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Papers: 4 May 2019 - 10 May 2019

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Therapeutic options for targeting inflammatory osteoarthritis pain.

Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte-macrophage colony-stimulating factor (GM-CSF)-CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation.

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Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain.

Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.

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Blocking COX-2 for sickle cell pain relief.

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MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus.

Patients suffering from cholestasis, the slowing or stoppage of bile flow, commonly report experiencing an intense, chronic itch. Numerous pruritogens are up-regulated in cholestatic patient sera, including bile acids (BAs). Acute injection of BAs results in itch in both mice and humans, and BA-modulating therapy is effective in controlling patient itch. Here, we present evidence that human sensory neuron-expressed Mas-related G protein-coupled receptor X4 (MRGPRX4), an orphan member of the family of GPCRs, is a BA receptor. Using Ca imaging, we determined that pathophysiologically relevant levels of numerous BAs activated MRGPRX4. No mouse Mrgpr orthologs were activated by BAs. To assess the in vivo relevance of BA activation of MRGPRX4, we generated a humanized mouse with targeted expression of MRGPRX4 in itch-encoding sensory neurons. BAs activated MRGPRX4 sensory neurons at higher levels compared with WT neurons. Compared with control animals, MRGPRX4 mice scratched more upon acute injection of BAs and in a model of cholestatic itch. Overall, these data suggest that targeting MRGPRX4 is a promising strategy for alleviating cholestatic itch.

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Aberrant interactions of cortical networks in chronic migraine: A resting-state fMRI study.

We investigated resting-state (RS)-fMRI using independent component analysis (ICA) to determine the functional connectivity (FC) between networks in chronic migraine (CM) patients and their correlation with clinical features.

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Development and Characterization of An Injury-free Model of Functional Pain in Rats by Exposure to Red Light.

We report the development and characterization of a novel, injury-free rat model in which nociceptive sensitization following red light is observed in multiple body areas reminiscent of widespread pain in functional pain syndromes. Rats were exposed to red light emitting diodes (RLED) (LEDs, 660 nanometer) at an intensity of 50 Lux for 8 hours daily for 5 days resulting in time- and dose-dependent thermal hyperalgesia and mechanical allodynia in both male and female rats. Females showed earlier onset of mechanical allodynia than males. The pronociceptive effects of RLED were mediated through the visual system. RLED-induced thermal hyperalgesia and mechanical allodynia were reversed with medications commonly used for widespread pain including gabapentin, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, and NSAIDs. Acetaminophen failed to reverse the RLED induced hypersensitivity. The hyperalgesic effects of RLED were blocked when bicuculline, a GABA-A receptor antagonist, was administered into the rostral ventromedial medulla (RVM) suggesting a role for increased descending facilitation in the pain pathway. Key experiments were subjected to a replication study with randomization, investigator-blinding, inclusion of all data and high levels of statistical rigor. RLED induced thermal hyperalgesia and mechanical allodynia without injury offers a novel injury free rodent model useful for the study of functional pain syndromes with widespread pain. RLED exposure also emphasizes the different biological effects of different colors light exposure. Perspective: This study demonstrates the effect of light exposure on nociceptive thresholds. These biological effects of red LED adds evidence to the emerging understanding of biological effects of light of different colors in animals and humans. Understanding the underlying biology of red light-induced wide spread pain may offer insights into functional pain states.

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Quantitative Assessment of Non-Pelvic Pressure Pain Sensitivity in Urological Chronic Pelvic Pain Syndrome: A MAPP Research Network Study.

Experimental pain sensitivity was assessed in individuals with urologic chronic pelvic pain syndrome (UCPPS) as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. A series of computer-controlled pressure stimuli were delivered to the thumbnail bed, an asymptomatic site distant from the area of UCPPS pain that is considered to be indicative of overall body pain threshold. Stimuli were rated according to a standardized magnitude estimation protocol. Pain sensitivity in UCPPS participants was compared to healthy controls and a mixed pain group composed of individuals with other chronic overlapping pain conditions, including fibromyalgia, chronic fatigue, and irritable bowel syndromes. Data from six participating MAPP testing sites were pooled for analysis. UCPPS participants (n = 153) exhibited an intermediate pain sensitivity phenotype: they were less sensitive relative to the mixed pain group (n = 35) but significantly more sensitive than healthy controls (n = 100). Increased pain sensitivity in UCPPS patients was associated with both higher levels of clinical pain severity and more painful body areas outside the pelvic region. Exploratory analyses in UCPPS participants revealed that pain sensitivity increased during periods of urological symptom flare and that less pressure pain sensitivity at baseline was associated with a greater likelihood of subsequent genitourinary pain improvement one year later. The finding that individuals with UCPPS demonstrate non-pelvic pain hypersensitivity that is related to clinical symptoms suggests that central nervous system mechanisms of pain amplification contribute to UCPPS.

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Antibodies binding the head domain of P2X4 inhibit channel function and reverse neuropathic pain.

P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting P2X4 have been unsuccessful largely due to the difficulty in engineering specificity and selectivity. Here, we describe for the first time the generation of a panel of diverse monoclonal antibodies (mAbs) to human and mouse P2X4, capable of both positive and negative modulation of channel function. The affinity optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity for human P2X4 and induced potent and complete block of P2X4 currents. Site-directed mutagenesis of P2X4 revealed the head domain as a key interaction site for inhibitory mAbs. Inhibition of spinal P2X4 either by intrathecal delivery of an anti-P2X4 mAb, or systemic delivery of an anti-P2X4 bi-specific mAb with enhanced blood-spinal cord barrier permeability, produced long lasting (>7 days) analgesia in a mouse model of neuropathic pain. We therefore propose that inhibitory mAbs binding the head domain of P2X4 have therapeutic potential for the treatment of neuropathic pain.

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Do chronic pain and comorbidities affect brain function in sickle cell patients? A systematic review of neuroimaging and treatment approaches.

Sickle cell disease (SCD) is a medical condition in which chronic pain is common and negatively impacts psychosocial function and quality of life. While the brain mechanisms underlying chronic pain are well studied in other painful conditions, the brain mechanisms underlying chronic pain and the associated psychosocial comorbidities are not well established in SCD. A growing literature demonstrates the effect of treatment of chronic pain, including pharmacological and nonpharmacological treatments, on brain function. The present systematic review aimed to: 1. determine the effects of chronic pain and psychosocial comorbidities on brain function of SCD patients; 2. summarize pharmacological and nonpharmacological approaches to treat these symptoms; and 3. identify areas for further investigation of potential beneficial effects of treatments on brain function. Titles were screened using predefined criteria, including SCD, and abstracts and full texts were reviewed by 2 independent reviewers. A total of 1,167 SCD articles were identified and 86 full articles were included covering 3 sections: chronic pain (4 studies), psychosocial comorbidities (11 studies), and pharmacological and nonpharmacological treatments (71 studies). Neuroimaging evidence demonstrates aberrant neural processing related to chronic pain and psychosocial comorbidities in SCD beyond ischemic stroke and cerebral hemorrhage. Although neuroimaging studies show an important role for psychological factors, pain management is nearly exclusively based on opioids. Behavior therapy appears useful to improve psychological symptoms as well as chronic pain and quality of life. Further investigation is required with larger cohorts, matched-controls, and examination of treatment-related neural mechanisms.

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Quantitative Sensory Testing (QST) and predicting outcomes for musculoskeletal pain, disability and negative affect: a systematic review and meta-analysis.

