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The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.
Learn More >Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that is linked to immune modulation and tissue regeneration. Here, we show that TNFR2 essentially promotes long-term pain resolution independently of sex. Genetic deletion of TNFR2 resulted in impaired neuronal regeneration and chronic nonresolving pain after chronic constriction injury (CCI). Further, pharmacological activation of TNFR2 using the TNFR2 agonist EHD2-sc-mTNF in mice with chronic neuropathic pain promoted long-lasting pain recovery. TNFR2 agonist treatment reduced neuronal injury, alleviated peripheral and central inflammation, and promoted repolarization of central nervous system (CNS)-infiltrating myeloid cells into an antiinflammatory/reparative phenotype. Depletion of regulatory T cells (Tregs) delayed spontaneous pain recovery and abolished the therapeutic effect of EHD2-sc-mTNF This study therefore reveals a function of TNFR2 in neuropathic pain recovery and demonstrates that both TNFR2 signaling and Tregs are essential for pain recovery after CCI. Therefore, therapeutic strategies based on the concept of enhancing TNFR2 signaling could be developed into a nonopioid therapy for the treatment of chronic neuropathic pain.
Learn More >Migraine is a common, highly disabling disorder. Its treatment involves acute and preventive therapy. Many of available preventive medications are not well tolerated, which results in poor compliance and limited effectiveness. Cannabinoids have been proposed for the treatment of migraine but their efficacy and tolerability are controversial.
Learn More >Pain catastrophizing has been shown to predict greater pain and less physical function in daily life for chronic pain sufferers, but its effects on close social partners have received much less attention. The overall purpose of the present study was to examine the extent to which pain catastrophizing is an interpersonal coping strategy that is maladaptive for patients and their spouses. A total of 144 older knee osteoarthritis patients and their spouses completed baseline interviews and a 22-day diary assessment. Multilevel lagged models indicated that, on days when patients reported greater catastrophizing in the morning, their spouses experienced more negative affect throughout the day. In addition, a higher level of punishing responses from the spouse predicted greater pain catastrophizing the next morning, independent of patient pain and negative affect. Multilevel mediation models showed that patients' morning pain catastrophizing was indirectly associated with spouses' negative affect and punishing responses via patients' own greater negative affect throughout the day. There was no evidence that spouses' empathic or solicitous responses either followed or preceded patients' catastrophizing. These findings suggest that cognitive-behavioral interventions that reduce pain catastrophizing should be modified for partnered patients to address dyadic interactions and the spouse's role in pain catastrophizing.
Learn More >Brain functional network properties are globally disrupted in multiple musculoskeletal chronic pain conditions. Back pain with lumbar disc herniation is highly prevalent and a major route for progression to chronic back pain. However, brain functional network properties remain unknown in such patients. Here, we examined resting-state fMRI-based functional connectivity networks in chronic back pain patients with clear evidence for lumbar disc herniation (LDH-CP, n = 146), in comparison to healthy controls (HC, n = 165). The study was conducted in China, thus providing the opportunity to also examine the influence of culture on brain functional reorganization with chronic pain. The data was equally subdivided into Discovery and Validation subgroups (n = 68 LDH-CP and n = 68 HC, for each subgroup), and contrasted to an off-site dataset (n = 272, NITRC 1000).Graph disruption indices derived from three network topological measurements, degree, clustering coefficient, and efficiency, which respectively represent network hubness, segregation, and integration, were significantly decreased compared to HC, across all predefined link densities, in both Discovery and Validation groups. On the other hand, global mean clustering coefficient and betweenness centrality were decreased in the discovery group and showed trend in the validation group. The relationship between pain and graph disruption indices was limited to males with high education. These results deviate somewhat from recent similar analysis for other musculoskeletal chronic pain conditions, yet we cannot determine whether the differences are due to types of pain or also to cultural differences between patients studied in China and the USA.
Learn More >Migraine headache is an episodic phenomenon, and patients with episodic migraine have ictal (headache), peri-ictal (premonitory, aura, and postdrome), and interictal (asymptomatic) phases. We aimed to find the functional characteristics of migraine brain regardless of headache phase using dynamic functional connectivity analysis. We prospectively recruited 50 patients with migraine and 50 age- and sex-matched controls. All subjects underwent a resting-state functional MRI. Significant networks were defined in a data-driven fashion from the interictal (>48 hours apart from headache phases) patients and matched controls (interictal dataset) and tested to ictal or peri-ictal patients and controls (ictal/peri-ictal dataset). Both static and dynamic analyses were used for the between-group comparison. A false discovery rate correction was performed. As a result, the static analysis did not reveal a network which was significant in both interictal and ictal/peri-ictal datasets. Dynamic analysis revealed significant between-group differences in seven brain networks in the interictal dataset, among which a frontoparietal network (controls > patients, p=0.0467), two brainstem networks (patients > controls, p=0.0467 and <0.001), and a cerebellar network (controls > patients, p=0.0408 and <0.001 in two states) remained significant in the ictal/peri-ictal dataset. Using these networks, migraine was classified with a sensitivity of 0.70 and specificity of 0.76 in the ictal/peri-ictal dataset. In conclusion, the dynamic connectivity analysis revealed more functional networks related to migraine than the conventional static analysis, suggesting a substantial temporal fluctuation in functional characteristics. Our data also revealed migraine-related networks which show significant difference regardless of headache phases between patients and controls.
Learn More >As well-established for patients with chronic pain, patients suffering from chronic itch also exhibit signs of peripheral and central sensitization. This has been linked to parallel neuroplastic sensitization processes. However, for chronic itch, sensitization has not yet been systematically assessed, studied, and hence validated. This review (Prospero CRD42016043002) summarizes and meta-analytically evaluates whether sensory aberrations including sensitization for itch occur in chronic itch.Databases PubMed, Embase, and Cochrane Library were searched for studies investigating somatosensory sensitivity assessment by quantitative sensory testing stimuli, including experimental cutaneous chemical pruritic provocations, in patients with chronic itch from skin-/neurological conditions and compared with healthy controls. Outcomes were extracted for lesional and non-lesional skin and risk of biases were assessed. Meta-analyses were performed when sufficient quantitative data were available.Of 4,667 identified papers, 46 were included and 25 were eligible for meta-analyses. Patients (66% atopic dermatitis) were found more sensitive than the controls to histamine-evoked itch in lesional skin (SMD: 0.66 [CI: 0.16,1.15]), but not non-lesionally (SMD: -0.26 [CI: -0.58;0.06]). Cowhage did not evoke more itch in non-lesional skin of patients as compared to the controls (SMD: 0.38 [CI: -0.04,0.81]). For numerous other chemical provocations as well as for mechanical, thermal, and electrical stimulation paradigms, results were ambiguous or based on few studies.Patients with chronic itch are only robustly sensitized to various chemical pruritic stimuli when applied lesionally. More studies on somatosensory aberrations in chronic itch conditions other than atopic dermatitis are needed to establish whether sensitization is robustly present across chronic itch conditions.
