properties which has previously shown depolarization of the muscle membrane in denervated muscles.
Learn More >The prevalence of chronic pain in cancer survivors is double that of the general US population. Opioids have been the foundation of cancer pain management for decades; however, there is a paucity of literature on long-term opioid therapy (LTOT) in cancer survivors. An understanding of factors related to LTOT use in cancer survivors is needed to address chronic pain and balance opioid harms in the expanding population of cancer survivors.
Learn More >Classification of headache disorders is dependent on a subjective self-report from patients and its interpretation by physicians. We aimed to apply objective data-driven machine learning approaches to analyze patient-reported symptoms and test the feasibility of the automated classification of headache disorders. The self-report data of 2162 patients were analyzed. Headache disorders were merged into five major entities. The patients were divided into training (n = 1286) and test (n = 876) cohorts. We trained a stacked classifier model with four layers of XGBoost classifiers. The first layer classified between migraine and others, the second layer classified between tension-type headache (TTH) and others, and the third layer classified between trigeminal autonomic cephalalgia (TAC) and others, and the fourth layer classified between epicranial and thunderclap headaches. Each layer selected different features from the self-reports by using least absolute shrinkage and selection operator. In the test cohort, our stacked classifier obtained accuracy of 81%, sensitivity of 88%, 69%, 65%, 53%, and 51%, and specificity of 95%, 55%, 46%, 48%, and 51% for migraine, TTH, TAC, epicranial headache, and thunderclap headaches, respectively. We showed that a machine-learning based approach is applicable in analyzing patient-reported questionnaires. Our result could serve as a baseline for future studies in headache research.
Learn More >The FUTUREPAIN study develops a short general-purpose questionnaire, based on the biopsychosocial model, to predict the probability of developing or maintaining moderate-to-severe chronic pain 7-10 years into the future.
Learn More >Previous studies have found a negative association between a conditioning pain modulating (CPM) response and pain catastrophizing among pain-free subjects. This study investigated the difference in CPM response between patients with chronic low back pain (CLBP) and healthy controls, and the association between pain catastrophizing and the CPM response.
Learn More >Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky.
Learn More >Fibromyalgia (FM) is a chronic condition characterized by widespread pain of unknown etiology associated with alterations in the central nervous system. Although previous studies demonstrated altered patterns of brain activity during pain processing in patients with FM, alterations in spontaneous brain oscillations, in terms of functional connectivity or microstates, have been barely explored so far. Here we recorded the EEG from 43 patients with FM and 51 healthy controls during open-eyes resting-state. We analyzed the functional connectivity between different brain networks computing the phase lag index after group Independent Component Analysis, and also performed an EEG microstates analysis. Patients with FM showed increased beta band connectivity between different brain networks and alterations in some microstates parameters (specifically lower occurrence and coverage of microstate class C). We speculate that the observed alterations in spontaneous EEG may suggest the dominance of endogenous top-down influences; this could be related to limited processing of novel external events and the deterioration of flexible behavior and cognitive control frequently reported for FM. These findings provide the first evidence of alterations in long-distance phase connectivity and microstate indices at rest, and represent progress towards the understanding of the pathophysiology of fibromyalgia and the identification of novel biomarkers for its diagnosis.
Learn More >Suicidality is common in patients with migraine. Here, we performed a systematic review and estimated the prevalence of suicidal ideation (SI) and suicide attempt (SA) in patients with migraine.
Learn More >N-docosahexaenoyl ethanolamine (DHEA; also known as synaptamide) binds to both the CB1 and CB2 cannabinoid receptors and has anti-inflammatory properties in vitro. However, the in vivo effects of DHEA are unknown. Therefore, this study was designed to understand the effects of DHEA in models of pain and inflammation in mice.
Learn More >To assess the expression of inflammatory cytokines in the affected and normal skin of postherpetic neuralgia (PHN) patients.
Learn More >Retrospective longitudinal cohort.