Hypersensitivity due to central pain mechanisms can influence recovery and lead to worse clinical outcomes, but the ability of quantitative sensory testing (QST), an index of sensitisation, to predict outcomes in chronic musculoskeletal disorders remains unclear. We systematically reviewed the evidence for ability of QST to predict pain, disability and negative affect using searches of CENTRAL, MEDLINE, EMBASE, AMED, CINAHL and PubMed databases up to April 2018. Title screening, data extraction, and methodological quality assessments were performed independently by 2 reviewers. Associations were reported between baseline QST and outcomes using adjusted (β) and unadjusted (r) correlations. Of the 37 eligible studies (n=3860 participants), 32 were prospective cohort studies and 5 randomised controlled trials. Pain was an outcome in 30 studies, disability in 11 and negative affect in 3. Meta-analysis revealed that baseline QST predicted musculoskeletal pain (mean r=0.31, 95%CI: 0.23 to 0.38, n=1057 participants) and disability (mean r=0.30, 95%CI: 0.19 to 0.40, n=290 participants). Baseline modalities quantifying central mechanisms such as temporal summation (TS) and conditioned pain modulation (CPM) were associated with follow-up pain (TS: mean r=0.37, 95%CI: 0.17 to 0.54; CPM: r=0.36, 95%CI: 0.20 to 0.50), whereas baseline mechanical threshold modalities were predictive of follow-up disability (mean r=0.25, 95%CI: 0.03 to 0.45). QST indices of pain hypersensitivity might help develop targeted interventions aiming to improve outcomes across a range of musculoskeletal conditions.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC) , where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

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Patient willingness to pay (WTP) for reductions in chronic low back pain and chronic neck pain.

Many recommended nonpharmacologic therapies for patients with chronic spinal pain require visits to providers such as acupuncturists and chiropractors. Little information is available to inform third-party payers' coverage policies regarding ongoing use of these therapies. This study offers contingent valuation-based estimates of patient willingness-to-pay (WTP) for pain reductions from a large (n=1583) sample of patients using ongoing chiropractic care to manage their chronic low-back and neck pain. Average WTP estimates were $45.98 (45.8) per month per 1-point reduction in current pain for chronic low-back pain and $37.32 (38.0) for chronic neck pain. These estimates met a variety of validity checks including that individuals' values define a downward-sloping demand curve for these services. Comparing these WTP estimates to patients' actual use of chiropractic care over the next 3 months indicates that these patients are likely "buying" perceived pain reductions from what they believe their pain would have been if they didn't see their chiropractor-i.e., they value maintenance of their current mild pain levels. These results provide some evidence for co-pay levels and their relationship to patient demand but call into question ongoing coverage policies that require documentation of continued improvement or of experienced clinical deterioration with treatment withdrawal. Perspective: This study provides estimates of reported willingness-to-pay for pain reduction from a large sample of patients using chiropractic care to manage their chronic spinal pain and compares these estimates to what these patients do for care over the next 3 months, to inform coverage policies for ongoing care.

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The market for migraine drugs.

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Recent advances in understanding/managing trigeminal neuralgia.

Despite recent advances in understanding and treating trigeminal neuralgia, its management remains a considerable challenge. Better classification of different types of facial pain and the identification of prognostic factors for different treatment options lead the way toward better quality of life for the individual patient. Although the principles of treating trigeminal neuralgia remain basically the same, antiepileptic drugs, muscle relaxants, and neuroleptic agents are widely used medical treatment options. They were not originally developed for treating trigeminal neuralgia. Carbamazepine was studied in adequate placebo-controlled clinical trials in the 1960s and is still considered the most effective drug. Among emerging treatment options currently under clinical investigation are local botulinum neurotoxin type A injections and a novel sodium channel blocker (CNV1014802) that selectively blocks the Na 1.7 sodium channel. Non-pharmacological treatment options are non-invasive electrical stimulation with either transcranial direct-current stimulation or repetitive transcranial magnetic stimulation which both require further evaluation in regard to applicability. Surgical options remain a valid choice for patients not responding to medical treatment and include Gasserian ganglion percutaneous techniques, gamma knife surgery, and microvascular decompression. There is continual effort to improve these techniques and predict the outcome for better patient selection.

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Diagnosis and management of sensory polyneuropathy.

Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.

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The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe: Separating Analgesia and Anxiety.

The periaqueductal gray (PAG) is a significant modulator of both analgesic and fear behaviors in both humans and rodents, but the underlying circuitry responsible for these two phenotypes is incompletely understood. Importantly, it is not known if there is a way to produce analgesia without anxiety by targeting the PAG, as modulation of glutamate or GABA neurons in this area initiates both antinociceptive and anxiogenic behavior. While dopamine (DA) neurons in the ventrolateral PAG (vlPAG)/dorsal raphe display a supraspinal antinociceptive effect, their influence on anxiety and fear are unknown. Using DAT-cre and Vglut2-cre male mice, we introduced designer receptors exclusively activated by designer drugs (DREADD) to DA and glutamate neurons within the vlPAG using viral-mediated delivery and found that levels of analgesia were significant and quantitatively similar when DA and glutamate neurons were selectively stimulated. Activation of glutamatergic neurons, however, reliably produced higher indices of anxiety, with increased freezing time and more time spent in the safety of a dark enclosure. In contrast, animals in which PAG/dorsal raphe DA neurons were stimulated failed to show fear behaviors. DA-mediated antinociception was inhibitable by haloperidol and was sufficient to prevent persistent inflammatory pain induced by carrageenan. In summary, only activation of DA neurons in the PAG/dorsal raphe produced profound analgesia without signs of anxiety, indicating that PAG/dorsal raphe DA neurons are an important target involved in analgesia that may lead to new treatments for pain.

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A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists.

Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings spurred efforts to develop opioids that signal primarily via G protein activation and do not, or only very weakly, recruit beta-arrestin. Development of such molecules targeting the mu opioid receptor initially outpaced those targeting the kappa, delta and nociceptin opioid receptors, with the G protein-biased mu opioid agonist oliceridine/TRV130 having completed phase III clinical trials with improved therapeutic window to treat moderate-to-severe acute pain. Recently however, there has been a sharp increase in the development of novel G protein-biased kappa agonists. It is hypothesized that G protein-biased kappa agonists can reduce pain and itch, but exhibit fewer side effects, such as anhedonia and psychosis, that have thus far limited the clinical development of unbiased kappa opioid agonists. Here we summarize recently discovered G protein-biased kappa agonists, comparing structures, degree of signal bias and preclinical effects. We specifically reviewed nalfurafine, 22-thiocyanatosalvinorin A (RB-64), mesyl-salvinorin B, 2-(4-(furan-2-ylmethyl)-5-((4-methyl-3-(trifluoromethyl)benzyl)thio)-4H-1,2,4-triazol-3-yl)pyridine (triazole 1.1), 3-(2-((cyclopropylmethyl)(phenethyl)amino)ethyl)phenol (HS666), -butyl–phenylethyl–3-hydroxyphenylethyl-amine (compound 5/BPHA), 6-guanidinonaltrindole (6'GNTI), and collybolide. These agonists encompass a variety of chemical scaffolds and range in both their potency and efficacy in terms of G protein signaling and beta-arrestin recruitment. Thus unsurprisingly, the behavioral responses reported for these agonists are not uniform. Yet, it is our conclusion that the kappa opioid field will benefit tremendously from future studies that compare several biased agonists and correlate the degree of signaling bias to a particular pharmacological response.

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Evaluating Mean Level and Within-Person Consistency in Migraine Pain Intensity and Migraine-Related Disability for AVP-825 vs Oral Sumatriptan: Results from the COMPASS Study, A Randomized Trial.

Consistency of response across multiple attacks is typically measured as the proportion of study participants who achieve a categorical endpoint over a specified number of attacks (ie, 2-hour pain-free response in 2 of 3 attacks). We applied a novel analytic approach for measuring consistency of response in the acute treatment of episodic migraine using data from the COMPASS study.

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The Neuroimmune Axis in Skin Sensation, Inflammation, and Immunity.