Learn More >Sensory neurons have recently emerged as critical mediators of immunity. Cohen et al. (2019) demonstrate that peripheral neurons utilize reflex arcs in order to rapidly condition the immune response in skin adjacent to the site of infection. This nerve reflex arc generates anticipatory immunity for more effective elimination of the pathogen if later exposed.
Learn More >During the past years, patient-reported outcomes (PROs) and patient-reported outcome measures (PROMs) have become of growing awareness and importance in medical research and practice. This review summarizes recent developments concerning PROs and PROMs related to pain in the acute postoperative as well as chronic settings and indicates gaps and challenges relevant for future research and clinical applications.
Learn More >To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine.
Learn More >To characterize unmet treatment needs in a sample of Migraine in America Symptoms and Treatment (MAST) Study participants using oral, acute prescription migraine medications.
Learn More >To provide updated evidence-based recommendations for migraine prevention using pharmacologic treatment with or without cognitive behavioral therapy in the pediatric population.
Learn More >Knee OA is a leading global cause of morbidity. This study investigates the effects of knee SF from patients with OA on the activity of dorsal root ganglion sensory neurons that innervate the knee (knee neurons) as a novel translational model of disease-mediated nociception in human OA.
Learn More >The brainstem has been discussed as the main player in the pathogenesis of migraine. Dysfunctional brainstem nuclei and their abnormal connections to other key brain centers may contribute to headache and other symptoms of migraine. In the present study, 32 patients with migraine without aura (MWoA) and 32 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI scans. We used masked independent analysis (mICA) to investigate whether patients with MWoA exhibited abnormal brainstem nuclei-cortical functional connectivity (FC). The mICA can suppress adjacent physiological noise and prevent results from being driven by the much stronger signals of the surrounding structures. Regional homogeneity (ReHo) was used to investigate whether the brainstem regions with abnormal FC to other brain areas exhibited abnormal regional neuronal activity. Patients with MWoA showed significantly weaker FC between the posterior pons and the left superior parietal lobule, the left middle temporal gyrus and the left middle frontal gyrus. Furthermore, patients with MWoA exhibited significantly decreased ReHo values in the posterior pons compared with HCs, and the posterior pons ReHo value was significantly negatively correlated with HIT-6 scores in the MWoA group. Patients with MWoA exhibited functional abnormalities in the posterior pons and weakened connections between the posterior pons and several key cortical brain areas involved in pain processing during the resting state. Perspective: This study provided increased evidence that the pons is involved in pathophysiological mechanism of migraine, and weakened connections suggest that the touch and pain sensation of migraine sufferers may not be properly relayed to cortical processing areas, which may be associated with the pathogenesis of MWoA.
Learn More >Although evolutionarily conserved to expel ectoparasites and aid in the clearance of toxins and noxious environmental stimuli from the host, the type 2 immune response can become pathologic in the setting of a variety of allergic disorders. Itch can be a behavioral extension of type 2 immunity by evoking scratching and, in the setting of disease, can become chronic and thus highly pathologic as well. Classically, our understanding of itch mechanisms has centered around the canonical IgE-mast cell-histamine axis. However, therapies aimed at blocking the histaminergic itch pathway have been largely ineffective, suggesting the existence of nonhistaminergic itch pathways. Indeed, recent advances in itch biology have provided critical new insight into a variety of novel therapeutic avenues for chronic itch in the setting of a number of allergic disorders. Here we highlight how these new developments will likely inform the problem of pruritus in a variety of well-established and emerging conditions in the field of allergy.
Learn More >Gerontological research reveals considerable interindividual variability in aging phenotypes, which has motivated research efforts to identify 'aging biomarkers.' Aging biomarkers are used to calculate biological age, which are better predictors of disease risk and residual lifespan when compared to chronological age alone. Emerging evidence using the epigenetic clock as an aging biomarker supports highly reliable individualized predictions about future health. The current study aimed to determine whether an epigenetic aging biomarker was associated with chronic pain in older adults (60-83 years old). A subset of participants (n=29) in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study underwent a blood draw, demographic, psychological, cognitive and pain assessments. We estimated Horvath's epigenetic clock and calculated the difference between epigenetic age and chronological age that has been previously reported to predict overall mortality risk. Older individuals without chronic pain (n=9) had significantly "younger" epigenetic age compared to those with chronic pain (n=20, p<0.05). Older epigenetic age was associated with greater pain during daily activities (r=0.494, p=0.010) and anatomical pain sites (r=0.741, p<0.001), but not pain frequency/duration. An older epigenetic age was also associated with higher vibratory detection thresholds (r=0.490, p=0.021), heat pain thresholds (r=-0.478, p=0.028), and pressure pain thresholds at the trapezius (r=-0.571, p=0.006), but not thermal detection, pressure pain at the quadriceps or pain inhibition (p's>0.05). Epigenetic aging was associated with greater emotional stability (r=-0.461, p=0.027), conscientiousness (r=-0.549, p=0.007) and lower extraversion (r=0.414, p=0.049), but not depression or affect (p's>0.05). Epigenetic aging was also associated with lower episodic (r=-0.698, p=0.001) and working memory (r=-0.760, p<0.001). Our findings suggest that chronic pain is associated with accelerated epigenetic aging in healthy, community-dwelling older individuals and future studies with larger samples are needed to confirm our findings. An aging biomarker such as the epigenetic clock may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.
Learn More >Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes Shank3 or Mecp2 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABA receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of Mecp2 and Shank3 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.
