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In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. Mutations in PRDM12 have been identified in CIP patients that indicate a putative role for this transcriptional regulator in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we find that Prdm12 is required for the initiation and maintenance of the expression of TrkA by acting as a modulator of Neurogenin1/2 transcription factor activity, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics.
Learn More >The sensation of pain is essential for the preservation of the functional integrity of the body. However, the key molecular regulators necessary for the initiation of the development of pain-sensing neurons have remained largely unknown. Here, we report that, in mice, inactivation of the transcriptional regulator PRDM12, which is essential for pain perception in humans, results in a complete absence of the nociceptive lineage, while proprioceptive and touch-sensitive neurons remain. Mechanistically, our data reveal that PRDM12 is required for initiation of neurogenesis and activation of a cascade of downstream pro-neuronal transcription factors, including NEUROD1, BRN3A, and ISL1, in the nociceptive lineage while it represses alternative fates other than nociceptors in progenitor cells. Our results thus demonstrate that PRDM12 is necessary for the generation of the entire lineage of pain-initiating neurons.
Learn More >All preclinical procedures for analgesic drug discovery involve two components: 1) a "pain stimulus" (the principal independent variable), which is delivered to an experimental subject with the intention of producing a pain state; and 2) a "pain behavior" (the principal dependent variable), which is measured as evidence of that pain state. Candidate analgesics are then evaluated for their effectiveness to reduce the pain behavior, and results are used to prioritize drugs for advancement to clinical testing. This review describes a taxonomy of preclinical procedures organized into an "antinociception matrix" by reference to their types of pain stimulus (noxious, inflammatory, neuropathic, disease related) and pain behavior (unconditioned, classically conditioned, operant conditioned). Particular emphasis is devoted to pain behaviors and the behavioral principals that govern their expression, pharmacological modulation, and preclinical-to-clinical translation. Strengths and weaknesses are compared and contrasted for procedures using each type of behavioral outcome measure, and the following four recommendations are offered to promote strategic use of these procedures for preclinical-to-clinical analgesic drug testing. First, attend to the degree of homology between preclinical and clinical outcome measures, and use preclinical procedures with behavioral outcome measures homologous to clinically relevant outcomes in humans. Second, use combinations of preclinical procedures with complementary strengths and weaknesses to optimize both sensitivity and selectivity of preclinical testing. Third, take advantage of failed clinical translation to identify drugs that can be back-translated preclinically as active negative controls. Finally, increase precision of procedure labels by indicating both the pain stimulus and the pain behavior in naming preclinical procedures.
Learn More >Since noxious stimulation usually leads to the perception of pain, pain has traditionally been considered sensory nociception. But its variability and sensitivity to a broad array of cognitive and motivational factors have meant it is commonly viewed as inherently imprecise and intangibly subjective. However, the core function of pain is motivational-to direct both short- and long-term behavior away from harm. Here, we illustrate that a reinforcement learning model of pain offers a mechanistic understanding of how the brain supports this, illustrating the underlying computational architecture of the pain system. Importantly, it explains why pain is tuned by multiple factors and necessarily supported by a distributed network of brain regions, recasting pain as a precise and objectifiable control signal.
Learn More >Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. In nerve-injured rats, oxytocin depolarized LTMRs towards normal (Em = -69 ± 1.9 mV) and, in 6 of 21 neurons, resulted in spontaneous action potentials. By contrast, oxytocin hyperpolarized HTMRs (Em = -68 ± 2.7 mV before vs -80 ± 3.2 mV during oxytocin exposure; P < 0.01). These effects were reversed after removal of oxytocin, and oxytocin had minimal effects in neurons from sham surgery animals. Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 μm, range 16-57 μm) than immunonegative neurons (26 ± 3.4 μm, range 15-43 μm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.
Learn More >To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions.
Learn More >Few investigations examine patterns of opioid and nonopioid analgesic prescribing and concurrent pain intensity ratings before and after institution of safer prescribing programs such as the October 2013 Veterans Health Administration system-wide Opioid Safety Initiative (OSI) implementation. We conducted a quasi-experimental pre-post observational study of all older U.S. veterans (≥50 years old) with osteoarthritis of the knee or hip. All associated outpatient analgesic prescriptions and outpatient pain intensity ratings from January 1, 2012 to December 31, 2016, were analyzed with segmented regression of interrupted time series. Standardized monthly rates for each analgesic class (total, opioid, nonsteroidal anti-inflammatory drug, acetaminophen, and other study analgesics) were analyzed with segmented negative binomial regression models with overall slope, step, and slope change. Similarly, segmented linear regression was used to analyze pain intensity ratings and percentage of those reporting pain. All models were additionally adjusted for age, sex, and race. Before OSI implementation, total analgesic prescriptions showed a steady rise, abruptly decreasing to a flat trajectory after OSI implementation. This trend was primarily due to a decrease in opioid prescribing after OSI. Total prescribing after OSI implementation was partially compensated by continuing increased prescribing of other study analgesics as well as a significant rise in acetaminophen prescriptions (post-OSI). No changes in nonsteroidal anti-inflammatory drug prescribing were seen. A small rise in the percentage of those reporting pain but not mean pain intensity ratings continued over the study period with no changes associated with OSI. Changes in analgesic prescribing trends were not paralleled by changes in reported pain intensity for older veterans with osteoarthritis.
Learn More >This study investigated the safety and efficacy of mirogabalin, a novel, potent, selective ligand of the α2δ subunit of voltage-dependent Ca channels, for the treatment of postherpetic neuralgia (PHN). In this multicenter, double-blind, placebo-controlled phase 3 study, Asian patients ≥20 years with PHN were randomized 2:1:1:1 to placebo or mirogabalin 15, 20, or 30 mg/day for up to 14 weeks (NCT02318719). The primary efficacy endpoint was the change from baseline in average daily pain score at week 14, defined as a weekly average of daily pain (0 = "no pain" to 10 = "worst possible pain," for the last 24 hours). Of 765 patients randomized, 763 received ≥ 1 dose of the study drug and were included in the analysis; 303, 152, 153, and 155 received placebo, mirogabalin 15, 20, or 30 mg/day, respectively. A total of 671 (87.7%) patients completed the study. At week 14, the difference in average daily pain score least squares mean vs placebo was -0.41, -0.47, and -0.77, respectively; all mirogabalin groups showed statistical significance. The most common treatment-emergent adverse events were somnolence, nasopharyngitis, dizziness, weight increase, and edema, and all of them were mild or moderate in severity. Mirogabalin was superior to placebo in all groups for relieving PHN and appeared well tolerated.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Functional abdominal pain disorders (FAPD) are common among young individuals. To date, relatively little is known regarding the function of the endogenous analgesic mechanisms in this vulnerable group. Therefore, this case-control study aimed to compare conditioned pain modulation (CPM), pressure algometry and psychosocial variables in 39 young children (aged 6-12 years) with FAPD and 36 age-and sex-matched pain-free controls. Pressure algometry was used to assess pressure pain thresholds at both symptomatic (umbilicus) as remote (trapezius and tibia) test sites. CPM was recorded as an increase in the pressure pain threshold at the trapezius test site in response to experimental conditioning pain imposed by the cold pressure task (12°C ± 1°C). The assessors were blinded to the diagnoses. Parent-proxy and/or self-reported questionnaires were used to assess child's pain intensity, functional disability, pain-related fear and parental pain catastrophizing. Compared with pain-free controls, young children with FAPD showed lower pressure pain thresholds at all test sites (P<0.05), a lower CPM response (P=0.02), more functional disability (P<0.001) and pain-related fear (P<0.001). Parents of children with FAPD catastrophized more about their child's pain than parents of healthy children (P<0.001). No sex differences were found for the experimental pain measurements (P>0.05), nor was there a significant correlation between the child-and parent questionnaires and the CPM-effect (P>0.05). In summary, young children with FAPD demonstrated secondary hyperalgesia and decreased functioning of endogenous analgesia.