Although connections between the immune and nervous systems have long been recognized, the precise mechanisms that underlie this relationship are just starting to be elucidated. Advances in sensory biology have unveiled novel mechanisms by which inflammatory cytokines promote itch and pain sensations to coordinate host-protective behavioral responses. Conversely, new evidence has emphasized the importance of immune cell regulation by sensory neurons. By focusing on itch biology and how it has been informed by the more established field of pain research, we highlight recent interdisciplinary studies that demonstrate how novel neuroimmune interactions underlie a diversity of sensory, inflammatory, and infectious diseases.

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Sex differences in negative affect and postoperative pain in patients undergoing total knee arthroplasty.

Knee osteoarthritis (OA) is among the most common and disabling persistent pain conditions, with increasing prevalence in the developed world, and affects women to a greater degree than men. In the USA, the growth of knee OA has been paralleled by an increase in rates of total knee arthroplasty (TKA), a surgical treatment option for late-stage knee OA. While TKA outcomes are generally good, postoperative trajectories of pain vary widely, with some patients reporting a complete absence of pain, but with a significant minority reporting worsening pain. Biopsychosocial factors, including anxiety and depression, are known to contribute importantly to the experience of joint pain, with women reporting a higher degree of negative affective symptoms.

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Targeted interventions to prevent transitioning from acute to chronic low back pain in high-risk patients: development and delivery of a pragmatic training course of psychologically informed physical therapy for the TARGET trial.

Low back pain (LBP) is a public health concern because it is highly prevalent and the leading cause of disability worldwide. Psychologically informed physical therapy (PIPT) is a secondary prevention approach that first aims to identify individuals at high risk for transitioning to chronicity and then provides tailored treatment to reduce that risk. Training models that are feasible to implement with acceptable training quality are needed to improve scalability for widespread implementation of PIPT. This manuscript describes the PIPT training program that was developed for training physical therapists providing PIPT in the TARGET trial.

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TsNTxP, a non-toxic protein from Tityus serrulatus scorpion venom, induces antinociceptive effects by suppressing glutamate release in mice.

Neuropathic pain is a common type of chronic pain caused by trauma or chemotherapy. However, this type of pain is undertreated. TsNTxP is a non-toxic protein isolated from the venom of the scorpion Tityus serrulatus, and it is structurally similar to neurotoxins that interact with voltage-gated sodium channels. However, the antinociceptive properties of this protein have not been characterized. The purpose of this study was to investigate the antinociceptive effects of TsNTxP in acute and neuropathic pain models. Male and female Swiss mice (25-30 g) were exposed to different models of acute pain (tail-flick test and nociception caused by capsaicin intraplantar injection) or neuropathic pain (chronic pain syndrome induced by paclitaxel or chronic constriction injury of the sciatic nerve). Hypersensitivity to mechanical or cold stimuli were evaluated in the models of neuropathic pain. The ability of TsNTxP to alter the release of glutamate in mouse spinal cord synaptosomes was also evaluated. The results showed that TsNTxP exerted antinociceptive effects in the tail-flick test to a thermal stimulus and in the intraplantar capsaicin administration model. Furthermore, TsNTxP was non-toxic and exerted antiallodynic effects in neuropathic pain models induced by chronic constriction injury of the sciatic nerve and administration of paclitaxel. TsNTxP reduced glutamate release from mouse spinal cord synaptosomes following stimulation with potassium chloride (KCl) or capsaicin. Thus, this T. serrulatus protein may be a promising non-toxic drug for the treatment of neuropathic pain.

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Effects of two isometheptene enantiomers in isolated human blood vessels and rat middle meningeal artery – potential antimigraine efficacy.

Racemic isometheptene [(RS)-isometheptene] is an antimigraine drug that due to its cardiovascular side-effects was separated into its enantiomers, (R)- and (S)-isometheptene. This study set out to characterize the contribution of each enantiomer to its vasoactive profile. Moreover, rat neurogenic dural vasodilatation was used to explore their antimigraine mechanism of action.

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Glucagon-Like Peptide-1 Receptor Agonist Treatment Does Not Reduce Abuse-Related Effects of Opioid Drugs.

Dependence on opioids and the number of opioid overdose deaths are serious and escalating public health problems, but medication-assisted treatments for opioid addiction remain inadequate for many patients. Glucagon-like pepide-1 (GLP-1) is a gut hormone and neuropeptide with actions in peripheral tissues and in the brain, including regulation of blood glucose and food intake. GLP-1 analogs, which are approved diabetes medications, can reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine, and nicotine in rodents. Investigations on effects of GLP-1 analogs on opioid reward and reinforcement have not been reported. We assessed the effects of the GLP-1 receptor agonist Exendin-4 (Ex4) on opioid-related behaviors in male mice, i.e., morphine-conditioned place preference (CPP), intravenous self-administration (IVSA) of the short-acting synthetic opioid remifentanil, naltrexone-precipitated morphine withdrawal, morphine analgesia (male and female mice), and locomotor activity. Ex4 treatment had no effect on morphine-induced CPP, withdrawal, or hyperlocomotion. Ex4 failed to decrease remifentanil self-administration, if anything reinforcing effects of remifentanil appeared increased in Ex4-treated mice relative to saline. Ex4 did not significantly affect analgesia. In contrast, Ex4 dose dependently decreased oral alcohol self-administration, and suppressed spontaneous locomotor activity. Taken together, Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction. This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central stimulants, and nicotine.

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Advanced visual network and cerebellar hyperresponsiveness to trigeminal nociception in migraine with aura.

Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA.

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MiR-30b-5p attenuates oxaliplatin-induced peripheral neuropathic pain through the voltage-gated sodium channel Na1.6 in rats.

Oxaliplatin is a third-generation derivative of platinum that is effective in the treatment of multiple solid tumors. However, it can cause peripheral neuropathic pain, and the molecular mechanisms of this effect remain unknown. We induced a model of peripheral neuropathic pain in rats by intraperitoneally injecting them with oxaliplatin twice a week for 4.5 weeks. We found that both the mRNA and protein expression levels of Na1.6 (encoded by the gene Scn8a) increased while the miR-30b-5p (shorthand for miR-30b) expression decreased in the dorsal root ganglion (DRG) of treated rats. Using TargetScan and miRanda predictive software, we discovered that Scn8a was a major target of miR-30b. Moreover, we found that miR-30b negatively regulated Scn8a by binding to the Scn8a 3'UTR in PC12 cells. In addition, Na1.6 and miR-30b were colocalized in the DRG neurons of naive rats. Overexpression of miR-30b using an miR-30b agomir attenuated neuropathic pain induced by oxaliplatin and inhibited both the mRNA and protein expression levels of Na1.6 both in vitro and in vivo. Conversely, the inhibition of miR-30b with an miR-30b antagomir resulted in neuropathic pain and an increase in the expression of Na1.6. More importantly, overexpression of miR-30b inhibited the proliferation of LS-174t cells (Colorectal cancer cells). These data suggest that miR-30b contributes to oxaliplatin-induced chronic neuropathic pain through Na1.6 downregulation and could be a novel therapeutic target for the treatment of oxaliplatin-induced neuropathic pain as a side effect of chemotherapy in cancer patients.

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Allergen-Induced Histaminergic and Non-histaminergic Activation of Itch C-Fiber Nerve Terminals in Mouse Skin.

Acute cutaneous exposure to allergen often leads to itch, but seldom pain. The effect of mast cell activation on cutaneous C-fibers was studied using innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Allergen (ovalbumin) injection into the isolated skin of actively sensitized mice strongly stimulated chloroquine (CQ)-sensitive C-fibers (also referred to as "itch" nerves), on the other hand, CQ-insensitive C-fibers were activated only modestly, if at all. The histamine H1 receptor antagonist pyrilamine abolished itch C-fibers response to histamine, but failed to significantly reduce the response to ovalbumin. Ovalbumin also strongly activated itch C-fibers in skin isolated from Mrgpr-cluster Δ mice. When pyrilamine was studied in the Mrgpr-cluster Δ mice thereby eliminating the influence of both histamine H1 and Mrgpr receptors (MrgprA3 and C11 are selectively expressed by itch nerves), the ovalbumin response was very nearly eliminated. The data indicate that the acute activation of itch C-fibers in mouse skin is largely secondary to the combined effect of activation of histamine H1 and Mrpgr receptors.