Learn More >Voltage-gated sodium (Na) channels initiate action potentials in nerve, muscle, and other electrically excitable cells. The structural basis of voltage gating is uncertain because the resting state exists only at deeply negative membrane potentials. To stabilize the resting conformation, we inserted voltage-shifting mutations and introduced a disulfide crosslink in the VS of the ancestral bacterial sodium channel NaAb. Here, we present a cryo-EM structure of the resting state and a complete voltage-dependent gating mechanism. The S4 segment of the VS is drawn intracellularly, with three gating charges passing through the transmembrane electric field. This movement forms an elbow connecting S4 to the S4-S5 linker, tightens the collar around the S6 activation gate, and prevents its opening. Our structure supports the classical "sliding helix" mechanism of voltage sensing and provides a complete gating mechanism for voltage sensor function, pore opening, and activation-gate closure based on high-resolution structures of a single sodium channel protein.
Learn More >Pain perception is associated with priming of the motor system and the orienting of attention in healthy adults. These processes correspond with decreases in alpha and beta power in the sensorimotor and parietal cortices. The goal of the present study was to determine whether these findings extend to individuals with chronic pain. Individuals with chronic jaw pain and pain-free controls anticipated and experienced a low pain or a moderate pain-eliciting heat stimulus. Although stimuli were calibrated for each subject, stimulus temperature was not different between groups. High-density EEG data were collected during the anticipation and heat stimulation periods and were analyzed using independent component analyses, EEG source localization, and measure projection analyses. Direct directed transfer function was also estimated to identify frequency specific effective connectivity between regions. Between group differences were most evident during the heat stimulation period. We report three novel findings. First, the chronic jaw pain group had a relative increase in alpha and beta power and a relative decrease in theta and gamma power in sensorimotor cortex. Second, the chronic jaw pain group had a relative increase in power in the alpha and beta bands in parietal cortex. Third, the chronic jaw pain group had less connectivity strength in the beta and gamma bands between sensorimotor cortex and parietal cortex. Our findings show that the effect of chronic pain attenuates rather than magnifies neural responses to heat stimuli. We interpret these findings in the context of system-level changes in intrinsic sensorimotor and attentional circuits in chronic pain.
Learn More >Previous studies suggest that regulatory microRNAs (miRs) may modulate neuro-inflammatory processes. The purpose of the present study was to examine the role of miR-17 following intervertebral disc herniation.
Learn More >For several widely-used patient-reported outcome measures (PROMs) in chronic musculoskeletal pain (CMSP) rehabilitation, it is still not known whether they are responsive to change, and what the smallest detectable change (SDC) and minimal clinically important change (MCIC) are. Knowledge of these values can be used to accurately interpret change scores in research and clinical practice.
Learn More >This study aimed to identify relationships between sensory function and pain in common pain conditions (Arthritis, Complex Regional Pain Syndrome (CRPS) and Fibromyalgia Syndrome (FMS)) and healthy participants. Sensory abnormalities are known to be concomitant with some types of chronic pain but comparison across pain conditions using existing research is difficult due to methodological differences. Pragmatic Quantitative Sensory Testing (QST) methods were used.
Learn More >Chronic pain is often linked to comorbidities such as anxiety and cognitive dysfunction, alterations that are reflected in brain plasticity in regions such as the prefrontal cortex and the limbic area. Despite the growing interest in pain-related cognitive deficits, little is known about the relationship between the emotional valence of the stimulus and the salience of its memory following painful injuries. We used the tibia fracture model of chronic pain in mice to determine whether pleasant and unpleasant odor location memories differ in their salience 7 weeks following the onset of the painful injury. Our results indicate that injured mice show a bias towards recalling unpleasant memories, thereby propagating the vicious cycle of chronic pain and negative affect. Next, we linked these behavioral differences to mechanisms of molecular plasticity by measuring the levels of global methylation and hydroxymethylation in the olfactory bulb. Compared to controls, global methylation levels were shown to be increased while hydroxymethylation levels were decreased in the olfactory bulb of injured mice, indicative of overall changes in DNA regulation machinery and the subsequent alterations in sensory systems.
Learn More >To assess the effects of migraine on important life domains and compare differences between respondents with episodic and chronic migraine and between sexes.
Learn More >Monitoring and modulating the diversity of signals used by neurons and glia in a closed-loop fashion is necessary to establish causative links between biochemical processes within the nervous system and observed behaviors. As developments in neural-interface hardware strive to keep pace with rapid progress in genetically encoded and synthetic reporters and modulators of neural activity, the integration of multiple functional features becomes a key requirement and a pressing challenge in the field of neural engineering. Electrical, optical and chemical approaches have been used to manipulate and record neuronal activity in vivo, with a recent focus on technologies that both integrate multiple modes of interaction with neurons into a single device and enable bidirectional communication with neural circuits with enhanced spatiotemporal precision. These technologies not only are facilitating a greater understanding of the brain, spinal cord and peripheral circuits in the context of health and disease, but also are informing the development of future closed-loop therapies for neurological, neuro-immune and neuroendocrine conditions.
Learn More >Pain is a necessary sensation that prevents further tissue damage, but can be debilitating and detrimental in daily life under chronic conditions. Neuronal activity strongly regulates the maturation of the somatosensory system, and aberrant sensory input caused by injury or inflammation during critical periods of early postnatal development can have prolonged, detrimental effects on pain processing. This review will outline the maturation of neuronal circuits responsible for the transmission of nociceptive signals and the generation of pain sensation-involving peripheral sensory neurons, the spinal cord dorsal horn, and brain-in addition to the influences of the neuroimmune system on somatosensation. This summary will also highlight the unique effects of neonatal tissue injury on the maturation of these systems and subsequent consequences for adult somatosensation. Ultimately, this review emphasizes the need to account for age as an independent variable in basic and clinical pain research, and importantly, to consider the distinct qualities of the pediatric population when designing novel strategies for pain management.