Learn More >Although chronic postsurgical pain (CPSP) is a major health care problem, pain-related functional interference has rarely been investigated. Using the PAIN OUT registry we evaluated patients' pain-related outcomes on the first postoperative day, and their pain-related interference with daily living (Brief Pain Inventory) and neuropathic symptoms (DN4: douleur neuropathique en 4 questions) at six months after surgery. Endpoints were pain interference total scores (PITS) and their association with pain and DN4 scores. Furthermore, possible risk factors associated with impaired function at M6 were analyzed by ordinal regression analysis with PITS groups (no to mild, moderate and severe interference) as a dependent three-stage factor. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Of 2,322 patients, 15.3% reported CPSP with an average pain score ≥3 (NRS 0-10). Risk for a higher PITS group increased by 190% (OR (95%-CI): 2.9 (2.7-3.2); p<0.001) in patients with, compared to without CPSP. A positive DN4 independently increased risk by 29% (1.3 (1.12-1.45), p<0.001). Pre-existing chronic pain (3.6 (2.6-5.1); p<0.001), time spent in severe acute pain (2.9 (1.3-6.4); p=0.008), neurosurgical back surgery in males (3.6 (1.7-7.6); p<0.001) and orthopedic surgery in females (1.7 (1.0-3.0); p=0.036) were the variables with strongest association with PITS. PITS might provide more precise information about patients' outcomes than pain scores only. As neuropathic symptoms increase PITS, a suitable instrument for their routine assessment should be defined.
Learn More >Data from preclinical research has been suggested to suffer from a lack of inherent reproducibility across laboratories. The goal of our study was to replicate findings from a previous report that demonstrated positive effects of Meteorin, a novel neurotrophic factor, in a rat model of neuropathic pain induced by chronic constriction injury (CCI). Notably, 5-6 intermittent s.c. injections of Meteorin had been reported to produce reversal of mechanical allodynia/thermal hyperalgesia post-injury wherein maximum efficacy of Meteorin was reached slowly and outlasted the elimination of the compound from the blood by several weeks. Here, we evaluated the efficacy of Meteorin in reversing hindpaw mechanical hyperalgesia and cold allodynia in male, Sprague-Dawley rats with CCI. Nociceptive behavior was monitored before and after CCI, and after drug treatment until day 42 post-injury. Systemic administration of recombinant mouse Meteorin (0.5 and 1.8 mg/kg, s.c.) at days 10, 12, 14, 17 and 19 after CCI produced a prolonged reversal of neuropathic hypersensitivity with efficacy comparable to that obtained with gabapentin (100 mg/kg, p.o.). Despite some protocol deviations (e.g. nociceptive endpoint, animal vendor, testing laboratory, investigator, etc.) being incurred these did not affect study outcome. By paying careful attention to key facets of study design, using bioactive material, and confirming drug exposure, the current data have replicated the salient findings of the previous study promoting confidence in further advancement of this novel molecule as a potential therapy for neuropathic pain.
Learn More >The role of sex hormones on postsurgical pain perception is basically unclear. Here we studied the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision.A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design). Somatosensory profiles were assessed at baseline and 1-72 h after incision by quantitative sensory testing (QST), compared between both cycle phases and related to individual plasma levels of gonadal hormones.Sensory testing at baseline revealed significantly lower pain thresholds (25 vs. 46 mN, p<0.005) and increased pain ratings to pinprick (0.96 vs. 0.47, p<0.0001) in the luteal phase; similar, one hour after incision, pain intensity to incision (38 vs. 21/100, p<0.005), pinprick hyperalgesia by rating (p<0.05) and area of secondary hyperalgesia (p<0.001) were enhanced in the luteal phase. Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r= 0.67, p<0.001), FSH (partial r=0.61, p<0.005) and negatively by testosterone (partial r=-0.44, p<0.05). Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r=0.70, r=0.46 and r=0.47, respectively; p<0.05-0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures.In conclusion, pinprick pain as well as incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone suggesting a major role for progesterone. Other hormones involved are testosterone (protective) and in part FSH.
Learn More >Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically, post-surgical pain continues to be a frequent and undermanaged condition. Here, we investigate the analgesic potential of pharmacological NaV1.7 inhibition in a mouse model of acute post-surgical pain, based on incision of the plantar skin and underlying muscle of the hind paw. We demonstrate that local and systemic treatment with the selective NaV1.7 inhibitor μ-theraphotoxin-Pn3a is effectively anti-allodynic in this model and completely reverses mechanical hypersensitivity in the absence of motor adverse effects. In addition, the selective NaV1.7 inhibitors ProTx-II and PF-04856264 as well as the clinical candidate CNV1014802 also reduced mechanical allodynia. Interestingly, co-administration of the opioid receptor antagonist naloxone completely reversed analgesic effects of Pn3a, indicating an involvement of endogenous opioids in the analgesic activity of Pn3a. Additionally, we found super-additive antinociceptive effects of sub-therapeutic Pn3a doses not only with the opioid oxycodone but also with the GABAB receptor agonist baclofen. Transcriptomic analysis of gene expression changes in dorsal root ganglia of mice post-surgery did not reveal any changes in mRNA expression of endogenous opioids or opioid receptors, however several genes involved in pain, including Runx1 (Runt related transcription factor 1), Cacna1a (CaV2.1) and Cacna1b (CaV2.2) were downregulated. In summary, these findings suggest that pain after surgery can be successfully treated with NaV1.7 inhibitors alone or in combination with baclofen or opioids, which may present a novel and safe treatment strategy for this frequent and poorly managed condition.
Learn More >Exercise is considered an important component of effective chronic pain management and it is well established that long term exercise training provides pain relief. In healthy, pain-free populations, a single bout of aerobic or resistance exercise typically leads to exercise induced hypoalgesia (EIH), a generalized reduction in pain and pain sensitivity that occurs during exercise and for some time afterwards. In contrast, EIH is more variable in chronic pain populations and is more frequently impaired; with pain and pain sensitivity decreasing, remaining unchanged or, in some cases, even increasing in response to exercise. Pain exacerbation with exercise may be a major barrier to adherence, precipitating a cycle of physical inactivity that can lead to long-term worsening of both pain and disability. In order to optimize the therapeutic benefits of exercise, it is important to understand how EIH works, why it may be impaired in some people with chronic pain and how this should be addressed in clinical practice. In this article, we provide an overview of EIH across different chronic pain conditions. We discuss possible biological mechanisms of EIH and the potential influence of sex and psychosocial factors, both in pain-free adults and, where possible, individuals with chronic pain. Clinical implications of impaired EIH are discussed and recommendations are made for future research, including further exploration of individual differences in EIH, the relationship between exercise dose and EIH, the efficacy of combined treatments and the use of alternative measures to quantify EIH. Perspective: This article provides a contemporary review of the acute effects of exercise on pain and pain sensitivity, including in people with chronic pain conditions. Existing findings are critically reviewed, clinical implications are discussed and recommendations are offered for future research.
Learn More >Persistent arm pain is a common problem following breast cancer surgery. Little is known about genetic factors that contribute to this type of postsurgical pain. Study purpose was to explore associations between persistent arm pain phenotypes and genetic polymorphisms among fifteen genes involved in catecholaminergic and serotonergic neurotransmission. Women (n=398) rated the presence and intensity of arm pain monthly for six months following breast cancer surgery. Three distinct latent classes of patients were identified (i.e., No Arm Pain (41.6%), Mild Arm Pain (23.6%), and Moderate Arm Pain (34.8%). Logistic regression analyses were used to evaluate for differences between genotype or haplotype frequencies and the persistent arm pain classes. Compared to the No Arm Pain class, three SNPs and one haplotype, in four genes, were associated with membership in the Mild Arm Pain class: COMT rs4633, HTR2A haplotype B02 (composed of rs1923886 and rs7330636), HTR3A rs1985242, and TH rs2070762. Compared to the No Arm Pain class, four SNPs in three genes were associated with membership in the Moderate Arm Pain class: COMT rs165656, HTR2A rs2770298 and rs9534511, and HTR3A rs1985242. Findings suggest that variations in catecholaminergic and serotonergic genes play a role in the development of persistent arm pain. PERSPECTIVE – Limited information is available on genetic factors that contribute to persistent arm pain following breast cancer surgery. Genetic polymorphisms in genes involved in catecholaminergic and serotonergic neurotransmission were associated with two persistent arm pain phenotypes. Findings may be used to identify patients are higher risk for this common pain condition.