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Spreading depression as a preclinical model of migraine.

Spreading depression (SD) is a slowly propagating wave of near-complete depolarization of neurons and glial cells across the cortex. SD is thought to contribute to the underlying pathophysiology of migraine aura, and possibly also an intrinsic brain activity causing migraine headache. Experimental models of SD have recapitulated multiple migraine-related phenomena and are considered highly translational. In this review, we summarize conventional and novel methods to trigger SD, with specific focus on optogenetic methods. We outline physiological triggers that might affect SD susceptibility, review a multitude of physiological, biochemical, and behavioral consequences of SD, and elaborate their relevance to migraine pathophysiology. The possibility of constructing a recurrent episodic or chronic migraine model using SD is also discussed.

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Sensitivity of functional targeted neuropeptide evaluation in testing pregabalin analgesic efficacy in a rat model of osteoarthritis pain.

The monosodium iodoacetate (MIA)-induced joint degeneration in rats is the most used animal model to screen analgesic drugs to alleviate osteoarthritis (OA) pain. This study aimed to evaluate the analgesic efficacy of pregabalin (PGB) in an MIA-induced OA model in rodents by using functional and neuroproteomic pain assessment methods. Treatment group included PGB in curative intent over 9 days compared to gold standard therapy (positive controls) and placebo (negative control). Functional assessments of pain (quantitative sensory testing and operant test) were performed concomitantly with spinal neuropeptides quantification. At day 21 post-OA induction, PGB in MIA rats reduced tactile allodynia (P = 0.028) and improved the place escape/avoidance behavior (P = 0.04) compared to values recorded at last time-point before initiating analgesic therapy. All spinal neuropeptide concentrations, such as substance P, calcitonin gene-related peptide, bradykinin and somatostatin, came back to normal (non affected) rat values, compared to their increase observed in MIA rats receiving the placebo (P < 0.0001). Initiated 13 days after chemical OA induction, repeated medication with PGB provided analgesia according to quantitative sensory testing, operant test and targeted neuropeptides pain assessment methods. This report highlights the interest of using reliable and sensitive methods like targeted neuropeptide quantification to detect the analgesic effects of a test article with concomitant functional assessments of pain when studying OA pain components. This article is protected by copyright. All rights reserved.

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Fremanezumab as a preventive treatment for episodic and chronic migraine.

The importance of calcitonin gene-related peptide (CGRP) in migraine pathogenesis is well established. Fremanezumab is a humanized IgG2a monoclonal antibody that binds to CGRP. Areas covered: In this paper we review the development of fremanezumab, from early development into approval. The authors focus on the efficacy and safety of fremanezumab in both migraine stages. The authors highlight studies conducted in special populations and focus on unique aspects of its development, as well as on clinical pearls supported by the data. Expert opinion: Fremanezumab was shown to be effective in episodic and chronic migraine, with a monthly and quarterly dose of administration, as monotherapy and add-on therapy. As with other monoclonal antibodies, anti-CGRP onset of action was remarkably quick, and the effect seems to be maintained over time. No overt safety concerns emerged from the clinical studies, although long term surveillance is necessary.

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Sensitized brain response to acute pain in patients using prescription opiates for chronic pain: A pilot study.

Chronic opiate use leads to a sensitized behavioral response to acute pain, which in turn, leads to escalating doses of opiates. This study was designed to test the hypothesis that chronic opiate usage is also associated with a sensitized neurobiological response to acute pain in individuals that have used prescription opiates for 6 or more months.

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Efficacy and safety of ASP1707 for endometriosis-associated pelvic pain: the phase II randomized controlled TERRA study.

Does the GnRH antagonist, ASP1707, reduce endometriosis-associated pelvic pain?

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Where is itch represented in the brain, and how does it differ from pain? An Activation Likelihood Estimation meta-analysis of experimentally-induced itch.

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Maternal Deprivation Alters Nociceptive Response in a Gender-Dependent Manner in Rats.

The present study aimed at investigating both the early and long-term effects of maternal deprivation as well as gender on neuromotor reflexes, anxiety behavior and thermal nociceptive responses. A total of 64 Wistar rats pups (32 males, 32 females) were utilized and were deprived of their mother for 3 h/daily, from postnatal day 1 (P1) until P10. Successively, animals were divided into 2 groups: control group (C) – pups no subjected to intervention; and the maternal-deprived group (MD): pups subjected to maternal deprivation. The neuromotor reflexes were evaluated through the righting reflex and negative geotaxis tests; the exploratory behavior by open field test (OFT); the anxiety-like behavior by elevated plus-maze test (EPM); the thermal nociceptive responses byhot plate (HP) and tail-flick (TFL) tests. All the animals subjected to maternal deprivation showed a delayed reflex response at P8 in the negative geotaxis test. In contrast, the OFT at P20 identified an effect of gender on the outer crossings and grooming as well as an interaction between gender and maternal deprivation on latency. Additionally, effect of maternal deprivation in the open and closed arms as well as gender effect in the protected head-dipping (PHD) and non-protected head-dipping (NPHD) were observed at P20 (EPM). In contrast, there were a gender effect on latency and an interaction between gender and maternal deprivation on rearing at P42. Moreover, in nociceptive tests was observed an analgesic effect induced by maternal deprivation; however, in the TFL test, only deprived females showed this effect. Surprisingly, only control animals presented an ontogeny nociceptive effect in the HP testat P21 and P43, which may be related to an increase in the inhibitory nociceptive pathways throughout life. In this way, we suggest maternal deprivation to be able to anticipate the maturation of the inhibitory nociceptive pathway. In conclusion, maternal deprivation induced a delayed reflex response at P8 and altered the anxiety and nociceptive behaviors according to the time after exposure to this stressor, in a gender-specific manner.

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How to define chronic pruritus – symptom or disease?

Chronic pruritus is defined by itching lasting 6 weeks or more and is known to be both a highly prevalent and burdensome symptom of many pruritogenic diseases. Its status as a symptom has many implications mainly that the symptom should evolve and subside with the disease. However, according to the clinical experience, chronic pruritus often does not parallel the disease course and requires an own management. It is speculated, that neuronal sensitization processes take place which lead to disconnection of the symptom from the underlying disease and establishment of an own course of pruritus. It is thus discussed that pruritus can be both – a symptom of diseases but also an entity by itself. Further studies are needed to learn more and improve our understanding of this condition. This article compares its role in pruritogenic diseases, encourages discussion on the topic and provides an overview of the proper questions to ask. This article is protected by copyright. All rights reserved.

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Volumetric brain correlates of approach-avoidance behavior and their relation to chronic back pain.

Avoiding any harm, such as painful experiences, is an important ability for our physical and mental health. This avoidance behavior might be overactive under chronic pain, and the cortical and subcortical brain volumetry, which also often changes in chronic pain states, might be a significant correlate of this behavior. In the present study, we thus investigated the association between volumetric brain differences using 3 T structural magnetic resonance imaging and pain- versus pleasure-related approach-avoidance behavior using an Approach Avoidance Task in the laboratory in chronic back pain (N = 42; mean age: 51.34 years; 23 female) and healthy individuals (N = 43; mean age: 45.21 years; 15 female). We found significant differences in hippocampal, amygdala and accumbens volumes in patients compared to controls. The patients` hippocampal volume was significantly positively related to pain avoidance, the amygdala volume to positive approach, and the accumbens volume negatively to a bias to pain avoidance over positive approach. These associations were significantly moderated by pain symptom duration. Cortical structure may thus contribute to an overacting pain avoidance system in chronic back pain, and could, together with a reduction in approaching positive stimuli, be related to maladaptive choice and decision-making processes in chronic pain.