Learn More >Transient receptor potential (TRP) channels are a family of functionally diverse and widely expressed cation channels involved in a variety of cell signaling and sensory pathways. Research in the last two decades has not only shed light on the physiological roles of the 28 mammalian TRP channels, but also revealed the involvement of specific TRP channels in a plethora of inherited and acquired human diseases. Considering the historical successes of other types of ion channels as therapeutic drug targets, small molecules that target specific TRP channels hold promise as treatments for a variety of human conditions. In recent research, important new findings have highlighted the central role of TRP channels in chronic pain, lower urinary tract disorders, and type 2 diabetes, conditions with an unmet medical need. Here, we discuss how these advances support the development of TRP-channel-based pharmacotherapies as valuable alternatives to the current mainstays of treatment.
Learn More >Microglia are specialized brain-resident macrophages with important functions in health and disease. To improve our understanding of these cells, the research community needs genetic tools to identify and control them in a manner that distinguishes them from closely related cell-types. We have targeted the recently discovered microglia-specific gene to generate knock-in mice expressing EGFP (JAX#031823) or CreERT2 (JAX#031820) for the identification and manipulation of microglia, respectively. Genetic characterization of the locus and qPCR-based analysis demonstrate correct positioning of the transgenes and intact expression of endogenous in the knock-in mouse models. Immunofluorescence analysis further shows that parenchymal microglia, but not other brain macrophages, are completely and faithfully labeled in the EGFP-line at different time points of development. Flow cytometry indicates highly selective expression of EGFP in CD11bCD45lo microglia. Similarly, immunofluorescence and flow cytometry analyses using a Cre-dependent reporter mouse line demonstrate activity of CreERT2 primarily in microglia upon tamoxifen administration with the caveat of activity in leptomeningeal cells. Finally, flow cytometric analyses reveal absence of EGFP expression and minimal activity of CreERT2 in blood monocytes of the and lines, respectively. These new transgenic lines extend the microglia toolbox by providing the currently most specific genetic labeling and control over these cells in the myeloid compartment of mice. Tools that specifically label and manipulate only microglia are currently unavailable, but are critically needed to further our understanding of this cell type. Complementing and significantly extending recently introduced microglia-specific immunostaining methods that have quickly become a new standard in the field, we generated two mouse lines that label and control gene expression in microglia with high specificity and made them publicly available. Using these readily accessible mice, the research community will be able to study microglia biology with improved specificity.
Learn More >Fabry disease belongs to lysosomal storage disorders and can be successfully treated today. On the contrary, the correct diagnostic classification of its symptoms can be challenging and most patients suffer from pain for years, until they are diagnosed correctly. The aim of this project was to characterize patients with unclassified extremity pain and to present a simple algorithm for a retrospective stratification approach.
Learn More >We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.
Learn More >In this study, we investigated age and sex differences in acute and chronic pain in rats. Groups of young (3-6 mo) and aged (20-24 mo) male and female Fischer 344 rats were used to assess basal thermal and mechanical thresholds, capsaicin-induced acute nocifensive responses and c-Fos expression in the spinal cord, and monoiodoacetate (MIA)-induced knee osteoarthritis (OA)-like pain responses. There was a significant sex, but not age, effect on thermal threshold on the hindpaw and mechanical threshold on the knee joint. No significant age and sex differences in capsaicin-induced nocifensive and c-Fos responses were observed. MIA induced a greater peak reduction of weight bearing responses in aged males than young rats. Aged females developed the most profound weight bearing deficit. With knee joint sensitivity as a primary outcome measure, MIA induced more pronounced and longer-lasting hyperalgesia in older rats, with aged female rats showing the worst effect. These data suggest that age may not have significant effect on acute nociceptive processing, but it significantly impacts OA-like pain, making aged rats, especially females, more vulnerable to chronic pain conditions. These preclinical models should provide important tools to investigate basic mechanisms underlying the impact of age and sex in chronic pain conditions.
Learn More >Multivariate analysis of T2-weighted signal, diffusion ADC, and DKI parameters and tractography were used to differentiate chronic non-specific low back pain (CLBP) patients and asymptomatic controls (AC).
Learn More >α-Conotoxin Vc1.1 inhibits the nicotinic acetylcholine receptor (nAChR) α9α10 subtype and has the potential to treat neuropathic chronic pain. To date, the crystal structure of Vc1.1 bound-α9α10 nAChR remains unavailable, thus understanding the structure-activity relationship of Vc1.1 with the α9α10 nAChR remains challenging. In this study, the Vc1.1 side chains were minimally modified to avoid introducing large local conformation perturbation to the interactions between Vc1.1 and α9α10 nAChR. The results suggest that the hydroxyl group of Vc1.1 Y10 forms hydrogen bond with the carbonyl group of α9 N107 and a hydrogen bond donor is required, whereas Vc1.1 S4 is adjacent to the α9 D166 and D169, and a positive charge residue at this position increases the binding affinity of Vc1.1. Furthermore, the carboxyl group of Vc1.1 D11 forms two hydrogen bonds with α9 N154 and R81 respectively, whereas introducing an extra carboxyl group at this position significantly decreases the potency of Vc1.1. Second generation mutants of Vc1.1 [S4Dab, N9A] and [S4Dab, N9W] increased potency at the α9α10 nAChR by 20-fold compared with that of Vc1.1. The [S4Dab, N9W] mutational effects at positions 4 and 9 of Vc1.1 are not cumulative but are coupled with each other. Overall, our findings provide valuable insights into the structure-activity relationship of Vc1.1 with the α9α10 nAChR and will contribute to further development of more potent and specific Vc1.1 analogues.
Learn More >Our knowledge of central sensitization (CS) in chronic low back pain (CLBP) is limited. 2011 fibromyalgia criteria and severity scales (2011 FM survey) has been used to determine FM positive as a surrogate of CS. The major features of CS including widespread hyperalgesia and dysfunction of the descending inhibitory pathways can be identified by pressure pain threshold (PPT) and conditioned pain modulation (CPM) tests. The purpose of the study was to examine neurophysiological characteristics and psychosocial symptoms in a subgroup of FM positive CLBP compared to FM negative CLBP patients.