Learn More >Pain is a common problem after stroke and is associated with poor outcomes. There is no consensus on the optimal method of pain assessment in stroke. A review of the properties of tools should allow an evidence based approach to assessment. We aimed to systematically review published data on pain assessment tools used in stroke, with particular focus on classical test properties of: validity, reliability, feasibility, responsiveness. We searched multiple, cross-disciplinary databases for studies evaluating properties of pain assessment tools used in stroke. We assessed risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool. We used a modified harvest plot to visually represent psychometric properties across tests. The search yielded 12 relevant articles, describing 10 different tools ( = 1,106 participants). There was substantial heterogeneity and an overall high risk of bias. The most commonly assessed property was validity (eight studies) and responsiveness the least (one study). There were no studies with a neuropathic or headache focus. Included tools were either scales or questionnaires. The most commonly assessed tool was the Faces Pain Scale (FPS) (6 studies). The limited number of papers precluded meaningful meta-analysis at level of pain assessment tool or pain syndrome. Even where common data were available across papers, results were conflicting e.g., two papers described FPS as feasible and two described the scale as having feasibility issues. Robust data on the properties of pain assessment tools for stroke are limited. Our review highlights specific areas where evidence is lacking and could guide further research to identify the best tool(s) for assessing post-stroke pain. Improving feasibility of assessment in stroke survivors should be a future research target. PROSPERO CRD42019160679 Available online at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019160679.
Learn More >It has been reported that N-cadherin and cAMP response element binding protein (CREB) in the spinal cord are critical for synaptogenesis and regulation of excitatory synapse function, which could underlie chronic pain development. The aim of the present study was to investigate the role of spinal N-cadherin/CREB signaling in postsurgical pain chronicity following chronic alcohol consumption.
Learn More >Chronic pain is common following stroke, however there is little known about the treatments for pain that are being accessed by stroke survivors, nor their perceived effectiveness.
Learn More >Although the evidence for attentional bias to pain-related information among individuals with chronic pain has been well established, there are a number of inconsistencies in the research that have been observed due to sample characteristics. Therefore, the present study expanded upon previous studies by including patients with a variety of chronic pain conditions and compared a chronic pain patient sample with healthy community sample. We also investigated how pain catastrophizing and other psychological factors in chronic pain patients affected attentional patterns to pain-related information. Forty chronic pain patients from the departments of neurology and rheumatology of an academic medical center hospital and 40 participants without chronic pain from a university that is located in Seoul, South Korea were recruited for the present study. Patients observed pictures of faces displaying pain that were presented simultaneously with faces with neutral expressions, while their eye movements were measured using an eye-tracking system. Independent -tests were conducted to investigate attentional preferences to pain stimuli between the chronic pain and control groups. No significant attentional differences in pain-neutral pairs were found for both chronic pain and control group. A one-way MANOVA was conducted to examine the role of pain catastrophizing on psychological factors and attentional engagement to pain stimuli. No significant results for the attentional bias to pain stimuli among chronic pain patients may indicate that chronic pain patients who have suffered from chronic pain for a long time and have been treated for their chronic pain in the hospital may interpret pain-related information not as threatening. Clinical implications related to use in pain treatment and future research suggestions are discussed.
Learn More >Breast cancer is the most frequent cancer in women. Chronic pain following mastectomy remains a significant problem. This study aimed to evaluate risk factors associated with postoperative chronic pain.
Learn More >Multidisciplinary pain management programs incorporating a cognitive-behavioral therapy (CBT) approach have been reported to be helpful for elderly people with chronic pain. However, it is unclear whether the same program for elderly people with chronic pain would translate to different cultures. This study investigated whether a multidisciplinary program based on that of Nicholas et al. (Pain 154(6):824-835, 2013) in Australia would be effective for elderly people with chronic pain in Japan.
Learn More >Effective treatments for chemotherapy-induced peripheral neuropathy (CIPN) remain unavailable. Given the significance of spinal cord glutamate transporters in neuronal plasticity and central sensitization, this study investigated the role of excitatory amino acid transporter 2 (EAAT2) and vesicular-glutamate transporter 2 (VGLUT2) in the development of paclitaxel-induced painful neuropathy. Paclitaxel (2 mg/kg, i.p., cumulative dose 8mg/kg) induced long-lasting mechanical allodynia (> 28days) with increased glutamate concentration and decreased EAAT2 expression with no changes in GABA/glycine or VGAT (vesicular GABA transporter) in rat spinal dorsal horn. VGLUT2 expression was upregulated and co-expressed with enhanced synaptophysin, characterizing nociceptive afferent sprouting and new synapse formation of glutamatergic neurons in the spinal cord dorsal horn. HDAC2 and transcription factor YY1 were also upregulated, and their interaction and co-localization were confirmed following paclitaxel treatment using co-immunoprecipitation (Co-IP). Inhibition or knockdown of HDAC2 expression by valproic acid (VPA), BRD6688 or HDAC2 siRNA (small interfering RNA) not only attenuated paclitaxel-induced mechanical allodynia but also suppressed HDAC2 upregulation, glutamate accumulation and the corresponding changes in EAAT2/VGLUT/synaptophysin expression and HDAC2/YY1 interaction. These findings indicate that loss of the balance between glutamate release and reuptake due to dysregulation EAAT2/VGLUT2/synaptophysin cascade in the spinal dorsal horn plays an important role in the development of paclitaxel-induced neuropathic pain. HDAC2/YY1 interaction as a complex appears essential in regulating this pathway, which can potentially be a therapeutic target to relieve CIPN by reversing central sensitization of spinal nociceptive neurons.