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Modulation of SUR1 K Channel Subunit Activity in the Peripheral Nervous System Reduces Mechanical Hyperalgesia after Nerve Injury in Mice.

The ATP-sensitive K channel (K) is involved in hypersensitivity during chronic pain and is presumed to be a downstream target of mu opioid receptors. Multiple subtypes of K channels exist in the peripheral and central nervous system and their activity may be inversely correlated to chronic pain phenotypes in rodents. In this study, we investigated the different K channel subunits that could be involved in neuropathic pain in mice. In chronic pain models utilizing spinal nerve ligation, SUR1 and Kir6.2 subunits were found to be significantly downregulated in dorsal root ganglia and the spinal cord. Local or intrathecal administration of SUR1-K channel subtype agonists resulted in analgesia after spinal nerve ligation but not SUR2 agonists. In ex-vivo nerve recordings, administration of the SUR1 agonist diazoxide to peripheral nerve terminals decreased mechanically evoked potentials. Genetic knockdown of SUR1 through an associated adenoviral strategy resulted in mechanical hyperalgesia but not thermal hyperalgesia compared to control mice. Behavioral data from neuropathic mice indicate that local reductions in SUR1-subtype K channel activity can exacerbate neuropathic pain symptoms. Since neuropathic pain is of major clinical relevance, potassium channels present a target for analgesic therapies, especially since they are expressed in nociceptors and could play an essential role in regulating the excitability of neurons involved in pain-transmission.

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Painful and Painless Diabetic Neuropathies: What Is the Difference?

The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN.

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The Failing Cascade: Comorbid Post Traumatic- and Opioid Use Disorders.

Opioid use disorder (OUD) is a mounting public health problem with substantial morbidity and mortality. Stress involvement in the course of OUD is generally accepted, but little is understood about the underlying neurobiological mechanisms in part due to a lack of laboratory-based models for chronic stress exposure. Post-traumatic stress disorder (PTSD) may be construed as a psychopathological prototype of chronic stress owing to the essential diagnostic criteria of experiencing and reliving a stressful event(s). Literature search on OUD and PTSD neurobiology was undertaken and the relevant data were integrated within four key areas: (1) OUD and PTSD comorbidity, (2) neurobiological overlap between OUD and PTSD; (3) chronic opioids- and stress-induced alterations of the reward-, stress- (i.e., "anti-reward") and related circuits and (4) mechanistically informed treatments of OUD and/or PTSD. Our findings suggest that even in the absence of prior opioid exposure PTSD patients may be susceptible for the development of OUD by the reason of similar (to those induced by opioids) reward alterations that may be targeted for therapeutic interventions.

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Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery.

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More precise phenotyping of cluster headache using prospective attack reports.

The clinical characteristics of cluster headache (CH) are based mainly on retrospective attack descriptions of "usual" attacks, but whether these reports are reliable is uncertain. We aimed to compare retrospective and prospective attack descriptions and describe the within- and between patient variability of attacks.

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Preliminary Evidence that Melatonin Is not a Biomarker With Children and Adolescents With Episodic Migraine.

To date, there have not been reliable biomarkers to identify impending migraine episodes. A prior study in adults with migraine demonstrated a reduction in the urinary metabolic substrate of melatonin (urinary 6-sulfatoxymelatonin; aMT6s) during a migraine. The aim of this study was to examine whether evening urinary melatonin metabolite levels could predict migraine the next day in children and adolescents with migraine.

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A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2.

ATP1A2 has been identified as the genetic cause of familial hemiplegic migraine type 2. Over 80 ATP1A2 mutations have been reported, but no data from Chinese family studies has been included. Here, we report the first familial hemiplegic migraine type 2 Chinese family with a novel missense mutation.

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Spinal and afferent PKC signaling mechanisms that mediate chronic pain in sickle cell disease.

Pain is the most characteristic feature of sickle cell disease (SCD). Patients with SCD live with unpredictable, recurrent episodes of acute painful crisis, as well as chronic unremitting pain throughout their lifetime. While most of the research and medical efforts have focused on treating vaso-occlusion crisis and acute pain, chronic pain remains a significant challenge faced by patients and physicians. Emerging evidence from human and animal studies has suggested the presence of a neuropathic component in SCD pain. New knowledge on the neurobiology of chronic pain in SCD has significant implications in unraveling the underlying mechanisms. This review focuses on the recent advances on the role of protein kinase C or PKC in promoting and maintaining chronic pain conditions. With a highlight of a specific PKC isoform, PKCδ, we aim to propose PKC as an essential regulator of chronic pain in SCD, which may ultimately lead to innovative therapeutic strategies for treating this devastating life-long problem in patients with SCD.

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Multiplex Epigenome Editing of DRG Neuron Receptors Abolishes Redundant IL-6, TNF-α, and IL-1β Signaling by the Degenerative IVD.

Back pain is the leading cause of disability worldwide and contributes to significant socioeconomic impacts worldwide. It has been hypothesized that the degenerative intervertebral disc (IVD) contributes to back pain by sensitizing nociceptive neurons innervating the IVD to stimuli that would not be painful to healthy patients; however, the inflammatory signaling networks mediating this sensitization remain poorly understood. A better understanding of the underlying mechanisms of degenerative IVD induced changes in nociception are required to improve our understanding and treatment of back pain. Towards these ends, we developed a novel in vitro model to investigate degenerative IVD induced changes in dorsal root ganglion (DRG) neuron activation by measuring DRG neuron activity following neuron seeding on human degenerative IVD tissue collected from patients undergoing surgical treatment for back pain. Lentiviral CRISPR epigenome editing vectors were built to down-regulate the inflammatory receptors TNFR1, IL1R1, and IL6st in DRG neurons in single-plex and multi-plex. Multiplex CRISPR epigenome editing of inflammatory receptors demonstrated that degenerative IVD tissue drives thermal sensitization through the simultaneous and redundant signaling of IL-6, TNF-α, and IL-1β. This work elucidates redundant signaling pathways in neuron interactions with the degenerative IVD and suggests the need for multiplex targeting of IL-6, TNF-α, and IL-1β for pain modulation in the degenerative IVD.

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CD11b+ cells markedly express the itch cytokine interleukin 31 in polymorphic light eruption.

Itch is one of the cardinal symptoms of polymorphic light eruption (PLE), the most common form of photodermatosis known to be mediated immunologically. Indeed, very often itch precedes the skin lesions of the condition or may be even the only symptom in PLE, which sometimes is aggravated to a burning sensation. There have been reports of a variant called PLE sine eruption, with intense pruritus on the sun-exposed parts without any visible skin changes. This article is protected by copyright. All rights reserved.

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Histamine, histamine receptors and neuropathic pain relief.

Histamine, acting via distinct histamine H , H , H and H receptors (H R, H R, H R, H R), regulates various physiological and pathological processes, including pain. In the last two decades, there has been a particular increase in evidence to support the involvement of H R and H R in the modulation of neuropathic pain, that remains challenging in terms of management. However, recent data show contrasting effects on neuropathic pain due to multiple factors that determine the pharmacological responses of histamine receptors and their underlying signal transduction properties (e.g., localization on either the pre- or postsynaptic neuronal membrane). This review summarizes the most recent findings on the role of histamine and the effects mediated by the four histamine receptors in response to the various stimuli associated with and promoting neuropathic pain. We particularly focus on mechanisms underlying histamine-mediated analgesia, as we aim to clarify the analgesic potential of histamine receptor ligands in neuropathic pain.