Learn More >Featuring a burning sensation in the tongue or other oral sites in the absence of observable lesions or laboratory findings, burning mouth syndrome (BMS) is a chronic intraoral pain disorder, which is one of the most common medically unexplained oral symptoms/syndromes. Previous studies have suggested that brain changes are involved in BMS; however, the small number of participants in these studies limited the conclusions that could be drawn. The present study aimed to further elucidate the brain anatomical and functional changes in BMS with a relatively large sample. Fifty-three patients (26 BMS patients and 27 gender- and age-matched controls) were recruited. Demographic information was collected interviews. Visual analogue scale (VAS), anxiety, and depression scale were administered. Participants underwent an MRI scan (including one high-resolution structural scan, one diffusion tensor image, and one session of resting state scan) on the same day. The results showed that BMS patients had higher depression and anxiety levels than controls. BMS patients showed lower gray matter volume (GMV) in the bilateral ventromedial prefrontal cortex (VMPFC) and increased functional connectivity between this region and the bilateral amygdala. Region of interest (ROI) analysis suggested that the functional connectivity between the bilateral VMPFC and amygdala correlated with the years of BMS illness in patients. The brain measures could predict the years of symptoms in the BMS group. These results suggest A potential neuromarker for the diagnosis and treatment of BMS.
Learn More >Nerve damage leads to the development of disabling neuropathic pain in susceptible individuals, where patients present with pain as well as co-morbid affective behavioural disturbances, such as anhedonia, decreased motivation and depression. In this study we aimed to characterise changes in neuroinflammation in the medial prefrontal cortex (mPFC) and hippocampus (HP) in a rat model of neuropathic pain (NP) and behavioural changes. 53 rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either, No effect, Acute effect or Lasting effect on the basis of changes in exploration behaviour in a radial-arm maze. Microglial and astrocyte morphology, as well as IL-1β, IL-6, IL-10, MCP-1, p38 MAPK and BDNF expression were quantified throughout the mPFC and HP using protein multiplex assays and immunofluorescence. All behavioural groups of CCI rats displayed equal levels of mechanical allodynia, however the characteristic withdrawal from pellet-seeking observed in Lasting effect rats was accompanied by neuroimmune activation within the contralateral ventral HP and mPFC. This includes increased expression of IL-1β, IL-6 and MCP-1, increased phospho-p38 MAPK expression in neurons and microglia, and a shift to a reactive microglial morphology in the caudal PL and IL, ventral CA1 and DG. Therefore, neuroinflammation in the mPFC and ventral HP may influence individual differences in radial-arm maze behaviour following CCI. Our data provide further evidence that individual differences in neuroimmune activation in the interconnected ventral HP-mPFC circuitry may play a role in the divergent behavioural trajectories following nerve injury, with neuroinflammation being coincident with affective behavioural changes in susceptible individuals.
Learn More >The study reported here investigated the role of the central vascular endothelial growth factor-A (VEGF-A) pathway in the development of trigeminal neuropathic pain following nerve injury. A Sprague-Dawley rat model of trigeminal neuropathic pain was produced using malpositioned dental implants. The left mandibular second molar was extracted under anesthesia and replaced with a miniature dental implant to induce injury to the inferior alveolar nerve. The inferior alveolar nerve injury produced a significant upregulation of astrocytic VEGF-A expression in the medullary dorsal horn. The nerve injury-induced mechanical allodynia was inhibited by an intracisternal infusion of VEGF-A164 antibody. Although both VEGF-A Receptor 1 (VEGF-A R1; colocalized with the blood-brain barrier) and VEGF-A Receptor 2 (VEGF-A R2; colocalized with astrocytes) participated in the development of trigeminal neuropathic pain following nerve injury, only the intracisternal infusion of a VEGF-A R1 antibody, and not that of a VEGF-A R2 antibody, inhibited the increased blood-brain barrier (BBB) permeability produced by nerve injury. Finally, we confirmed the participation of the central VEGF-A pathway in the development of trigeminal neuropathic pain by reducing VEGF-A expression using VEGF-A164 siRNA. This suppression of VEGF-A produced significant prolonged anti-allodynic effects. These results suggest that the central VEGF-A pathway plays a key role in the development of trigeminal neuropathic pain following nerve injury through two separate pathways: VEGF-A R1 and VEGF-A R2. Hence, a blockade of the central VEGF-A pathway provides a new therapeutic avenue for the treatment of trigeminal neuropathic pain.
Learn More >Bone cancer pain (BCP) is common in patients with advanced cancers as tumors metastasize to bone. Pathogenesis of BCP is complex and poorly understood which leads to inefficiency of clinical treatment. During pathological pain status, astrocytes are activated and release various inflammatory cytokines, which result in the development of peripheral and central sensitization. As energy factory, mitochondria undergo frequent fusion and fission and play essential role for astrocyte function. 2-bromopalmitate (2-BP) is an inhibitor of protein palmitoylation, and its function on BCP was unclear. In this paper, we aimed to investigate the potential curative effects and mechanisms of 2-BP on bone cancer pain. BCP rat model was established through intratibial inoculation of rat mammary gland carcinoma cells (MRMT-1) into the left tibia of Sprague-Dawley female rats. As a result, BCP rats exhibited bone destruction and sensitive nociceptive behavior. And increased leukocyte infiltration, activation of astrocytes, and imbalance of mitochondrial fission and fusion dynamics were observed in spinal cord of BCP rats. Intrathecal 2-BP administration significantly attenuated pain behavior of BCP rats. Meanwhile, 2-BP administration reduced spinal inflammation, reversed spinal mitochondrial fission and fusion dynamic imbalance, and further inhibited spinal mitochondrial apoptosis in BCP rats. In C6 cell level, 2-BP treatment decreased Drp1 expression and increased OPA1 expression in a dose-dependent manner, and inhibited CCCP-induced mitochondrial membrane potential change. These data illustrated that 2-BP attenuated bone cancer pain by reversing mitochondrial fusion and fission dynamic imbalance in spinal astrocytes.
Learn More >The CDC Guideline for Prescribing Opioids for Chronic Pain recommends considering prescribing naloxone when factors that increase risk for overdose are present (e.g., history of overdose or substance use disorder, opioid dosages ≥50 morphine milligram equivalents per day [high-dose], and concurrent use of benzodiazepines). In light of the high numbers of drug overdose deaths involving opioids, 36% of which in 2017 involved prescription opioids, improving access to naloxone is a public health priority. CDC examined trends and characteristics of naloxone dispensing from retail pharmacies at the national and county levels in the United States.