Learn More >Little is known about the epidemiology of neuropathic pain in primary care patients consulting with low back-related leg pain. We aimed to describe prevalence, characteristics and clinical course of low back-related leg pain patients with and without neuropathic pain, consulting with their family doctor in the UK.
Learn More >Objectives Studies have shown that self-compassion plays a protective role against depression in women with chronic pain (CP). However, the majority of studies in CP have used the total score of the self-compassion scale (SCS), which have raised concerns due to potential overlap, not only between the uncompassionate self-responding factors and psychopathology, but also between self-compassion as a whole and other well-known psychological processes (e.g., mindfulness, acceptance, psychological flexibility). This calls for a more nuanced understanding of which components of (un)compassionate self-responding adds to better mental health in CP. Methods This study explores the unique contribution of compassionate and uncompassionate self-responding to depressive symptoms in women with CP undergoing pain consultation (n = 49). Results Correlation analyses suggest that compassionate self-responding only significantly correlates with progress in valued living, while the uncompassionate self-responding significantly correlates with pain fusion, pain avoidance, obstructions to valued living and depression. Multiple regression analysis showed that self-compassion contributes to depressive symptoms (R2 = 8%) above and beyond pain intensity and disability (R2 = 12%) and psychological (in) flexibility processes (R2 = 31%), and uncompassionate (but not compassionate) self-responding uniquely contributes to depressive symptoms (sr 2 = 18%). Conclusions Findings suggest that uncompassionate self-responding is a stronger contributor to depression in CP than compassionate self-responding. Clinical implications are further discussed.
Learn More >Headaches are not only responsible for restrictions in everyday life in adults. In children and adolescents, regular headaches lead also to reduced life quality and limitations in the social sphere, in school education, and in professional careers. Here, we provide an overview on the frequency of headache in children and adolescents with the aim of increasing awareness about this particular health issue.
Learn More >Objectives Cooled radiofrequency (cRF) is an effective treatment for sacroiliac pain. In contrast to conventional radiofrequency denervation, this technique allows enlarging the area of denervation by cooling the radiofrequency probe. However, there is sparse knowledge about the impact of interventional procedures like cRF treatment of sacroiliac joint pain on psychological comorbidities. The aim of this retrospective study was to evaluate the outcome of cRF in chronic pain patients regarding the psychological outcomes anxiety, depression, sleep quality and pain related disability. Methods In this retrospective observational study 29 interventions were performed over a period of two years in 28 patients. Pre- and post-interventional pain levels, depression and anxiety scores, pain-related disability, treatment satisfaction and sleep quality were assessed by standardized and validated questionnaires. Pain medication was recorded prior to the intervention and at follow-up. Results Hospital Anxiety and Depression Scale (HADS-D) scores for depression showed a statistically significant reduction after therapy which did not remain significant after Bonferroni-Holm correction. Anxiety as measured by the HADS-A score did not show a statistically significant change. No statistically significant improvement was observed in the pain disability index. Patients reported fewer sleep disorders after treatment. Mean pain (NRS) was statistically significantly reduced 1 week post intervention and at time of follow-up. There was no clear reduction of analgesic medication. Conclusions Besides pain reduction, our data show a positive influence on sleep quality, possibly on depression, but not on anxiety and pain disability.
Learn More >Chronic constriction injury (CCI) is widely used as an animal neuropathic pain model. Neuropathic pain is considered to exist when withdrawal latency to thermal stimulation is decreased after inducing a CCI to the sciatic nerve. However, it is known that CCI leads to changes in skin temperature and that skin temperature can affect withdrawal latency. Aim of this study was to compare withdrawal latencies of constricted and contralateral hind limbs, to thermal stimulation, at the same artificially-induced skin temperatures.