Learn More >Diagnostic uncertainty, the perception of a lack of or incorrect label to explain symptoms, has been reported by parents of youth with chronic pain. This study was the first to examine diagnostic uncertainty in both youth with chronic pain and their parents using qualitative methodology. Individual, face-to-face, semi-structured interviews were conducted with twenty youth with chronic pain recruited from a pediatric chronic pain program. Independent interviews were also conducted with one of their parents. Interviews explored participants' memories and perceptions around diagnosis. In-depth thematic analysis revealed four themes: (1) The Function of a Diagnosis. Parents and youth struggled with the meaning of the diagnosis, needed further explanation for the pain, and perceived the 'right' diagnosis (i.e., one that fit with their beliefs) as justification for the pain. (2) Haunted by Something Missing. Negative test results did not provide relief or counter the belief that something serious could have been missed by clinicians. (3) The Search for an Alternative Diagnosis. A search persisted for the 'right' diagnosis, particularly when a non-pharmacological treatment plan was provided. (4) Mistrust in the Medical System. Clinician communication and perceptions of clinicians' uncertainty impacted parent and youth 'buy in' to the diagnosis. Findings suggest that many youth with chronic pain and their parents experience diagnostic uncertainty, which is integrally tied to their past experiences with the medical system. Greater understanding of diagnostic uncertainty may help tailor how clinicians deliver diagnoses to achieve 'buy in', increase understanding of pain and diagnosis, and improve treatment response. Perspective: A major challenge that youth with chronic pain and their parents face is understanding the cause of the pain. Youth with chronic pain and their parents experience uncertainty about their diagnosis, which may be linked to their 'buy in' and treatment response.
Learn More >A growing body of evidence suggests that chronic pain is associated with perceptual changes, such as impaired tactile acuity and laterality judgements. A recent study on low back pain showed that tactile acuity was reduced immediately after acute pain induction. Biologically, acute pain should lead to enhanced rather than disruptive changes in tactile acuity to meaningfully respond to potentially damaging nociceptive stimuli. In this double-blinded experiment, 30 healthy volunteers attended three experimental sessions (injection, sham-injection and control condition) separated by one week each, to investigate the effect of acute nociception on tactile precision and laterality judgements. In the real injection condition, acute pain was induced by hypertonic saline solution injected into the mid portion of the trapezius muscle. Tactile acuity (two-point discrimination and an estimation task) and laterality judgements were measured before and during pain perception. In the sham condition the injection was mimicked by a sham procedure (without piercing the skin), in the control condition no intervention took place. Results showed that tactile acuity remained intact (P=0.92) indicating that experimentally induced neck pain did not affect tactile precision. The time needed to complete the laterality judgement task improved over-time in all conditions reflecting a learning effect (P=0.05), We conclude that acute neck pain does not result in perceptual distortions, possibly reflecting a higher protection demand for the neck, a body region in close anatomical proximity to neural centers responsible for vital functions. This data -in the context of existing evidence- indicates that tactile acuity may respond differently to noxious stimulation in different anatomical regions. Perspective: In this study, a sensory adaptation to acute neck pain was investigated. It was found that experimental neck pain did not elicit changes in the sensory axis leaving tactile acuity intact in otherwise healthy subjects. These data support site-specific sensory adaptation to pain.
Learn More >Pain sensitivity in chronic neck pain patients may be influenced by health conditions related to higher levels of widespread pressure pain hypersensitivity (sensitization). Trigger points have also been reported to play a role in the sensitization process.
Learn More >Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility.
Learn More >An evaluation of the behavioral inhibition and behavioral activation system (BIS-BAS) model of pain.
This study evaluated the behavioral inhibition and activation system (BIS-BAS) model of pain. Frontal alpha asymmetry (FAA) as a possible neurophysiological correlate of the BIS-BAS was also explored, as was the role of personality factors.
Learn More >To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine.
Learn More >To review pharmacokinetic and pharmacodynamic characteristics of antibodies that bind to soluble ligands within the framework of calcitonin gene-related peptide antibodies.
Learn More >To use clustering analysis of patient symptoms to discover common patient subtypes in females and males with interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
Learn More >Paediatric chronic pain is a significant problem that can have devastating impacts on quality of life. Multimodal interdisciplinary interventions are the mainstay of paediatric treatment. The aim of this article is to provide a comprehensive review of the effectiveness of interdisciplinary interventions in the management of paediatric chronic pain.
Learn More >The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration.
Learn More >Collapsin response mediator proteins (CRMPs) are a family of ubiquitously expressed, homologous phosphoproteins best known for coordinating cytoskeletal formation and regulating cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. These functions are tightly regulated by post-translational modifications including phosphorylation, SUMOylation, oxidation, and O-GlcNAcylation. While CRMP2's physiological functions rely mostly on its non-phosphorylated state, dysregulation of CRMP2 phosphorylation and SUMOylation has been reported to be involved in the pathophysiology of multiple diseases including cancer, chronic pain, spinal cord injury, neurofibromatosis type 1, and others. Here, we provide a consolidated update on what is known about CRMP2 signaling and function, first focusing on axonal growth and neuronal polarity, then illustrating the link between dysregulated CRMP2 post-translational modifications and diseases. We additionally discuss the roles of CRMP2 in non-neuronal cells, both in the CNS and regions of the periphery. Finally, we offer thoughts on the therapeutic implications of modulating CRMP2 function in a variety of diseases.
Learn More >Often, persistent post-traumatic headache and migraine are phenotypically similar. However, the similarities and differences in the neuropathological underpinnings of persistent post-traumatic headache and migraine require further understanding. We used diffusion tensor imaging (DTI) and a novel method for detecting subtle changes in fibertract integrity by measuring node-by-node parameters along each tract to compare fibertract profiles between those with migraine and those with persistent post-traumatic headache, and compared both cohorts to a group of controls.
Learn More >The automatic detection of migraine states using electrophysiological recordings may play a key role in migraine diagnosis and early treatment. Migraineurs are characterized by a deficit of habituation in cortical information processing, causing abnormal changes of somatosensory evoked potentials. Here, we propose a machine learning approach to utilize somatosensory evoked potential-based biomarkers for migraine classification in a noninvasive setting.
Learn More >Sleep disturbance and chronic pain are related. The present study evaluated both direct and indirect (mediated) pathways through which sleep disturbance might be related to chronic pain intensity and function.
Learn More >There is a need for reliable and valid clinical assessment tools for quantifying allodynia in neuropathic pain. Allodynography has been proposed as a useful standardized procedure for clinical assessment of mechanical allodynia. This study (www.clinicaltrials.gov NCT02070367) undertook preliminary investigation of the measurement properties of allodynography, a new standardized clinical examination procedure for mapping the area of cutaneous allodynia.
Learn More >To optimally select chronic pain patients for different treatments, as it is of interest to identify patient characteristics that might moderate treatment effect. Our aim was to evaluate the impact of possible moderators on the effect of acupuncture treatment using a large data set.
Learn More >Previous research has shown that youth with chronic pain who presented for a multidisciplinary evaluation report a history of adverse childhood experiences (ACEs) (eg, abuse, neglect, parent/guardian separation or divorce) at a high rate (over 80%) and that those with pain and ACEs experience increased psychosocial impairment. Outside of chronic pain, evidence also suggests that youth with a history of ACEs experience poorer treatment outcomes. However, no study to date has examined treatment outcomes in youth with chronic pain and a history of ACEs. The current study aimed to examine the role of ACEs in multidisciplinary intensive pain rehabilitation treatment outcomes for youth with chronic pain.
Learn More >The gabapentinoid drugs gabapentin and pregabalin were originally developed as antiseizure drugs but now are prescribed mainly for treatment of pain. For gabapentin, the only pain-related indication approved by the US Food and Drug Administration (FDA) is postherpetic neuralgia. For pregabalin, FDA-approved indications related to pain are limited to postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy or spinal cord injury, and fibromyalgia. Despite these limited indications, gabapentin and pregabalin are widely prescribed off-label for various other pain syndromes. Such use is growing, possibly because clinicians are searching increasingly for alternatives to opioids.
Learn More >Migraine is a common, severe disease, affecting the brain and blood vessels, causing much pain, time missed from work and family, and severe disability. It affects approximately 12% of most Western populations studied and affects women three times more than men. Cluster headache is a much less common dysfunction of the hypothalamus, involving the sphenopalatine ganglion and other areas; it causes more frequent, shorter, and even more intense pain than migraine. The pain usually comes in cycles and is associated with ipsilateral autonomic features and associated with irritability and inability to stay still. It affects less than 0.1% of the population and is slightly more prevalent in men than women. Although we have some acute care and preventive medications for both types of headache, no treatment is optimal for each patient and some will not respond well or have significant adverse events to existing therapies.
Learn More >Chronic pain is known to be associated with functional and structural changes in the brain. Inflammatory bowel disease (IBD) presents with chronic abdominal pain in almost 35% of all patients. This study investigates structural and functional changes in magnetic resonance imaging (MRI) after transcranial direct current stimulation (tDCS) applied to ameliorate pain in IBD.