Learn More >Marijuana use is common among patients on long-term opioid therapy (LTOT) for chronic pain, but there is a lack of evidence to guide clinicians' response.
Learn More >We investigated the calcium dynamics of dorsal root ganglion (DRG) neurons using transgenic mice to target expression of the genetically encoded calcium indicator (GECI), GCaMP6s, to a subset of neurons containing parvalbumin (PV), a calcium-binding protein present in proprioceptors and low-threshold mechanoreceptors. This study provides the first analysis of GECI calcium transient parameters from large-diameter DRG neurons. Our approach generated calcium transients of consistent shape and time-course, with quantifiable characteristics. Four parameters of calcium transients were determined to vary independently from each other and thus are likely influenced by different calcium-regulating mechanisms: peak amplitude, rise time (RT), decay time, and recovery time. Pooled analysis of 188 neurons demonstrated unimodal distributions, providing evidence that PV+ DRG neurons regulate calcium similarly as a population despite their differences in size, electrical properties, and functional sensitivities. Calcium transients increased in size with elevated extracellular calcium, longer trains of action potentials, and higher stimulation frequencies. RT and decay time increased with the addition of the selective sarco/endoplasmic reticulum calcium ATPases (SERCA) blocker, thapsigargin (TG), while peak amplitude and recovery time remained the same. When elevating bath pH to 8.8 to block plasma-membrane calcium ATPases (PMCA), all measured parameters significantly increased. These results illustrate that GECI calcium transients provide sufficient resolution to detect changes in electrical activity and intracellular calcium concentration, as well as discern information about the activity of specific subclasses of calcium regulatory mechanisms.
Learn More >Transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS) have been described as promising alternatives to treat different pain syndromes. This study evaluated the effects of TMS and tDCS in the treatment of chronic orofacial pain, through a systematic review.
Learn More >The primary objective of this systematic review was to identify the characteristics of physicians who prescribe opioids to adults with chronic pain. This review was limited to studies examining fully-trained physicians, as relevant characteristics of resident physicians and non-physician clinicians may differ. A comprehensive search of databases from January 1, 1980 to December 5, 2017 was conducted. Eligible study designs included (1) randomized trials; (2) nonrandomized prospective and retrospective studies; and (3) cross-sectional observational studies. The risk of bias in the included studies was assessed using an adapted version of the Newcastle-Ottawa Scale for cross-sectional studies. A total of 2508 records were screened and 22 studies met inclusion criteria. The majority of studies were cross-sectional (n=20) and the total number of participants was 8433. The risk of bias was high overall. The majority of physicians were confident managing and prescribing opioids for chronic pain but had high levels of dissatisfaction. Physicians reported high awareness of the potential for opioid misuse and were concerned about inadequate prior training in pain management. The majority of physicians were less likely to prescribe for patients with a history of substance abuse and reported major concerns about regulatory scrutiny. This systematic review provides the foundation for the development of prospective studies aimed at further elucidating the constellation of mechanisms that influence physicians who manage pain and prescribe opioids.
Learn More >Therapeutic virtual reality (VR) has emerged as an effective, drug-free tool for pain management, but there is a lack of randomized, controlled data evaluating its effectiveness in hospitalized patients. We sought to measure the impact of on-demand VR versus "health and wellness" television programming for pain in hospitalized patients.
Learn More >To study the long-term evolution of patients with lower-limb Complex Regional Pain Syndrome (CRPS), focusing on functional and proprioceptive aspects and quality of life. In 20 patients suffering from chronic distal lower-limb CRPS diagnosed using Budapest criteria, we assessed joint position sense and strength of the knee muscles at the CRPS and unaffected leg, functional exercise capacity, pain, CRPS severity score, quality of life and kinesiophobia. Similar assessments were performed in 20 age-matched controls. The joint position performance (at 45°) was significantly lower for the CRPS leg as compared to controls. The knee extensor strength of the CRPS leg was significantly reduced as compared to the unaffected leg (-27%) and controls (-42%). CRPS patients showed significantly reduced performance at the 6 min-walk test as compared to their age group predicted value and controls. Patients suffering from CRPS for 3.8 years in average still exhibit high pain, severity and kinesiophobia scores. Long-term deficits in strength and proprioceptive impairments are observed at the knee joint of the CRPS leg. This persistent functional disability has significant repercussions on the quality of life. We highlight the importance of including strength and proprioceptive exercises in the therapeutic approaches for CPRS patients. IMPLICATIONS FOR REHABILITATION The long-term evolution of patients suffering from lower-limb Complex Regional Pain Syndrome is associated with persistent disability, pain and impacts the quality of life. Strength, proprioceptive, functional and subjective assessments are necessary to better identify deficits. Rehabilitation should focus on the overall deficit of the affected and contralateral limb.
Learn More >To investigate the correlation between the numerical rating scale, visual analogue scale, and pressure threshold by algometry in women with chronic pelvic pain.
Learn More >This study determined the role of miR-1906 in neuropathic pain and proliferation in neuronal cells using a chronic constriction injury (CCI)-induced neuropathic pain (NP) rat model.
Learn More >Some studies have indicated that a local injection of Botulinum Toxin Type A (BTX-A) is a promising therapy for trigeminal neuralgia (TN). However, BTX-A treatment is still ineffective for approximately 10-43% of patients. We therefore investigated which factors are associated with the therapeutic effect in BTX-A treatment of medically refractory, classical TN.
Learn More >We aimed to evaluate the role of caffeinated beverage intake as a potential trigger of migraine headaches on that day or on the following day.
Learn More >Is acupuncture an effective postherpetic neuralgia treatment? A systematic review and meta-analysis.