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Glutamate Transport System as a Key Constituent of Glutamosome: Molecular Pathology and Pharmacological Modulation in Chronic Pain.

Neural uptake of glutamate is executed by the structurally related members of the SLC1A family of solute transporters: GLAST /EAAT1, GLT-1 /EAAT2, EAAC1 /EAAT3, EAAT4, ASCT2. These plasma membrane proteins ensure supply of glutamate, aspartate and some neutral amino acids, including glutamine and cysteine, for synthetic, energetic and signaling purposes, whereas effective removal of glutamate from the synaptic cleft shapes excitatory neurotransmission and prevents glutamate toxicity. Glutamate transporters (GluTs) possess also receptor-like properties and can directly initiate signal transduction. GluTs are physically linked to other glutamate signaling-, transporting- and metabolizing molecules (e.g., glutamine transporters SNAT3 and ASCT2, glutamine synthetase, NMDA receptor, synaptic vesicles), as well as cellular machineries fueling the transmembrane transport of glutamate (e.g., ion gradient-generating Na/K-ATPase, glycolytic enzymes, mitochondrial membrane- and matrix proteins, glucose transporters). We designate this supramolecular functional assembly as 'glutamosome'. GluTs play important roles in the molecular pathology of chronic pain, due to the predominantly glutamatergic nature of nociceptive signalling in the spinal cord. Down-regulation of GluTs often precedes or occurs simultaneously with development of pain hypersensitivity. Pharmacological inhibition or gene knock-down of spinal GluTs can induce/aggravate pain, whereas enhancing expression of GluTs by viral gene transfer can mitigate chronic pain. Thus, functional up-regulation of GluTs is turning into a prospective pharmacotherapeutic approach for the management of chronic pain. A number of novel positive pharmacological regulators of GluTs, incl. pyridazine derivatives and β-lactams, have recently been introduced. However, design and development of new analgesics based on this principle will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of the glutamate transport system in nociceptive circuits.

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Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta-Analysis of 26 Studies.

Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme.

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Government Legislation in Response to the Opioid Epidemic.

Opioid misuse and abuse in the USA has evolved into an epidemic of tragic pain and suffering, resulting in the estimated death of over 64,000 people in 2016. Governmental regulation has escalated alongside growing awareness of the epidemic's severity, both on the state and federal levels.

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Membrane Stabilizer Medications in the Treatment of Chronic Neuropathic Pain: a Comprehensive Review.

Neuropathic pain is often debilitating, severely limiting the daily lives of patients who are affected. Typically, neuropathic pain is difficult to manage and, as a result, leads to progression into a chronic condition that is, in many instances, refractory to medical management.

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Marco Polo of Australian neurology.

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Influence of chronotype on migraine characteristics.

The aim of this study was to investigate chronotype in migraine patients and possible influences on the clinical expression of the disease.

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Unveiling the Relationship Between Central Parkinsonian Pain and Motor Symptoms in Parkinson’s Disease.

Pain in Parkinson's disease (PD) is a common and heterogeneous non-motor symptom. Though the characteristics and predictors of pain in general and of central pain in particular are still largely unknown.

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Care Disparities in Chronic Pain.

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Synthesizing the Strength of the Evidence of Complementary and Integrative Health Therapies for Pain.

Pain and opioid use are highly prevalent, leading for calls to include nonpharmacological options in pain management, including complementary and integrative health (CIH) therapies. More than 2,000 randomized controlled trials (RCTs) and many systematic reviews have been conducted on CIH therapies, making it difficult to easily understand what type of CIH therapy might be effective for what type of pain. Here we synthesize the strength of the evidence for four types of CIH therapies on pain: acupuncture, therapeutic massage, mindfulness techniques, and tai chi.

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Discharged and dismissed: A qualitative study with back pain patients discharged without treatment from orthopaedic consultations.

Consultation-based reassurance for patients with low back pain (LBP) in primary care has been shown to be associated with patients' outcomes. Little is known about the role of reassurance in people with LBP consulting with orthopaedic spinal care teams. Reassurance may be important, especially in cases where surgery is not indicated and patients are discharged without treatment.

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Pregnancy, Birth, Neonatal, and Postnatal Neurological Outcomes After Pregnancy With Migraine.

Prevalence of migraine is high during the reproductive age. Although migraine often improves during pregnancy, the risk of adverse pregnancy, birth, neonatal, and neurological outcomes in mother and offspring remains poorly understood.

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Long-term results of an intensive cognitive behavioral pain management program for patients with chronic low back pain: a concise report of an extended cohort with a minimum of 5-year follow-up.

Treatment options for chronic low back pain (CLBP) include cognitive behavioral interventions. Most of these interventions only have small and short-lived effects. Using strict inclusion criteria for participation in an intensive combined physical and psychological program, encouraging effects were reported at 1-year follow-up. This study evaluates the long-term follow-up results of the same program. The hypothesis is that previously reported results are maintained.

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Potential lower extremity amputation-induced mechanisms of chronic low back pain: role for focused resistance exercise.

Approximately 185 000 individuals undergo limb amputations every year. Of this population, 40% experience lower extremity amputations. A common musculoskeletal condition that develops after amputation is chronic low back pain (LBP). LBP may be a consequence of one or combined mechanical factors including muscle atrophy, strength loss, level of amputation, kinematic traits of movement, mechanical loading and forces, prosthetic design/use and leg length discrepancy. Secondary consequences of LBP may collectively include the dependence of pain medications, impaired physical function, and diminished quality of life (QOL).

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The effect of interactive virtual reality on pain perception: a systematic review of clinical studies.

The aim of this systematic review was to evaluate the effect of immersive and non-immersive interactive virtual reality on pain perception in patients with a clinical pain condition.

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Feasibility of a traditional and teletreatment approach to mirror therapy in patients with phantom limb pain: a process evaluation performed alongside a randomized controlled trial.

To evaluate the delivery, acceptance and experiences regarding a traditional and teletreatment approach to mirror therapy as delivered in a randomized controlled trial.

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Network and pathway-based analysis of microRNA role in neuropathic pain in rat models.

The molecular mechanisms underlying neuropathic pain (NP) remain poorly understood. Emerging evidence has suggested the role of microRNAs (miRNAs) in the initiation and development of NP, but the specific effects of miRNAs in NP are largely unknown. Here, we use network- and pathway-based methods to investigate NP-induced miRNA changes and their biological functions by conducting a systematic search through multiple electronic databases. Thirty-seven articles meet the inclusion criteria. Venn analysis and target gene forecasting are performed and the results indicate that 167 overlapping target genes are co-regulated by five down-regulated miRNAs (rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206). Protein-protein interaction network analysis shows that 77 genes exhibit interactions, with cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunit beta (degree = 11) and cAMP-response element binding protein 1 (degree = 10) having the highest connectivity degree. Gene ontology analysis shows that these target genes are enriched in neuron part, neuron projection, somatodendritic compartment and nervous system development. Moreover, analysis of Kyoto Encyclopedia of Genes and Genomes reveals that three pathways, namely, axon guidance, circadian entrainment and insulin secretion, are significantly enriched. In addition, rno-miR-183, rno-miR-96, rno-miR-30b, rno-miR-150 and rno-miR-206 are consistently down-regulated in the NP models, thus constituting the potential biomarkers of this disease. Characterizing these miRNAs and their target genes paves way for their future use in clinical practice.

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The Chinese Association for the Study of Pain (CASP): Expert Consensus on the Cervicogenic Headache.

Cervicogenic headache is a relatively common but unique form of headache, and in China, as well as in several other countries, both diagnosis and a clear evidence-based treatment plan remain controversial. Therefore, the Chinese Association for the Study of Pain organized a meeting of pain management experts and created an expert consensus on the diagnosis and treatment of cervicogenic headache in China. This article summarizes the conclusions of the consensus group regarding the epidemiology, etiology, clinical features, diagnosis, differential diagnosis, treatment, and rehabilitation of cervicogenic headache in China.