Learn More >Recent studies indicate that presynaptic long-term potentiation (pre-LTP) in the anterior cingulate cortex (ACC) may contribute to chronic pain-related anxiety. In addition to the ACC, the insular cortex (IC) has also been indicated in chronic pain and its related emotional disorders. In the present study, we used a 64-channel multielectrode dish (MED64) system to record pre-LTP in the IC. We showed that low-frequency stimulation paired with a GluK1-containing kainate receptor agonist induced NMDA receptor-independent pre-LTP in the IC of wide-type (WT) mice. This form of pre-LTP was blocked in the IC of adenylyl cyclase subtype 1 (AC1) KO mice. Furthermore, a selective AC1 inhibitor NB001 blocked pre-LTP in the IC with a dose-dependent manner. Taken together, our results suggest that AC1 contributes to pre-LTP in the IC of adult mice and NB001 may produce anxiolytic effects by inhibiting pre-LTP in the ACC and IC.
Learn More >We explored the atypical functional connectivity (FC) between the anterior cingulate cortex (ACC) and other brain areas in rats subjected to repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Rats were subdivided according to the frequency of the IS infusions. FC analysis seeded on the ACC was performed on rats 21 days after IS infusion. Glyceryl trinitrate was injected following baseline scanning in the low-frequency IS (LF-IS) group and magnetic resonance imaging (MRI) data were acquired 1 hour after the injection. The rats exhibited nociceptive behavior after high-frequency IS (HF-IS) infusion. The ACC showed increased FC with the cerebellum in the IS groups. The medulla showed increased FC with the ACC in the ictal period in the LF-IS rats. Several areas showed increased FC with the ACC in the HF-IS group, including the pontine tegmentum, midbrain, thalamus, corpus callosum, hippocampus, and retrosplenial, visual, sensory, and motor cortices. This study indicated that the medulla participates in the early stage of a migraine attack and may be associated with the initiation of migraine. Sensitization of the trigeminal nociceptive pathway might contribute to the cutaneous allodynia seen in chronic migraine. Brain areas important for memory function may be related to the chronification of migraine. Electrophysiological studies should examine those migraine-related areas and provide new targets for migraine treatment and prevention.
Learn More >Telomere length, a measure of cellular aging, is inversely associated with chronic pain severity. While psychological resilience factors (e.g., optimism, acceptance, positive affect, active coping) are associated with lower levels of clinical pain and greater physical functioning, it is unknown whether resilience may buffer against telomere shortening in individuals with chronic pain. Additionally, a broader conceptualization of resilience that includes social and biobehavioral factors may improve our understanding of the relationship between resilience, chronic pain, and health outcomes. In individuals with and without chronic knee pain, we investigated whether: 1) psychological resilience would be positively associated with telomere length, and if 2) a broader conceptualization of resilience including social and biobehavioral factors would strengthen the association. Seventy-nine adults, 45-85 years of age, with and without knee pain completed demographic, health, clinical pain, psychological, social, and biobehavioral questionnaires. Resilience levels were determining by summing the total number of measures indicating resilience based on published clinical ranges and norms. Blood samples were collected and telomere length determined. In regression analyses controlling for sex, race, age, and characteristic pain intensity, greater psychological resilience and psychosocial/biobehavioral resilience were associated with longer telomeres (p = .0295 and p = .0116, respectively). When compared, psychosocial/biobehavioral resilience was significantly more predictive of telomere length than the psychological resilience (p < .0001). Findings are promising and encourage further investigations to enhance understanding of the biological interface of psychosocial and biobehavioral resilience factors in individuals with musculoskeletal chronic pain conditions.
Learn More >Deep brain stimulation in the ventral tegmental area (VTA-DBS) has provided remarkable therapeutic benefits in decreasing headache frequency and severity in patients with medically refractory chronic cluster headache (CH). However, to date the effects of VTA-DBS on cognition, mood and quality of life have not been examined in detail.
Learn More >To investigate the whole-brain resting-state functional connectivity in patients with chronic migraine (CM) using a data-driven method.
Learn More >Identifying factors that influence the course of low back pain (LBP) is important to help clinicians to identify those patients at higher risk of non-recovery. The objective of this systematic review was to investigate the prognostic role of physical activity in the course of LBP.
Learn More >Chronic neuropathic pain is known to alter the primary motor cortex (M1) function. Less is known about the normal, physiological effects of experimental neurogenic pain on M1. The objective of this study is to determine how short-interval intracortical inhibition (SICI) is altered in the M1 representation area of a muscle exposed to experimental pain compared to SICI of another muscle not exposed to pain. The cortical representation areas of the right abductor pollicis brevis (APB) and biceps brachii (BB) muscles of 11 subjects were stimulated with a multi-locus transcranial magnetic stimulation device while the resulting motor-evoked potentials (MEPs) were recorded with electromyography. Single- and paired-pulse TMS was administered in seven conditions, including one with the right hand placed in cold water. The stimulation intensity for the conditioning pulses in the paired-pulse examination was 80% of the resting motor threshold (RMT) of the stimulated site and 120% of RMT for both the test and single pulses. The paired-pulse MEP amplitudes were normalized with the mean amplitude of the single-pulse MEPs of the same condition and muscle. SICI was compared between conditions. After the cold pain, the normalized paired-pulse MEP amplitudes decreased in APB, but not in BB, indicating that SICI was potentially increased only in the cortical area of the muscle subjected to pain. These data suggest that SICI is increased in the M1 representation area of a hand muscle shortly after exposure to pain has ended, which implies that short-lasting pain can alter the inhibitory balance in M1.
Learn More >The descending nociceptive inhibitory pathways often malfunction in people with chronic pain. Conditioned pain modulation (CPM) is an experimental evaluation tool for assessing the functioning of these pathways. Spinal cord stimulation (SCS), a well-known treatment option for people with failed back surgery syndrome (FBSS), probably exerts its pain-relieving effect through a complex interplay of segmental and higher-order structures.
Learn More >This study investigated the analgesic effects of two doses (15 and 65 mg) of PF-06372865, a novel α2/α3/α5 gamma-aminobutyric acid A (GABA) subunit selective partial positive allosteric modulator (PAM), compared with placebo and pregabalin (300 mg) as a positive control.
Learn More >Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to 'personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
Learn More >Microglial cells in the central nervous system (CNS) are crucial in maintaining a healthy environment for neurons to function properly. However, aberrant microglial cell activation can lead to excessive generation of neurotoxic proinflammatory mediators and neuroinflammation, which represents a contributing factor in a wide spectrum of CNS pathologies, including ischemic stroke, traumatic brain damage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, psychiatric disorders, autism spectrum disorders, and chronic neuropathic pain. Oxidative stress is a salient and common feature of these conditions and has been strongly implicated in microglial cell activation and neuroinflammation. The transient receptor potential melastatin-related 2 (TRPM2) channel, an oxidative stress-sensitive calcium-permeable cationic channel, is highly expressed in microglial cells. In this review, we examine the recent studies that provide evidence to support an important role for the TRPM2 channel, particularly TRPM2-mediated Ca signaling, in mediating microglial cell activation, generation of proinflammatory mediators and neuroinflammation, which are of relevance to CNS pathologies. These findings lead to a growing interest in the TRPM2 channel, a new player in neuroinflammation, as a novel therapeutic target for CNS diseases.
Learn More >Inflammation causes activation of nociceptive sensory nerves, resulting in debilitating sensations and reflexes. Inflammation also induces mitochondrial dysfunction through multiple mechanisms. Sensory nerve terminals are densely packed with mitochondria, suggesting that mitochondrial signaling may play a role in inflammation-induced nociception. We have previously shown that agents that induce mitochondrial dysfunction, such as antimycin A, activate a subset of nociceptive vagal sensory nerves that express transient receptor potential (TRP) channels ankyrin 1 (A1) and vanilloid 1 (V1). However, the mechanisms underlying these responses are incompletely understood. Here, we studied the contribution of TRPA1, TRPV1 and reactive oxygen species (ROS) to antimycin A-induced vagal sensory nerve activation in dissociated neurons and at the sensory terminals of bronchopulmonary C-fibers. Nociceptive neurons were defined chemically and genetically. Antimycin A-evoked activation of vagal nociceptors in a Fura2 Ca assay correlated with TRPV1 responses compared to TRPA1 responses. Nociceptor activation was dependent on both TRP channels, with TRPV1 predominating in a majority of responding nociceptors and TRPA1 predominating only in nociceptors with the greatest responses. Surprisingly, both TRPA1 and TRPV1 were activated by HO when expressed in HEK293. Nevertheless, targeting ROS had no effect of antimycin A-evoked TRPV1 activation in either HEK293 or vagal neurons. In contrast, targeting ROS inhibited antimycin A-evoked TRPA1 activation in HEK293, vagal neurons and bronchopulmonary C-fibers, and a ROS-insensitive TRPA1 mutant was completely insensitive to antimycin A. We therefore conclude that mitochondrial dysfunction activates vagal nociceptors by ROS-dependent (TRPA1) and ROS-independent (TRPV1) mechanisms.