Postherpetic neuralgia (PHN) refers to pain which remains after the healing of rashes from herpes zoster. Previous literatures have shown that acupuncture has potential benefits for PHN, but evidence remains lacking. Thus, we have performed a systematic review and meta-analysis to identify the effectiveness of acupuncture in the treatment of PHN.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of several anti-neoplastics and a main cause of sensory disturbances in cancer survivors, negatively impacting patients' quality of life. Peripheral nerve degeneration or small fibre neuropathy is generally accepted as the underlying mechanism in the development of CIPN. Recent evidence has contributed to clarify the determinant role of cytokines and chemokines in the process leading to neuronal hyperexcitability. Exposure to oxaliplatin triggers alterations in peripheral neuropathic pathways previously linked to IL-8 pathway. We investigated a novel selective inhibitor of IL-8 receptors, DF2726A, and showed its effects in counteracting CINP pathways, extending the relevance of the activation of IL-8 pathway to the class of platinum chemotherapeutics. Based on our results, we suggest that DF2726A might be a promising candidate for clinical treatment of CIPN conditions due to its efficacy and optimized pharmacokinetic/pharmacodynamic profile.
Learn More >Spinal cord injury (SCI) leads to sensorimotor deficits and autonomic changes. Macrophages and microglia could be polarized into the classically activated pro-inflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype. Transmembrane protein with unknown function 16F (TMEM16F) exhibits functional diversity and may contribute to microglial function. However, the effects of TMEM16F on the modulation of macrophage/microglial polarization are still not fully understood. In the study, TMEM16F up-regulation was detected after SCI in mice, and TMEM16F protein was found in macrophages/microglia in injured spinal cord sections. Depletion of TMEM16F improved motor function in male mice with SCI. M1-type macrophages/microglia accumulated in lower numbers in the injured spinal cord of TMEM16F-knockout (KO) mice. M2 polarization inhibited by SCI was improved in mice with TMEM16F deficiency. TMEM16F deletion also attenuated microglial/macrophage pro-inflammatory response. Furthermore, significant down-regulation of A disintegrin and metalloprotease 17 (ADAM17) was observed in TMEM16F-KO mice. Importantly, TMEM16F-promoted M1 polarization and -inhibited M1 polarization were largely associated with the suppression of ADAM17. Overall, our findings provided new insights into the regulatory mechanisms of macrophage/microglial polarization, thereby possibly facilitating the development of new therapeutic strategies for SCI through the regulation of TMEM16F/ADAM17 signaling.
Learn More >Adults with persistent pain frequently report cannabis use to help manage their symptoms. The impact of cannabis use on cognition in the presence of concurrent symptoms of depression and anxiety is poorly understood.
Learn More >Neurofeedback (NFB) is a neuromodulatory technique that enables voluntary modulation of brain activity in order to treat neurological condition, such as central neuropathic pain (CNP). A distinctive feature of this technique is that it actively involves participants in the therapy. In this feasibility study, we present results of participant self-managed NFB treatment of CNP.
Learn More >Preemptive Analgesia With Oxycodone Is Associated With More Pain Following Total Joint Arthroplasty.
Preemptive multimodal analgesia (PMA) is a commonly used technique to control pain following total joint arthroplasty. PMA protocols use multiple analgesics immediately preoperatively to prevent central sensitization and amplification of pain during surgery. While benefits of some individual components of a PMA protocol have been established, there are little data to support inclusion or exclusion of opioids in this context.
Learn More >Cannabis is often used to manage pain among persons who suffer from chronic pain. Yet, despite much literature suggesting cannabis use problems are associated with mental health problems, little work has examined mechanisms of this relationship among a chronic pain population. Chronic pain is also associated with emotion dysregulation. Individuals with chronic pain who experience cannabis use problems may have less capacity to regulate negative emotions, which could relate to greater anxiety, depression, and suicidal ideation. Thus, the current study explored whether emotion dysregulation explained, in part, the relation between cannabis use problems and anxiety, depression, and suicidal ideation among adults with chronic pain. Participants were 431 opioid-using adults with current moderate to severe chronic pain, 176 were current cannabis users, of which 30.20% reported cannabis use problems. Results indicated a significant indirect relationship between cannabis use problems and anxiety [95% CI (.03, .05)], depression [95% CI (.03, .06)], and suicidal ideation [95% CI (.01, .01)] via emotion dysregulation. Tests of specificity suggested potential for a bi-directional effect for suicidal ideation (.001). Initial findings suggest that emotion dysregulation may be an important mechanism in the relationship between cannabis use problems and mental health among adults with chronic pain.
Learn More >Neuropathic pain represents one of the most common complications associated with diabetes mellitus (DM) that impacts quality of life. Accumulating studies have highlighted the involvement of microRNAs (miRNAs) in DM. Thus, the current study aimed to investigate the roles of microRNA-155 (miR-155) in diabetic peripheral neuropathy (DPN). In vitro DPN models were established using rat Schwann cells (SCs) by treatment with 5.5 mM glucose. Gain- or loss-of-function studies were conducted to determine the effect of miR-155 on Nrf2, cellular function, reactive oxygen species, and inflammation. Rat DNP models were established by streptozotocin injection and damage of sciatic nerve. Next, miR-155 antagomir or agomir was employed to investigate the effects associated with miR-155 on motor and sciatic nerve conduction velocity (MNCV, SNCV), angiogenesis and inflammatory response in vivo. Nrf2 was identified to be a target of miR-155 by dual-luciferase reporter gene assay. Silencing of miR-155 or restoration of Nrf2 promoted cell proliferation, inhibited apoptosis and alleviated inflammation in vitro. miR-155 antagomir-induced inhibition increased MNCV and SNCV, strengthened angiogenesis and alleviated inflammation in DPN rats. Additionally, the effects exerted by miR-155 were reversed when Nrf2 was restored both in vitro and in vivo. Taken together, the key findings of our study provide evidence indicating that miR-155 targeted and suppressed Nrf2 in DPN. miR-155 silencing was found to alleviate sciatic nerve injury in DPN, highlighting its potential as a therapeutic target for DPN.
Learn More >Prognostic screening of people with low back pain (LBP) improves utilisation of primary healthcare resources. Whether this also applies to secondary healthcare remains unclear. Therefore, this study aims to develop prognostic models to determine at baseline which patients with persistent LBP are likely to have a good and poor outcome to a 5-week programme of combined education and exercise ('UPLIFT') delivered in a secondary healthcare setting.
Learn More >Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets.
Learn More >Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long-term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra (PATH) study showed subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, we assess patient-reported outcomes in patients on SCIG.
Learn More >Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (K1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20-30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.