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N-Acylethanolamine acid amidase (NAAA) inhibitor F215 as a novel therapeutic agent for osteoarthritis.

Osteoarthritis (OA), characterized by cartilage damage, synovitis inflammation and chronic pain, is a common degenerative joint disease that may lead to physical disability. In the present study, we first explored the association between N-Acylethanolamine acid amidase (NAAA) and OA progression, and then examined the capability of the NAAA inhibitor F215 to attenuate osteoarthritis. Increased NAAA expressions and decreased PEA levels in synovial membrane and lumbar spinal cord were observed in MIA induced osteoarthritic rats. F215 (i.a., and i.p.) significantly protected against cartilage damage and synovial inflammation by directly increasing PEA levels in joints, or normalization of PEA levels and resolution of inflammation in spinal cord. Moreover, F215 also markedly alleviated osteoarthritic pain in rats, and the therapeutic effects of F215 were blocked by the PPAR-α antagonist MK886. The results revealed that NAAA may has been implicated in OA progression, and treatment with NAAA inhibitor F215 alleviated OA development by preventing cartilage damage, reducing inflammation, and alleviating pain. Our study suggested that NAAA inhibitor might be a novel therapeutic agent for OA treatment.

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At-Home Cortical Stimulation for Neuropathic Pain: a Feasibility Study with Initial Clinical Results.

The clinical use of noninvasive cortical stimulation procedures is hampered by the limited duration of the analgesic effects and the need to perform stimulation in hospital settings. Here, we tested the feasibility and pilot efficacy of an internet-based system for at-home, long-duration, medically controlled transcranial motor cortex stimulation (H-tDCS), via a double-blinded, sham-controlled trial in patients with neuropathic pain refractory to standard-of-care drug therapy. Each patient was first trained at hospital, received a stimulation kit, allotted a password-protected Web space, and completed daily tDCS sessions during 5 weeks, via a Bluetooth connection between stimulator and a minilaptop. Each session was validated and internet-controlled by hospital personnel. Daily pain ratings were obtained during 11 consecutive weeks, and afterwards via iterative visits/phone contacts. Twenty full procedures were completed in 12 consecutive patients (500 daily tDCS sessions, including 20% sham). No serious adverse effects were recorded. Superficial burning at electrode position occurred in 2 patients, and nausea/headache in two others, all of whom wished to pursue stimulation. Six out of the 12 patients achieved satisfactory relief on a scale combining pain scores, drug intake, and quality of life. Daily pain reports correlated with such combined assessment, and differentiated responders from nonresponders without overlap. Clinical improvement in responders could last up to 6 months. Five patients asked to repeat the whole procedure when pain resumed again, with comparable results. At-home, long-duration tDCS proved safe and technically feasible, and provided long-lasting relief in 50% of a small sample of patients with drug-resistant neuropathic pain.

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FBXW5 reduction alleviates spinal cord injury (SCI) by blocking microglia activity: A mechanism involving p38 and JNK.

Traumatic spinal cord injury (SCI) is a major cause of death and lifelong disability in the world. However, the pathological process of SCI has not been fully understood. F-box/WD repeat-containing protein 5 (FBXW5), a subunit of the SCF-type E3 ubiquitin ligase complex, plays an essential role in regulating various pathologies. However, little is known about the effects of FBXW5 on the progression of SCI. In this study, using a rodent model with SCI, we found that FBXW5 expression was markedly down-regulated in spinal dorsal horn of rats after SCI surgery. Rats with FBXW5 knockdown showed the improved paw withdrawal latency responding to thermal stimuli on the ipsilateral side while showed no significant influence on the basal threshold on the contralateral side. In addition, SCI-induced increase of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6, was obviously decreased by FBXW5 knockdown, along with microglia inactivation as evidenced by the reduced expression of Iba-1. Moreover, immunofluorescent staining suggested that FBXW5 was co-localized with Iba-1 in spinal cord tissues of SCI rats. Furthermore, p38, Jun kinase (JNK) and extracellular signal-regulated kinase (ERK)-1/2 activation was significantly increased by SCI in spinal dosal horn of rats. Notably, FBXW5 knockdown markedly reduced the expression of phosphorylated p38 and JNK without affecting ERK1/2 activity in SCI rats. What's more, suppressing p38 and JNK activation significantly alleviated SCI-induced abnormal behavior in rats, along with reduced expression of pro-inflammatory cytokines. Taken together, these results provided evidence that down-regulation of FBXW5 was involved in the prevention of SCI.

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How to integrate monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor in daily clinical practice.

Migraine is a major public health issue associated with significant morbidity, considerable negative impact on quality of life, and significant socioeconomic burden. Preventive treatments are required to reduce the occurrence and the severity of acute attacks and to minimize the use of abortive medications and the associate risk of drug-related adverse events, as well as the onset of medication-overuse headache and chronification of migraine. We performed a review of all available evidence on the safety and efficacy of monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor for the preventive treatment of migraine to provide evidence-based guidance on their use in clinical practice. Monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are mechanism-specific drugs for the preventive treatment of migraine. Double-blind randomized clinical trials have shown that monoclonal antibodies targeting the calcitonin gene-related peptide or its receptor are effective across all the spectrum of migraine patients who require prevention and have a good safety and tolerability profile. Nevertheless, high costs limit the affordability of those drugs at the moment.

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Is insulin resistance the cause of fibromyalgia? A preliminary report.

Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.

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The Effects of Cobalt Protoporphyrin IX and Tricarbonyldichlororuthenium (II) Dimer Treatments and Its Interaction with Nitric Oxide in the Locus Coeruleus of Mice with Peripheral Inflammation.

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: 1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; 2) effects of CoPP and tricarbonyldichlororuthenium(II)dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP,and mitogen-activated protein kinases (MAPK)in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activationin all genotypes. Both treatments blocked NOS1 overexpression,and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation andshows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.

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Cervical musculoskeletal impairments in migraine and tension type headache: A systematic review and meta-analysis.

Neck pain is common in migraine and tension type headache (TTH). This review aimed to examine the evidence for cervical musculoskeletal impairments in these headaches.

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The α9α10 Nicotinic Acetylcholine Receptor Antagonist αO-Conotoxin GeXIVA[1,2] Alleviates and Reverses Chemotherapy-Induced Neuropathic Pain.

Oxaliplatin is a third-generation platinum drug and is widely used as a first-line therapy for the treatment of colorectal cancer (CRC). However, a large number of patients receiving oxaliplatin develop dose-limiting painful neuropathy. Here, we report that αO-conotoxin GeXIVA[1,2], a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype, can relieve and reverse oxaliplatin-induced mechanical and cold allodynia after single and repeated intramuscular (IM) injections in rats. Treatments were started at 4 days post oxaliplatin injection when neuropathic pain emerged and continued for 8 and 16 days. Cold score and mechanical paw withdrawal threshold (PWT) were detected by the acetone test and von Frey test respectively. GeXIVA[1,2] significantly relieved mechanical and cold allodynia in oxaliplatin-treated rats after a single injection. After repeated treatments, GeXIVA[1,2] produced a cumulative analgesic effect without tolerance and promoted recovery from neuropathic pain. Moreover, the long lasting analgesic effect of GeXIVA[1,2] on mechanical allodynia continued until day 10 after the termination of the 16-day repeated treatment procedure. On the contrary, GeXIVA[1,2] did not affect acute mechanical and thermal pain behaviors in normal rats after repeated injections detected by the von Frey test and tail flick test. GeXIVA[1,2] had no influence on rat hind limb grip strength and body weight after repeated treatments. These results indicate that αO-conotoxin GeXIVA[1,2] could provide a novel strategy to treat chemotherapy-induced neuropathic pain.