Learn More >Neuromodulatory techniques have been studied to treat drug addiction or compulsive eating as well as different chronic pain conditions, such as neuropathic and inflammatory pain in the clinical and preclinical settings. In this study, we aimed to investigate the effect of transcranial direct current stimulation (tDCS) on the association of alcohol withdrawal with neuropathic pain based on nociceptive and neurochemical parameters in rats. Thirty-six adult male Wistar rats were randomized into five groups: control, neuropathic pain, neuropathic pain + tDCS, neuropathic pain + alcohol, and neuropathic pain + alcohol + tDCS. The neuropathic pain model was induced by chronic constriction injury (CCI) to the sciatic nerve. Rats were then exposed to alcohol (20%) by oral gavage administration for 15 days (beginning 24 h after CCI). tDCS was started on the 17th day after surgery and lasted for 8 consecutive days. The nociceptive test (hot plate) was performed at baseline, 16 days after CCI, and immediately and 24 h after the last session of tDCS. Rats were killed by decapitation, and structures were removed and frozen for biochemical analysis (nerve growth factor and interleukin (IL-1α, IL-1β, and IL-10 measurements). Neuropathy-induced thermal hyperalgesia was reversed by tDCS, an effect that was delayed by alcohol abstinence. In addition, tDCS treatment induced modulation of central levels of IL-1α, IL-1ß, and IL-10 and neurotrophic growth factor. We cannot rule out that the antinociceptive effect of tDCS could be related to increased central levels of IL-1α and IL-10. Therefore, tDCS may be a promising non-pharmacological therapeutic approach for chronic pain treatment.
Learn More >Chronic pruritus is one of the main symptoms in dermatology. We investigated a new intervention for chronic pruritus by neurostimulation through matrix electrodes. In this randomized controlled trial, 29 patients with chronic pruritus caused by a variety of dermatological diseases were allocated to an experimental group (EG; n = 14, 4-Hz neurostimulation of the itching area through matrix electrodes) or the control group (CG; n = 15, placement of matrix electrodes without neurostimulation). Outcome measures were the itching sensation as measured by a Numerical Rating Scale immediately after the intervention and the intermediate effect measured by the average itching sensation on the day before the intervention compared with the average itching sensation on day 1, 2 and 3 after the intervention. Regarding the short-term effect on itching, the anova showed a significant interaction effect for the 5-min stimulation with a larger reduction in the EG with a large effect size of d = 1.10. The average reduction in itching intensity was 78.2% for the EG compared with 34.3% for the CG. For the intermediate effect, no significant interaction was found (F = 1.721, P = 0.199). Comparing the itching sensation at day 0 with day 3, the interaction effect showed a statistical trend toward a greater reduction in the EG (F = 3.178, P = 0.086; statistical trend, d = 0.69). This study proved that neurostimulation through matrix electrodes is effective in the short-term reduction of itching in patients with chronic pruritus caused by dermatological diseases. Additional studies are needed with larger patient pools and covering longer study periods.
Learn More >Many HIV patients develop chronic pain and use opioid-derived medicine as primary analgesics. Emerging clinical evidence suggests that chronic use of opioid analgesics paradoxically heightens pain states in patients. This side effect of opioid analgesics has a significant negative impact on clinical practice, but the underlying pathogenic mechanism remains elusive. Using a mouse model of HIV-associated pain, we simulated the development of morphine exacerbation on pain and investigated potential underlying cellular and molecular pathways. We found that repeated morphine treatment promoted astrocyte activation in the spinal dorsal horn (SDH) and up-regulation of pro-inflammatory cytokines IL-1β and TNF-α. Furthermore, we observed that morphine administration potentiated mitochondrial reactive oxygen species (ROS) in the SDH of the HIV pain model, especially on astrocytes. Systemic application of the ROS scavenger phenyl-N-t-butyl nitrone (PBN) not only blocked the enhancement of gp120-induced hyperalgesia by morphine but also astrocytic activation and cytokine up-regulation. These findings suggest a critical role of ROS in mediating the exacerbation of gp120-induced pain by morphine. Graphical abstract.
Learn More >This study utilizes the Science of Behavior Change (SOBC) experimental medicine approach to evaluate the effects of a 3-month, individually prescribed progressive exercise training program on neurobiological, cognitive and motivational mechanisms by which our exercise-training paradigm may foster exercise maintenance. We will investigate hypothesized relationships between exercise-training associated augmentation of neuropeptide Y (NPY) system function and improvements in self-regulation and reward sensitivity-cognitive control and motivational processes posited to promote self-efficacy and intrinsic motivation, which have been shown to predict exercise maintenance. This study will recruit Veterans with chronic low back pain and posttraumatic stress disorder (PTSD). Procedures include a baseline, acute cardiopulmonary exercise challenge assessment that will inform the exercise prescription for a 12-week progressive exercise training program comprised of three 45-minute aerobic exercise sessions per week-all of which will be supervised by an exercise physiologist. Additionally, a week-7 and week-14 exercise challenge assessment will track changes in NPY system function and the variables of interest. We hypothesize that increases in the capacity to release NPY in response to acute exercise testing will be associated with improvements in self-regulation and reward sensitivity, which will in turn be associated with self-efficacy and intrinsic motivation to maintain regular exercise. Ninety participants will be randomized either to the "active exercise training condition" or to the "wait list symptom monitoring condition". The study aims to demonstrate the feasibility of procedures and elucidate mechanisms relevant to developing individually prescribed, motivationally based exercise regimens to reduce negative consequences of PTSD and low back pain over the long-term. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.