Learn More >Chronic pain, including arthritis, affects about 100 million adults in the United States. Complexity and diversity of the pain experience across time and people and its fluctuations across and within days show the need for valid pain reports that do not rely on patient's long-term recall capability. Smartwatches can be used as digital ecological momentary assessment (EMA) tools for real-time collection of pain scores. Smartwatches are generally less expensive than smartphones, are highly portable, and have a simpler user interface, providing an excellent medium for continuous data collection and enabling a higher compliance rate.
Learn More >Non-selective glutamate AMPA receptor antagonists are efficacious in chronic pain, but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in CNS. Recently, LY3130481 has been shown to selectively block AMPA receptors co-assembled with the auxiliary protein, TARP γ8, which is highly expressed in hippocampus, but also in pain pathways, including anterior cingulate (ACC) and somatosensory (SS) cortices and spinal cord, suggesting that selective blockade γ8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant γ8-containing AMPA receptors was modulated by co-expression with other TARPs; γ2 subunits affected activity more than γ3 subunits. Consistent with these findings, LY3130481 had decreasing potency on receptors from rat hippocampal, cortical, spinal cord, and cerebellar neurons that was replicated in tissue from human brain. LY3130481 partially suppressed, whereas the non-selective AMPA antagonist GYKI53784 completely blocked AMPA receptor-dependent EPSPs in ACC and spinal neurons in vitro. Similarly, LY3130481 attenuated short-term synaptic plasticity in spinal sensory neurons in vivo in response stimulation of peripheral afferents. LY3130481 also significantly reduced nocifensive behaviors after intraplantar formalin that was correlated with occupancy of CNS γ8-containing AMPA receptors. In addition, LY3130481 dose-dependently attenuated established gait impairment after joint damage and tactile allodynia after spinal nerve ligation; all in the absence of motor side effects. Collectively, these data demonstrate that LY3130481 can suppress excitatory synaptic transmission and plasticity in pain pathways containing γ8/AMPA receptors and significantly reduce nocifensive behaviors, suggesting a novel, effective and safer therapy for chronic pain conditions.
Learn More >Autophagy is a lysosomal degradation pathway that maintains tissue homeostasis by recycling damaged and aged cellular components, which plays important roles in development of the nervous system, as well as in neuronal function and survival. In addition, autophagy dysfunction underlies neuropathic pain. Thus, the modulation of autophagy can alleviate neuropathic pain. Here, we describe the definition, mechanisms of autophagy and neuropathic pain. On this basis, we further discuss the role of autophagy dysfunction in neuropathic pain. This review updates our knowledge on autophagy mechanisms which propose potential therapeutic targets for the treatment of neuropathic pain.
Learn More >Motor cortex stimulation (MCS) is an effective therapy for refractory neuropathic pain. MCS increases the nociceptive threshold in healthy rats via endogenous opioids, inhibiting thalamic nuclei and activating the periaqueductal gray. It remains unclear how the motor cortex induces top-down modulation of pain in the absence of persistent pain. Here, we investigated the main nuclei involved in the descending analgesic pathways and the spinal nociceptive neurons in rats that underwent one session of MCS and were evaluated with the paw pressure nociceptive test. The pattern of neuronal activation in the dorsal raphe nucleus (DRN), nucleus raphe magnus (NRM), locus coeruleus (LC), and dorsal horn of the spinal cord (DHSC) was assessed by immunoreactivity (IR) for Egr-1 (a marker of activated neuronal nuclei). IR for serotonin (5HT) in the DRN and NRM, tyrosine hydroxylase (TH) in the LC, and substance P (SP) and enkephalin (ENK) in the DHSC was also evaluated. MCS increased the nociceptive threshold of the animals; this increase was accompanied by activation of the NRM, while DRN activation was unchanged. However, cortical stimulation induced an increase in 5HT-IR in both serotonergic nuclei. MCS did not change the activation pattern or TH-IR in the LC, and it inhibited neuronal activation in the DHSC without altering SP or ENK-IR. Taken together, our results suggest that MCS induces the activation of serotonergic nuclei as well as the inhibition of spinal neurons, and such effects may contribute to the elevation of the nociceptive threshold in healthy rats. These results allow a better understanding of the circuitry involved in the antinociceptive top-down effect induced by MCS under basal conditions, reinforcing the role of primary motor cortex in pain control.
Learn More >Psychologically Informed Physical Therapy (PIPT) aims to identify individuals at high risk for transitioning to chronicity and merge impairment-focused physical therapy with cognitive behavioral therapy principles. Treatment monitoring is an important part of PIPT and involves identifying changes in clinical measures to inform clinical decision making.
Learn More >The influence of the genetic polymorphism of enzymes and receptors involved in paracetamol metabolism and mechanism of action has not been investigated. This trial in healthy volunteers investigated the link between paracetamol pain relief and the genetic polymorphism of 23 enzymes and receptors.
Learn More >Adolescents are heavy users of social media as a venue to share experience and obtain information. Adolescents with chronic pain may be no different. Given that adolescents with chronic pain report feelings of social isolation, of being different, and lack peer understanding, social media may help them obtain social support. We conducted a scoping review of YouTube to identify how adolescents with chronic pain use this platform to connect with other adolescents.
Learn More >Many trigeminal neuropathic pain patients suffer severe chronic pain. The neuropathic pain might be related with cross-excitation of the neighboring neurons and satellite glia cells (SGCs) in the sensory ganglia and increasing the pain signals from the peripheral tissue to the central nervous system. We induced trigeminal neuropathic pain by infraorbital nerve constriction injury (IONC) in Sprague-Dawley rats. We tested cytokine (CXCL2 and IL-10) levels in trigeminal ganglia (TGs) after trigeminal neuropathic pain induction, and the effect of direct injection of the anti-CXCL2 and recombinant IL-10 into TG. We found that IONC induced pain behavior. Additionally, IONC induced satellite glial cell activation in TG and cytokine levels of TGs were changed after IONC. CXCL2 levels increased at day 1 of neuropathic pain induction and decreased gradually, with IL-10 levels showing the opposite trend. Recombinant IL-10 or anti-CXCL2 injection into TG decreased pain behavior. Our results show that IL-10 or anti-CXCL2 are therapy options for neuropathic pain.
Learn More >This paper overviews available literature addressing behavioral and psychological aspects of cluster headache. Behavioral correlates of sleep and drug use are explored, as are the psychological correlates pertaining to psychopathology and cognitive functioning. We conclude with a review of the few investigations addressing adjunctive behavioral treatments for cluster headache, and provide suggestions for possible ways to enhance effects of behavioral interventions for this painful and difficult to treat headache disorder.
Learn More >The emergence of several fentanyl-related substances in the recreational drug marketplace has resulted in a surge of opioid overdose deaths in the United States. Many of these substances have never been examined in living organisms under controlled conditions. In the present study, seven fentanyl-related substances were tested in adult male Swiss Webster mice for their effects on locomotion and antinociception and compared to those of fentanyl and morphine. In locomotor activity tests, fentanyl (1, 10 mg/kg), morphine (100, 180 mg/kg), isobutyrylfentanyl (10 mg/kg), crotonylfentanyl (10 mg/kg), para-fluorobutyrylfentanyl (10, 100 mg/kg), para-methoxybutyrylfentanyl (10 mg/kg), thiophenefentanyl (100 mg/kg), and benzodioxolefentanyl (0.1 mg/kg) produced significant (p ≤ 0.05) dose-dependent increases in locomotion. Valerylfentanyl, however, was without effects on locomotion up to 100 mg/kg. In warm-water tail-withdrawal tests, all substances produced significant (p ≤ 0.05) dose-dependent increases in antinociception with increasing ED values (CI) of isobutyrylfentanyl [0.0768 mg/kg (0.044-0.128)] > fentanyl [0.0800 mg/kg (0.0403-0.164)] > para-methoxybutyrylfentanyl [0.106 mg/kg (0.0516-0.195)] > crotonylfentanyl [0.226 mg/kg (0.176-0.292)] > para-fluorobutyrylfentanyl [0.908 mg/kg (0.459-1.58)] > thiophenefentanyl [4.66 mg/kg (3.65-5.95)] > valerylfentanyl [6.43 mg/kg (3.91-10.5)] > morphine [7.82 mg/kg (5.42-11.0)] > benzodioxolefentanyl [46.3 mg/kg (25.8-83.4)]. Naltrexone (1 mg/kg) increased antinociceptive ED values several fold in decreasing magnitudes of isobutyrylfentanyl (233x) > para-methoxybutyrylfentanyl (37.7x) > thiophenefentanyl (34.6x) > valerylfentanyl (11.9x) > para-fluorobutyrylfentanyl (10.9x) > benzodioxolefentanyl (8.42x) > crotonylfentanyl (6.27x) > fentanyl (3.95x) > morphine (1.48x). These findings establish that locomotor and antinociceptive effects of several fentanyl-related substances are similar to those of morphine and fentanyl and are mediated by opioid receptors.