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Medial branch radiofrequency ablation outcomes in patients with centralized pain.

We hypothesized that patients with characteristics of centralized pain (fibromyalgia (FM)-like phenotype) would be less likely to respond to radiofrequency ablation (RFA), which may explain some of the failures of this peripherally directed therapy.

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Brain Electrical Activity Associated With Visual Attention and Reactive Motor Inhibition in Patients With Fibromyalgia.

Fibromyalgia (FM) is a generalized chronic pain condition associated with multiple cognitive impairments, including altered inhibitory processes. Inhibition is a key component of human executive functions and shares neural substrate with pain processing, which may explain the inhibitory deficits in FM. Here, we investigated the integrity of brain inhibitory mechanisms in these patients.

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Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia.

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8CD103 T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures.

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Self-regulatory ability, fatigue, and the experience of pain: Mechanistic insights from pain-free undergraduates.

Self-regulatory (SR) ability is an important resource for managing pain, but chronic pain patients experience chronic self-regulatory fatigue even when they are not in pain. Pressure pain thresholds (PPT) and pain inhibition are two mechanisms that differentiate people with and without chronic pain. It was hypothesized that trait SR ability would be associated with higher PPT and better pain inhibition and that PPT and pain inhibition would be lower following high versus low SR fatigue. Three studies tested these hypotheses. Study 1 had 240 pain-free undergraduates complete measures of trait SR ability and PPT; 122 also provided data on pain inhibition. Study 2 had 38 of Study 1's participants return for two additional sessions in which they underwent PPT testing under conditions of high or low SR fatigue (within-person, counterbalanced). Study 3 repeated these procedures with pain inhibition as the outcome (n = 39). Results revealed that individual differences in SR ability were not associated with PPT or pain inhibition (all ps > 0.05). Within people, neither PPT (F(1, 36) = 1.57, p = 0.22) nor pain inhibition (F(1, 37) = 1.79, p = 0.19) were significantly different under conditions of low versus high SR fatigue. Results do not support the hypotheses that PPT or pain inhibition associate with individual differences in trait SR ability or transient changes in state SR fatigue in the absence of pain. Instead, the SR deficits in chronic pain patients may arise from the experience of chronic pain.

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Effects of Mindfulness-Based Stress Reduction on Depression, Anxiety, and Pain in Patients With Postherpetic Neuralgia.

The aim of this study was to explore the effects of mindfulness-based stress reduction (MBSR) on reducing the psychological and physical symptoms in patients with postherpetic neuralgia (PHN). A total of 50 patients with PHN from January 2017 to September 2018 were selected into the intervention group and the control group. Both groups received routine care, whereas the intervention group also was given an 8-week of MBSR. Psychological (depression and anxiety) and physical (pain) symptoms were assessed before and after the intervention. The study demonstrated evidence of MBSR effectiveness in reducing depression (p < 0.01), anxiety (p < 0.01), and pain (p < 0.01) scores after intervention for herpetic patients with neuralgia. MBSR can effectively alleviate depression, anxiety, and pain in patients with PHN. Our results provide clinical effectiveness evidence that MBSR works to improve the psychological and physical symptoms with the greatest improvement occurring during the 8-week program.

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Robot-assisted line bisection in patients with Complex Regional Pain Syndrome.

Complex Regional Pain Syndrome (CRPS) is characterized by pain, motor and inflammatory symptoms usually affecting one limb. Cognitive difficulties have been reported to affect patients' ability to represent, perceive and use their affected limb. It is debated whether these difficulties result from deficits in controlling goal-directed movements in space or from a learned strategy to protect the affected limb. In order to dissociate the two hypotheses, patients with upper-limb CRPS were asked to move with their unaffected hand towards visual targets projected at different positions on a horizontal semi-reflexive mirror. By means of a robotic handle placed below the screen, they were asked to move a cursor, to reach and cross lines at their estimated midpoint. In some of the stimulation series, the affected hand was placed below the mirror so that some lines appeared projected onto that hand. Vision of the hands and the robotic handle was preserved or prevented by opening or closing a shutter below the mirror. Lines were displayed on the mirror according to which part of the body was affected (ispi- vs. contralateral) and the actual position of the affected hand (inside vs. outside the workspace). Comparatively to control participants, CRPS patients generally biased their estimation by bisecting the lines towards their left side, irrelative of which part of the body was affected and the position of the affected hand, both in ipsi- and contralateral space, with only a few exceptions. Our results are in line with previous studies having described a visuospatial deficit in CRPS patients and discard the explanation of observed symptoms in terms of learned nonuse strategies, as only the unaffected hand was used to perform the task. It is suggested that CRPS patients can display difficulties to perform tasks requesting visuo-motor coordination, reflecting the complex cortical reorganization occurring in CRPS.

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Use of the PROMIS-29® to identify subgroups of mothers with chronic pain.

Children of mothers with chronic pain are at increased risk for poor health, but few studies have examined what characteristics of maternal chronic pain may be associated with children's risk. This study identified subgroups of mothers based on patterns of pain, physical function, and emotional function on the 29-item Patient-Reported Outcomes Measurement Information System® (PROMIS-29®) and evaluated associations between maternal subgroups and children's pain and emotional functioning.

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The Impact of Surgical Amputation and Valproic Acid on Pain and Functional Trajectory: Results from the Veterans Integrated Pain Evaluation Research (VIPER) Randomized, Double-Blinded Placebo-Controlled Trial.

To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery.

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Widespread Pressure Pain Hyperalgesia Is Not Related to Pain in Patients with Parkinson’s Disease.

Pain is one of the most frequent nonmotor impairments in Parkinson's disease (PD) and is hypothesized to be associated with altered nociceptive pain processing. Our aims were to investigate differences in widespread pressure pain sensitivity between PD patients with and without pain and healthy controls and to assess the relationship of health-related quality of life and sleep quality with pressure pain sensitivity.

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The Role of Spirituality in Pain, Function, and Coping in Individuals with Chronic Pain.

Chronic pain is a multidimensional experience associated with psychosocial (e.g., pain-related beliefs and pain coping responses) and spiritual factors. Spirituality is a universal aspect of the human experience that has been hypothesized to impact pain experience via its effects on pain, physical/psychological function, resilience and pain-related beliefs, and pain coping responses. However, research evaluating the associations between measures of spirituality and measures of pain and function in individuals with chronic pain is limited. This study seeks to address this limitation.

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Evolving Spinal Cord Stimulation Technologies and Clinical Implications in Chronic Pain Management.

Spinal cord stimulation (SCS), based on the gate theory of nociception, has been shown to be effective in the management of chronic pain conditions. While early-generation technology offered many patients improvement in their pain and symptoms, limitations including paresthesia, dependence on mapping, decreased chronological efficacy, and inadequate coverage left many patients with persistent pain and overt therapeutic failure.

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Quality of postoperative pain management in Ethiopia: A prospective longitudinal study.

The annual number of surgical operations performed is increasing throughout the world. With this rise in the number of surgeries performed, so too, the challenge of effectively managing postoperative pain. In Africa, there are scanty data available that make use of multi-center data to characterize the quality of postoperative pain management. In this study using a longitudinal data, we have attempted to characterize the quality of postoperative pain management; among patients scheduled for major elective orthopedic, gynecologic and general surgery.

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An ethnography of chronic pain management in primary care: The social organization of physicians’ work in the midst of the opioid crisis.

This study reports on physicians' experiences with chronic pain management. For over a decade prescription opioids have been a primary treatment for chronic pain in North America. However, the current opioid epidemic has complicated long-standing practices for chronic pain management which historically involved prescribing pain medication. Caring for patients with chronic pain occurs within a context in which a growing proportion of patients suffer from chronic rather than acute conditions alongside rising social inequities.

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