Learn More >Transient receptor potential vanilloid type 1 (TRPV1) receptors activated by heat and capsaicin are expressed in trigeminal nociceptive neurons and implicated in the generation of migraine pain. Genetic studies suggested that single-nucleotide polymorphism (SNP) 1911A>G (rs8065080), leading to amino acid substitution Ile585Val, in the TRPV1 gene affects functional activity of TRPV1 receptors and is involved in different pain conditions. However, this polymorphism has not been tested in migraine patients. The objective of this pilot study was to investigate genetic factors of migraine susceptibility. We evaluated frequency distribution of AA, AG, and GG variants of SNP 1911A>G in the TRPV1 gene in patients with episodic and chronic migraine compared with healthy individuals. The study included 46 patients diagnosed with migraine (27 episodic and 19 chronic) and 50 healthy individuals as a control group. DNA from peripheral blood was used to test TRPV1 SNP using allele-specific PCR combined with gel electrophoresis. The genotype frequency distribution in episodic migraine was comparable with that in controls (AA 33%, AG 56%, GG 11% and AA 34%, AG 46%, GG 20%, respectively). On the contrary, in chronic migraine, the distribution differed significantly (p < 0.05) (AA 68%, AG 32%, GG 0%). This are first indications for a distinctive genotype frequency distribution of TRPV1 1911A>G in chronic migraine patients compared with episodic migraine patients and controls. Our data confirm a different predisposition to chronic pain in migraine and give a prerequisite for a new look at the nature of chronification of migraine, proposing that the absence of GG genotype may be considered as possible risk biomarker of episodic migraine evolution to chronic form.
Learn More >Chronic daily pain is experienced by 11.2% of United States adults and psychosocial factors have significant impact on self-reported pain. Most research in this area has focused on pain-related conditions, not the general population. This study sought to understand the associations between clinically significant chronic pain and multiple dimensions of social relationship quality in a general population.
Learn More >Visceral pain can be disabling for patients and challenging to treat in the clinic. Spinal cord stimulation is a NICE approved treatment for chronic neuropathic pain, presenting potential advantages over conventional therapies for managing chronic visceral pain. A retrospective study revealed that a specific type of spinal cord stimulation, BurstDR (Abbott, TX, USA), was effective at improving pain and quality of life in patients with chronic visceral pain. Baseline pain scores significantly correlated with change at follow-up, suggesting it may be possible to identify potential responders from the outset. BurstDR was safe: rates of revision, explantation and complications were low. Clinical trials exploring the long-term effects of BurstDR including a control arm are needed. Findings could have the potential to inform best practice and improve outcomes for individuals with chronic visceral pain.
Learn More >Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of , and and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway.
Learn More >Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are important in managing acute and chronic pain secondary to inflammation. As a greater understanding of the risks of gastrointestinal (GI), cardiovascular (CV) and renal events with NSAIDs use has emerged, guidelines have evolved to reflect differences in risks among NSAIDs. Updated guidelines have yet to reflect new evidence from recent trials which showed similar CV event rates with celecoxib compared to naproxen and ibuprofen, and significantly better GI tolerability for celecoxib. This practice advisory paper aims to present consensus statements and associated guidance regarding appropriate NSAID use based on a review of current evidence by a multidisciplinary group of expert clinicians. This paper is especially intended to guide primary care practitioners within Asia in the appropriate use of NSAIDs in primary care. Following a literature review, group members used a modified Delphi consensus process to determine agreement with selected recommendations. Agreement with a statement by 75% of total voting members was defined a priori as consensus. For low GI risk patients, any nonselective NSAID plus proton pump inhibitor (PPI) or celecoxib alone is acceptable treatment when CV risk is low; for high CV risk patients, low-dose celecoxib or naproxen plus PPI is appropriate. For high GI risk patients, celecoxib plus PPI is acceptable for low CV risk patients; low-dose celecoxib plus PPI is appropriate for high CV risk patients, with the alternative to avoid NSAIDs and consider opioids instead. Appropriate NSAID prescription assumes that the patient has normal renal function at commencement, with ongoing monitoring recommended. In conclusion, appropriate NSAID use requires consideration of all risks.
Learn More >DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.
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