Learn More >Neck pain is considered a common characteristic of migraine attacks. The relationship between neck pain and migraine can be explained by central sensitization of the trigeminocervical complex, where superior cervical afferents and the trigeminal nerve converge. However, few studies have evaluated motor control of cervical muscles in individuals with migraine. Thus, the purpose of the present study was to determine the extensor/flexor ratio of neck muscle strength and electromyographic activity during a test of maximal voluntary isometric contraction and craniocervical flexion in individuals with migraine and individuals without history of migraine or other headaches.
Learn More >Patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) commonly experience learning and memory decline and the underlying pathogenesis remains unclear. Therefore, we aimed to study the effects of CP/CPPS on cognitive function by using a mouse model of experimental autoimmune prostatitis (EAP). Non-obese diabetic mice were immunized subcutaneously by prostate antigen and adjuvant twice and tested for cognitive performance by Morris water maze and novel object recognition test after the EAP induction. Then, dendritic complexity and spine densities were measured by using the Golgi-Cox procedure. Transmission electron microscopy was used to observe the synaptic morphology. In addition, activation of microglia and its association with synapses were also investigated by immunofluorescence staining. Our results showed that EAP induced a notable decrease in the learning and memory ability of mice, simultaneously causing a reduction in dendritic complexity detected by Sholl analysis. Likewise, the spine densities and synaptic proteins including synaptophysin and postsynaptic density protein 95 (PSD95) were significantly decreased in the EAP group. These observations were also accompanied by structural changes in synaptic plasticity. Additionally, EAP mice showed microglial activation in the hippocampus, and these activated microglia further increased contact with synaptic terminals. Taken together, our data are the first to indicate that EAP induces cognitive declines and structural neuroplastic changes in mice, accompanied by microglial activation and microglia-synapse contacts.
Learn More >Chronic non-malignant pain has a major impact on the well-being, mood and productivity of those affected. Opioids are increasingly prescribed to manage this type of pain, but with a risk of other disabling symptoms, when their effectiveness has been questioned. This trial is designed to implement and evaluate a patient-centred intervention targeting withdrawal of strong opioids in people with chronic pain.
Learn More >Irritable bowel syndrome patients frequently complain of pain in body regions somatotopically distinct from the gut, suggesting the involvement of an exaggerated signaling process in both visceral and somatic sensory pathways. Increasing evidence has shown that sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibers toward sensory neurons in dorsal root ganglia maintains and exacerbates the neuropathic and inflammatory pain, as well as colonic inflammation. The aim of the present study was to determine whether electroacupuncture could alleviate the visceral and secondary somatic hyperalgesia in colitis rats by suppressing the TH-IR expression in related dorsal root ganglia. After trinitrobenzene sulfonic acid irritation, rats developed inflammatory tissue damage in the distal colon, which was accompanied by visceral hypersensitivity and secondary hind paw hyperalgesia, as indicated by enhanced visceromotor response to colorectal distension and decreased mechanical and thermal withdrawal latency of the hind paw. Additionally, excessive TH-IR fibers sprouted toward calcitonin gene-related peptide immunoreactive sensory neurons, and TH-IR neurons also increased in the sixth lumbar dorsal root ganglia of colitis rats. Both electroacupuncture and guanethidine attenuated visceral and referred hind paw hyperalgesia by inhibiting the over-expression of TH-IR neurons and fibers in the sixth lumbar dorsal root ganglia. Moreover local inflammatory damage in the distal colon was restored after 7 days of electroacupuncture intervention. These results suggest that electroacupuncture relieved visceral and referred hind paw hypersensitivity in colitis rats by inhibiting TH expression in the sixth lumbar dorsal root ganglia.
Learn More >Distress, suffering, and care-seeking behavior are characteristics of pain-related disease and illness. Pain that transitions from an acute to a chronic phase carries with it the potential of further effects: these include a worsening of the disease or illness; high-impact chronic pain; and substantial personal, societal, and economic burden. The biopsychosocial model directly addresses these multiple processes, yet clinical frameworks supporting this model are not universally implemented. This paper explores barriers to clinical implementation of a full biopsychosocial framework for temporomandibular disorders (TMD) and other orofacial pain (OFP) conditions. In June 2016, INfORM invited OFP researchers to a workshop designed to optimize the DC/TMD Axis-II. Workshop groups identified five sources of implementation barriers: (1) cultures and societies, (2) levels-of-care settings, (3) health services, (4) cross-cultural validity of self-report instruments, and (5) provider and patient health literacy. Three core problems emerged: (A) mental health aspects are seldom fully considered, thus impairing the recognition of illness, (B) training in use of validated multi-axial assessment protocols is under-rated and insufficiently used, and (C) clinical assessment often fails to recognize that sensory and emotional dimensions are fundamental aspects of pain. To improve patient care, these barriers and problems require action. Most importantly, TMD/OFP educators and researchers need to coordinate globally and (i) be educated in the biopsychosocial model, (ii) implement evidence-based biopsychosocial guidelines for assessment and management of OFP conditions at their institutions, (iii) incorporate this model in undergraduate and postgraduate dental curricula, and (iv) be responsive to stakeholders, including regulatory authorities and practitioners. This article is protected by copyright. All rights reserved.
Learn More >The chronic constriction injury (CCI) of the sciatic nerve is a nerve injury-based model of neuropathic pain (NP). Comorbidities of NP such as depression, anxiety, and cognitive deficits are associated with a functional reorganization of the medial prefrontal cortex (mPFC). Here, we have employed an adapted model of CCI by placing one single loose ligature around the sciatic nerve in mice for investigating the alterations in sensory, motor, affective, and cognitive behavior and in electrophysiological and biochemical properties in the prelimbic division (PrL) of the mPFC. Our adapted model of CCI induced mechanical allodynia, motor, and cognitive impairments and anxiety- and depression-like behavior. In the PrL division of mPFC was observed an increase in GABA and a decrease in d-aspartate levels. Moreover an increase in the activity of neurons responding to mechanical stimulation with an excitation, mPFC (+), and a decrease in those responding with an inhibition, mPFC (-), was found. Altogether these findings demonstrate that a single ligature around the sciatic nerve was able to induce sensory, affective, cognitive, biochemical, and functional alterations already observed in other neuropathic pain models and it may be an appropriate and easily reproducible model for studying neuropathic pain mechanisms and treatments.
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