Learn More >Spinal D-serine plays an important role in nociception via an increase in phosphorylation of the NMDA receptor GluN1 subunit (pGluN1). However, the cellular mechanisms underlying this process have not been elucidated. Here we investigate the possible role of neuronal nitric oxide synthase (nNOS) in the D-serine-induced potentiation of NMDA receptor function and the induction of neuropathic pain in a chronic constriction injury (CCI) model. Intrathecal administration of the serine racemase inhibitor, LSOS or the D-serine degrading enzyme, DAAO on post-operative days 0-3 significantly reduced the CCI-induced increase in NO levels and NADPH-diaphorase staining in lumbar dorsal horn neurons, as well as the CCI-induced decrease in phosphorylation (Ser847) of nNOS (pnNOS) on day 3 post-CCI surgery. LSOS or DAAO administration suppressed the CCI-induced development of mechanical allodynia and PKC-dependent (Ser896) phosphorylation of GluN1 on day 3 post-surgery, which were reversed by the co-administration of the NO donor, SIN-1. In naïve mice, exogenouse D-serine increased NO levels via decreases in pnNOS. D-serine-induced increases in mechnical hypersensitivity, NO levels, PKC-dependent pGluN1, and NMDA-induced spontaneous nociception were reduced by pretreatment with the nNOS inhibitor, 7-nitroindazole or with the NMDA receptor antagonists, 7-chlorokynurenic acid and MK-801. Collectively we show that spinal D-serine modulates nNOS activity and concomitant NO production leading to increases in PKC-dependent pGluN1, and ultimately contributing to the induction of mechanical allodynia following peripheral nerve injury.
Learn More >Dynorphin A is increased in neuropathic pain models. Activation of α7 n acetylcholine receptor (nAchR) reduces inflammation and pain. Whether activation of α7 nAchR affects dynorphin A release is unknown. The experiments evaluated the proinflammatory effect of dynorphin A in the spinal nerve ligation-induced neuropathic pain models and the effect of α7 nAchR activation on the dynorphin A content. α7 nAchR agonist, PHA-543613 and its antagonist, methyllycaconitine citrate were used and dynorphin A content was measured after spinal nerve ligation and in microglia cultures to test the analgesic mechanisms of α7 nAchR activation. The results showed that dynorphin A content peaked 3 to 7 days after nerve injury, and dynorphin A anti-serum intrathecal injection decreased IL-β and TNF-α content a week after nerve injury. Activation of α7 nAchR by PHA-543613 alleviated neuropathic pain behaviors and decreased dynorphin A concentration in the ipsilateral spinal cords. Also, PHA-543613 decreased dynorphin A release from the microglia cultures to LPS stimulation by activation of α7 nAchR. Our results suggest that dynorphin A contribute to the development and maintenance of neuropathic pain and that decreasing dynorphin A content by activation of α7 AchR of microglia is a potential therapeutic target for treating neuropathic pain.
Learn More >The mechanisms underlying central post-stroke pain are not well understood and there is no satisfactory treatment. Here, in a rat model of stroke, we measured nociceptive threshold using current stimulation of primary afferent neurons in both hind paws. Male Wistar rats underwent middle cerebral artery occlusion (MCAO) for 50 min. Nociceptive thresholds for Aβ, Aδ and C fiber stimulation (at 2000, 250, and 5 Hz, respectively, using a Neurometer), and neurological deficits, were measured for 23 days after MCAO. Sensory thresholds in both hind paws were significantly lower in MCAO model rats than in control rats for 23 days after MCAO, with the greatest difference seen in Aδ fibers and the smallest in C fibers. Brain infarct area was measured histologically, and the correlation between neurological deficit and infarct size was examined. Neurological deficits were worse in animals with larger infarcts. Furthermore, correlations were observed between infarct size, neurological deficit, and sensory threshold of Aδ fibers 1 day after MCAO. These findings indicate that rats develop hyperalgesia after MCAO and that sensory abnormalities in Aδ fibers after cerebral ischemia may play an important role in post-stroke pain.
Learn More >Peripheral nerve stimulation is the direct electrical stimulation of named nerves outside the central neuraxis to alleviate pain in the distribution of the targeted peripheral nerve. These treatments have shown efficacy in treating a variety of neuropathic, musculoskeletal, and visceral refractory pain pathologies; although not first line, these therapies are an important part of the treatment repertoire for chronic pain. With careful patient selection and judicious choice of stimulation technique, excellent results can be achieved for a variety of pain etiologies and distributions. This article reviews current and past practices of peripheral nerve stimulation and upcoming advancements in the field.
Learn More >Chronic pain is the most common non-motor symptom among Parkinson's disease (PD) patients, with 1.85 million estimated to be in debilitating pain by 2030. Subthalamic deep brain stimulation (STN DBS) programmed for treating PD motor symptoms has also shown to significantly improve pain scores. However, even though most patient's pain symptoms improve or disappear, 74% of patients treated develop new pain symptoms within 8 years. Previously we have shown that duloxetine and STN high frequency stimulation (HFS) significantly increase mechanical thresholds more than either alone. The current project specifically investigates the effects of gabapentin and morphine alone and with high (150 Hz; HFS) and low (50 Hz; LFS) frequency stimulation in the 6-hydroxydopamine rat model for PD., We found that HFS, LFS, gabapentin 15 mg/kg and morphine 1mg/kg all independently improve Von Frey (VF) thresholds. Neither drug augments the HFS response significantly. Morphine at 1mg/kg showed a trend to increasing thresholds compared to LFS alone (p=0.062). Interestingly, gabapentin significantly reduced (p=0.019) the improved VF thresholds and Randall Selitto thresholds seen with LFS. Thus, though neither drug augments DBS, we found effects of both compounds independently increase VF thresholds, informing use of our model of chronic pain in PD. Gabapentin's reversal of LFS effects warrants further exploration.
Learn More >We present long-term follow-up results and analysis of stimulation sites of a prospective cohort study of six patients with chronic cluster headaches undergoing deep brain stimulation of the ipsilateral posterior hypothalamic region.
Learn More >The ability to detect noxious stimulation is essential to an organism's survival and wellbeing. Chronic pain is characterized by abnormal sensitivity to normal stimulation coupled with a feeling of unpleasantness. This condition afflicts people worldwide and severely impacts their quality of life and has become an escalating health problem. The spinal cord dorsal horn is critically involved in nociception and chronic pain. Especially, the substantia gelatinosa (SG) neurons of lamina II, which receives nociceptive inputs from primary afferents. Two major models are used to study chronic pain in animals, including nerve injury and the injection of a complete Freund's adjuvant (CFA) into the hind paw. However, how these models induce glutamatergic synaptic plasticity in the spinal cord is not fully understood. Here, we studied synaptic plasticity on excitatory transmissions in the adult rat SG neurons. Using in vitro and in vivo whole-cell patch-clamp recording methods, we analyzed spontaneous excitatory postsynaptic currents (sEPSCs) 2 weeks following nerve injury and 1 week following CFA injection. In the spinal slice preparation, these models increased both the frequency and amplitude of sEPSCs in SG neurons. The frequency and amplitude of sEPSCs in the nerve injury and the CFA group were reduced by the presence of tetrodotoxin (TTX). By contrast, TTX did not reduce the sEPSCs compared with miniature EPSCs in naïve rats. Next, we analyzed the active electrophysiological properties of neurons, which included; resting membrane potentials (RMPs) and the generation of action potentials (APs) in vitro. Interestingly, about 20% of recorded SG neurons in this group elicited spontaneous APs (sAPs) without changing the RMPs. Furthermore, we performed in vivo whole-cell patch-clamp recording in SG neurons to analyze active electrophysiological properties under physiological conditions. Importantly, in vivo SG neurons generated sAPs without affecting RMP in the nerve injury and the CFA group. Our study describes how animal models of chronic pain influence both passive and active electrophysiological properties of spinal SG neurons.
Learn More >We surveyed urine microbiota of females diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) and matched control participants enrolled in the National Institutes of Health (NIH) Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network using the culture-independent methodology. Midstream urine specimens were analyzed with the Plex-ID molecular diagnostic platform that utilizes polymerase chain reaction⁻electrospray ionization⁻time-of-flight⁻mass spectrometry (PCR-ESI-TOF MS) to provide a comprehensive identification of bacterial and select fungal species. IC/BPS and control participants were evaluated for differences (presence, diversity, and abundance) in species and genus. Urine specimens obtained from 181 female IC/BPS and 182 female control participants detected a total of 92 species (41 genera). Mean (SD) species count was 2.49 (1.48) and 2.30 (1.28) among IC/BPS and control participants, respectively. Overall species composition did not significantly differ between IC/BPS and control participants at any level ( = 0.726 species level, = 0.222 genus level). IC/BPS participants urine trended to an overabundance of ( = 0.09) detected but had a lower prevalence of compared with control participants ( = 0.002). The relative abundance data analysis mirrored the prevalence data differences with no significant differences in most species or genus abundance other than and ( = 0.08 and = 0.001, respectively). No cause and/or effect conclusion can be drawn from this observation, but it suggests that a more comprehensive evaluation (vaginal, bowel, catheterized bladder and/or tissue-based specimens) of the lower urinary tract microbiota in IC/BPS patients is warranted.
Learn More >Background and aims There is a growing body of evidence, that pain is common at school age. Less is known about the repeatability of pain questionnaires for children. This study aimed to assess the test-retest repeatability of the Finnish version of the electronic pain questionnaire for school-aged children. Methods Primary (n = 79) and lower secondary (n = 127) schoolchildren aged 10-15 years from two schools from the Jyväskylä region of Finland, filled in an electronic questionnaire twice in an interval of 2 weeks. It captured the frequency of pain symptoms with a five-point Likert-scale questionnaire covering nine areas of the body for the last 3 months. The intraclass correlation coefficient (ICC) values 0.40-0.59 reflected fair and 0.60-0.74 good repeatability. Results The highest prevalences of pain were in the head (29%) and neck and shoulder (NS) (23%) areas. ICC values showed good repeatability for questions about pain frequency in the head, NS and lower extremities. In primary school, these values were good in the lower extremities and fair in NS, lower back and the head. In lower secondary school, the ICC values were good in NS and the head, fair in the stomach and lower extremities. Conclusions This electronic questionnaire was an acceptably repeatable indicator to measure the frequency of pain in the most prevalent pain areas: the head and NS. Implications It is important to be aware of the impact of health-related outcomes on children's ability to be successful in their lives. With the help of a simple electronic questionnaire, it is possible to cost-effectively capture, for example, the prevalence and frequency of pain during the school hours. The identification of children's pain symptoms accurately provides more possibilities to prevent and to minimize the chronic pain among schoolchildren.
Learn More >The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.
Learn More >The 5-HT receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, K = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain C = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.
Learn More >Visual cortical hyperexcitability is now known to be an underlying factor for aberrant visual experience, including hallucinations, and pattern or light induced visual discomfort. Such factors have also been observed in neurological and non-clinical groups (albeit in attenuated form) – consistent with the notion of a continuum of anomalous experiences. Utilizing an exploratory factor analysis (EFA) approach (n = 300), Study 1 developed a revised proxy screening measure for visual cortical hyperexcitability – the Cortical Hyperexcitability index – II(CHi-II). The EFA revealed a stable 3-factor solution which can be characterised as; (i) Heightened Visual Sensitivity and Discomfort (HVSD); (ii) Aura-like Hallucinatory Experience (AHE); and, (iii) Distorted Visual Perception (DVP). Study 2 tested both a self-reported migraine group and a control group on the CHi-II in conjunction with a computerised pattern-glare task that is known to reflect visual cortical hyperexcitability. The migraine group produced significantly elevated scores on both the AHE and HVSD factors of the CHi-II, relative to controls. Among the non-migraine group, subjects who scored higher in the pattern-glare task also produced significantly elevated scores on the AHE factor compared to those with low pattern-glare task scores. Collectively, these findings support the utility of the CHi-II as an indirect proxy measure for signs of cortical hyperexcitability and reveal new categorical distinctions for the nature of the anomalous perceptions. These perceptions may well reflect diverse neurocognitive underpinnings leading to advancements in our understanding of aberrations in conscious experience.
Learn More >This review seeks to establish the role of beta-blockers (B-adrenergic receptor antagonists) in the pathophysiology of migraine prophylaxis, compare the efficacy of this group of medications with other common prophylactic agents, and also explore the relative benefits of using individual beta-blockers compared with others.
Learn More >The term context sensitivity refers to whether a response is in tune with the ever changing demands of the context, while insensitivity is the lack of responding to these cues. To date, we know little about how well patients with pain respond emotionally to changes in the cues provided by the social context, that is, how emotionally context (in)sensitive they are and if this is related to problem severity. The aim of this experimental study was to test a method for determining levels of context sensitivity in individuals with subacute and chronic pain and to explore the link between context (in)sensitivity and pain-related problems. We operationalized context (in)sensitivity as participants' emotional responses (observed facial expressions and self-reported affect) and pain bothersomeness in these contexts and explored the association between these context-(in)sensitive social-emotional responses and pain-related problems.
Learn More >To explore the role of strong negative emotions in spinal nociception, we evaluated the effect of fear-relevant videos of small animals on the nociceptive withdrawal reflex (NWR) and reflex-related pain perception in healthy subjects with a specific phobia of small animals. Twenty healthy subjects with a specific phobia of small animals diagnosed according to DSM-V criteria were included in this study. The NWR was evoked in the lower limb by stimulating the sural nerve and recording EMG activity in the biceps femoris. NWR pain-related perception was quantified on an 11-point numerical rating scale (NRS). Subjects were examined during 4 recording sessions. In the baseline session, no images were projected. In the other sessions, the subjects were invited to watch a video containing either neutral or phobic content. To evaluate neurovegetative responses, we measured heart rate using a pulse oximeter during each recording session. A series of clinical rating scales were administered to subjects to evaluate disgust, fear, and anxiety. The NWR amplitude was significantly increased during the phobic video session and was associated with the fear inventory scale scores. Women showed higher NWR amplitude values during the phobic video session and a lower recovery rate during the after-effect video session than did men. The NWR amplitude and related pain perception were dissociated from each other during the phobic video session, as the NRS score remained unchanged while the NWR increased in amplitude. Emotions induced by the viewing of phobic videos seem to enhance the activation of the spinal circuitries involved in nociception and the withdrawal reaction without interfering with pain processing pathways or dissociating the reflex response from related pain perception. This effect appears to differ by sex, as it was more intense and longer lasting in women than in men. Emotions induced by phobic video viewing increase the alertness devoted to the defensive reaction by emphasizing nociceptive responses independently from pain perception. The NWR may represent an interesting tool for exploring the interaction between strong negative emotions and spinal nociception. A better understanding of this mechanism may be a theoretical prerequisite for the optimization of pain management in several chronic pain syndromes.
Learn More >Morphine is a potent opioid analgesic used to alleviate moderate or severe pain, but the development of drug tolerance and dependence limits its use in pain management. Our previous studies showed that the candidate protein for I1 imidazoline receptor, imidazoline receptor antisera-selected (IRAS)/Nischarin, interacts with μ opioid receptor (MOR) and modulates its trafficking. However, there is no report of the effect of IRAS on morphine tolerance and physical dependence. In the present study, we found that IRAS knockout (KO) mice showed exacerbated analgesic tolerance and physical dependence compared to wild-type (WT) mice by chronic morphine treatment. Chronic morphine treatment down-regulated the expression of MOR in spinal cord of IRAS KO mice, while had no significant effect on MOR expression in WT mice. We observed the compensatory increase of cAMP accumulation in spinal cord after morphine tolerance, and this change was more significant in KO mice than WT mice. Furthermore, KO mice showed more elevation in the phosphorylation of AMPA receptor GluR1-S845 than WT mice, while the total expression of GluR1 remained unchanged after morphine dependence. Altogether, these data suggest that IRAS may play an important role in the development of morphine tolerance and physical dependence in vivo through modulating MOR expression, as well as AMPA GluR1-S845 phosphorylation, which might be one of the mechanisms underlying the development of opiate addiction.
Learn More >Background and aims The painDETECT questionnaire (PD-Q) has been widely used as a screening tool for the identification of neuropathic pain (NeP) as well as a tool for the characterization of patients' pain profile. In contrast to other NeP screening tools, the PD-Q is the only screening tool with weighted sensory descriptors. It is possible that responses to the PD-Q sensory descriptors are influenced by psychological factors, such as catastrophizing or anxiety, which potentially might contribute to an overall higher score of PD-Q and a false positive identification of NeP. This study aimed to explore (i) the relationship between psychological factors (catastrophizing, anxiety, depression and stress) and the total PD-Q score and (ii) if psychological factors are associated with false positive identifications of NeP on the PD-Q compared to clinically diagnosed NeP. Methods The study was a retrospective review of 1,101 patients attending an outpatient pain centre. Patients were asked to complete the PD-Q, the Pain Catastrophizing Scale (PCS), the Depression, Anxiety and Stress Scale (DASS) and the Brief Pain Inventory (BPI). For patients who were identified by PD-Q as having NeP, their medical records were reviewed to establish if they had a clinical diagnosis of NeP. Results Accounting for missing data, complete datasets of 652 patients (mean age 51 (SD14) years, range 18-88; 57% females) were available for analysis. Based on PD-Q scoring, NeP was likely present in 285 (44%) patients. Depression, anxiety, stress, catastrophizing, BPI pain and BPI interference were all significantly related to each other (p < 0.0001) and patients displaying these traits were significantly more likely to have a positive PD-Q score (p < 0.0001). For patients classified by PD-Q as having NeP, only 50% of patients had a clinical diagnosis of NeP. Anxiety was significantly associated with a false positive classification of NeP on PD-Q (p = 0.0036). Conclusions Our retrospective study showed that psychological factors including catastrophizing, depression, anxiety, and stress were all influential in producing a higher score on the PD-Q. We observed a high rate of false positive NeP classification which was associated with the presence of anxiety. Implications Clinicians and researchers should be aware that a patient's psychological state may influence the responses to PD-Q and consequently the final PD-Q score and its NeP classification.
Learn More >Background and aims In 2008, the International Association for the Study of Pain Special Interest Group on Neuropathic Pain (NeuPSIG) proposed a clinical grading system to help identify patients with neuropathic pain (NeP). We previously applied this classification system, along with two NeP screening tools, the painDETECT (PD-Q) and Leeds Assessment of Neuropathic Symptoms and Signs pain scale (LANSS), to identify NeP in patients with neck/upper limb pain. Both screening tools failed to identify a large proportion of patients with clinically classified NeP, however a limitation of our study was the use of a single clinician performing the NeP classification. In 2016, the NeuPSIG grading system was updated with the aim of improving its clinical utility. We were interested in field testing of the revised grading system, in particular in the application of the grading system and the agreement of interpretation of clinical findings. The primary aim of the current study was to explore the application of the NeuPSIG revised grading system based on patient records and to establish the inter-rater agreement of detecting NeP. A secondary aim was to investigate the level of agreement in detecting NeP between the revised NeuPSIG grading system and the LANSS and PD-Q. Methods In this retrospective study, two expert clinicians (Specialist Pain Medicine Physician and Advanced Scope Physiotherapist) independently reviewed 152 patient case notes and classified them according to the revised grading system. The consensus of the expert clinicians' clinical classification was used as "gold standard" to determine the diagnostic accuracy of the two NeP screening tools. Results The two clinicians agreed in classifying 117 out of 152 patients (ICC 0.794, 95% CI 0.716-850; κ 0.62, 95% CI 0.50-0.73), yielding a 77% agreement. Compared to the clinicians' consensus, both LANSS and PD-Q demonstrated limited diagnostic accuracy in detecting NeP (LANSS sensitivity 24%, specificity 97%; PD-Q sensitivity 53%, specificity 67%). Conclusions The application of the revised NeP grading system was feasible in our retrospective analysis of patients with neck/upper limb pain. High inter-rater percentage agreement was demonstrated. The hierarchical order of classification may lead to false negative classification. We propose that in the absence of sensory changes or diagnostic tests in patients with neck/upper limb pain, classification of NeP may be further improved using a cluster of clinical findings that confirm a relevant nerve lesion/disease, such as reflex and motor changes. The diagnostic accuracy of LANSS and PD-Q in identifying NeP in patients with neck/upper limb pain remains limited. Clinical judgment remains crucial to diagnosing NeP in the clinical practice. Implications Our observations suggest that in view of the heterogeneity in patients with neck/upper limb pain, a considerable amount of expertise is required to interpret the revised grading system. While the application was feasible in our clinical setting, it is unclear if this will be feasible to apply in primary health care settings where early recognition and timely intervention is often most needed. The use of LANSS and PD-Q in the identification of NeP in patients with neck/upper limb pain remains questionable.
Learn More >Nerve stimulation is a reversible technique that is used successfully for the treatment of traumatic neuropathic pain, complex regional pain syndrome, and craniofacial neuropathic pain. Nerve field stimulation targets painful regions rather than a single nerve and has expanded indications, including axial low back pain. Appropriate patient education and motivation are crucial prior to surgery. Ongoing research is necessary to provide high-level evidence for the use of nerve stimulation. Most electrodes are primarily designed for spinal cord stimulation, hence the need to develop nerve electrodes dedicated for nerve stimulation.
Learn More >Intrathecal drug delivery has been well established an effective and safe method for the treatment of pain, including palliative cancer-related and chronic nonmalignant pain. In this article, we discuss the role of intrathecal pain therapy in the management of chronic, refractory nonmalignant pain. Common indications, patient selection criteria, medication options, complications, and adverse events are discussed within the context of results from randomized controlled trials, clinical consensus guidelines, and best available literature to date.
Learn More >Persistent postoperative opioid use is thought to contribute to the ongoing opioid epidemic in the United States. However, efforts to study and address the issue have been stymied by the lack of a standard definition, which has also hampered efforts to measure the incidence of and risk factors for persistent postoperative opioid use. The objective of this systematic review is to (1) determine a clinically relevant definition of persistent postoperative opioid use, and (2) characterize its incidence and risk factors for several common surgeries. Our approach leveraged a group of international experts from the Perioperative Quality Initiative-4, a consensus-building conference that included representation from anesthesiology, surgery, and nursing. A search of the medical literature yielded 46 articles addressing persistent postoperative opioid use in adults after arthroplasty, abdominopelvic surgery, spine surgery, thoracic surgery, mastectomy, and thoracic surgery. In opioid-naive patients, the overall incidence ranged from 2% to 6% based on moderate-level evidence. However, patients who use opioids preoperatively had an incidence of >30%. Preoperative opioid use, depression, factors associated with the diagnosis of substance use disorder, preoperative pain, and tobacco use were reported risk factors. In addition, while anxiety, sex, and psychotropic prescription are associated with persistent postoperative opioid use, these reports are based on lower level evidence. While few articles addressed the health policy or prescriber characteristics that influence persistent postoperative opioid use, efforts to modify prescriber behaviors and health system characteristics are likely to have success in reducing persistent postoperative opioid use.
Learn More >Gender disparities in chronic pain are well documented in the literature. However, little is known regarding the relationship between physical activity (PA) and gender disparities in chronic pain. This study described gender differences in prevalence of chronic pain and PA, and identified a type of leisure time PA that individuals frequently chose in a nationally representative sample of US adults ( = 14,449). Data from the National Health Nutrition Examination Survey 1999⁻2004 were analyzed. Individuals were categorized into no chronic pain (NCP), localized chronic pain (LCP), and widespread chronic pain (WCP) groups based on responses to a pain questionnaire. A self-report PA questionnaire was used to estimate the time spent in different types of PA. Women showed higher prevalence of LCP and WCP compared to men. Men spent more hours per week for leisure time PA compared to women, but men and women showed similar prevalence of sufficient PA to meet a PA recommendation (≥150 min/week of moderate-to-vigorous intensity PA) across chronic pain categories. However, the prevalence of sufficient PA was substantially higher among men and women with NCP compared to men and women with LCP and WCP. Additionally, both men and women chose walking as the primary type of leisure time PA. Together, gender disparities exist in the prevalence of chronic pain and hours spent for leisure time PA. More research is needed to explore the role of increasing leisure time PA, such as walking, in reducing gender disparities in chronic pain.
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