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Papers: 27 Jul 2019 - 2 Aug 2019

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Race/Ethnicity Does Not Moderate the Relationship Between Adverse Life Experiences and Temporal Summation of the Nociceptive Flexion Reflex and Pain: Results From the Oklahoma Study of Native American Pain Risk.

Adverse life experiences (ALEs) are associated with hyperalgesia and chronic pain, but the underlying mechanisms are poorly understood. One potential mechanism is hyperexcitability of spinal neurons (ie, central sensitization). Given that Native Americans (NAs) are more likely to have ALEs and to have a higher prevalence of chronic pain, the relationship between ALEs and spinal hyperexcitability might contribute to their pain risk. The present study assessed temporal summation of the nociceptive flexion reflex (TS-NFR; a correlate of spinal hyperexcitability) and pain (TS-Pain) in 246 healthy, pain-free non-Hispanic whites and NAs. The Life Events Checklist was used to assess the number of ALEs. Multilevel growth models were used to predict TS-NFR and TS-Pain, after controlling for age, perceived stress, psychological problems, negative and positive affect, and painful stimulus intensity. ALEs and negative affect were significantly associated with greater pain, but not enhanced TS-Pain. By contrast, ALEs were associated with enhanced TS-NFR. Race did not moderate these relationships. This finding implies that ALEs promote hyperalgesia as a result of increased spinal neuron excitability. Although relationships between ALEs and the nociceptive flexion reflex/pain were not stronger in NAs, given prior evidence that NAs experience more ALEs, this factor might contribute to the higher prevalence of chronic pain in NAs. PERSPECTIVE: This study found a dose-dependent relationship between ALEs and spinal neuron excitability. Although the relationship was not stronger in NAs than non-Hispanic whites, given prior evidence that NAs experience more ALEs, this could contribute to the higher prevalence of chronic pain in NAs.

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Cutaneous TRPV1 Neurons Trigger Protective Innate Type 17 Anticipatory Immunity.

Cutaneous TRPV1 neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1 neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1 neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1 neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1 neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.

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IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.

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A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy.

Homocysteinemia is a metabolic condition characterized by abnormally high level of homocysteine in the blood and is considered to be a risk factor for peripheral neuropathy. However, the cellular mechanisms underlying toxic effects of homocysteine on the processing of peripheral nociception have not yet been investigated comprehensively. Here, using a rodent model of experimental homocysteinemia, we report the causal association between homocysteine and the development of mechanical allodynia. Homocysteinemia-induced mechanical allodynia was reversed upon pharmacological inhibition of T-type calcium channels. In addition, our in vitro studies indicate that homocysteine enhances recombinant T-type calcium currents by promoting the recycling of Cav3.2 channels back to the plasma membrane via a PKC-dependent signaling pathway that requires the direct phosphorylation of Cav3.2 at specific loci. Altogether, these results reveal an unrecognized signaling pathway that modulates the expression of T-type calcium channels, and may potentially contribute to the development of peripheral neuropathy associated with homocysteinemia.

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Dermorphin [D-Arg2, Lys4] (1-4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury.

Opioid use for chronic pain is limited by severe central adverse effects. We examined whether activating mu-opioid receptors (MORs) in the peripheral nervous system attenuates spinal cord injury (SCI) pain-like behavior in mice. We produced a contusive SCI at the T10 vertebral level and examined motor and sensory dysfunction for 6 weeks. At 6 weeks, we tested the effect of subcutaneous (s.c.) injection of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting MOR-preferring agonist, on mechanical and heat hypersensitivity. Basso mouse scale score was significantly decreased after SCI, and mice showed hypersensitivity to mechanical and heat stimulation at the hind paw beginning at 2 weeks, as indicated by increased paw withdrawal frequency to mechanical stimulation and decreased paw withdrawal latency to heat stimulation. In wild-type SCI mice, DALDA (1 mg/kg, s.c.) attenuated heat but not mechanical hypersensitivity. The effect was blocked by pretreatment with an intraperitoneal injection of methylnaltrexone (5 mg/kg), a peripherally restricted opioid receptor antagonist, and was also diminished in Pirt-MOR conditional knockout mice. DALDA did not adversely affect exploratory activity or induced preference to drug treatment in SCI mice. In vivo calcium imaging showed that DALDA (1, 10 mg/kg, s.c.) inhibited responses of small DRG neurons to noxious heat stimulation in Pirt-GCaMP6s mice after SCI. Western blot analysis showed upregulation of MOR in the lumbar spinal cord and sciatic nerves at 6 weeks post-SCI. Our findings suggest that peripherally acting MOR agonist may inhibit heat hypersensitivity below the injury level with minimal adverse effects.

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Conditioned pain modulation as biomarker of chronic pain: a systematic review of its concurrent validity.

Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms since it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear to what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area, in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported non-significant correlations between CPM efficiency and clinical manifestations of pain, while the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need of future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.

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The Nociceptive Innervation Of The Normal And Osteoarthritic Mouse Knee.

To document the nociceptive innervation of the normal and osteoarthritic murine knee.

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Nerve growth factor-mediated photoablation of nociceptors reduces pain behavior in mice.

Nerve growth factor (NGF) and its receptors TrkA and p75 play a key role in the development and function of peripheral nociceptive neurons. Here, we describe novel technology to selectively photoablate TrkA-positive nociceptors through delivery of a phototoxic agent coupled to an engineered NGF ligand and subsequent near-infrared illumination. We demonstrate that this approach allows for on demand and localized reversal of pain behaviors in mouse models of acute, inflammatory, neuropathic, and joint pain. To target peripheral nociceptors, we generated a SNAP-tagged NGF derivative NGF that binds to TrkA/p75 receptors but does not provoke signaling in TrkA-positive cells or elicit pain behaviors in mice. NGF was coupled to the photosensitizer IRDye700DX phthalocyanine (IR700) and injected subcutaneously. After near-infrared illumination of the injected area, behavioral responses to nociceptive mechanical and sustained thermal stimuli, but not innocuous stimuli, were substantially reduced. Similarly, in models of inflammatory, osteoarthritic, and neuropathic pain, mechanical hypersensitivity was abolished for 3 weeks after a single treatment regime. We demonstrate that this loss of pain behavior coincides with the retraction of neurons from the skin which then reinnervate the epidermis after 3 weeks corresponding with the return of mechanical hypersensitivity. Thus NGF-mediated photoablation is a minimally invasive approach to reversibly silence nociceptor input from the periphery, and control pain and hypersensitivity to mechanical stimuli.

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Stress signaling in pain control.

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Assessment and treatment recommendations for pediatric pain: the influence of patient race, patient gender, and provider pain-related attitudes.

Previous studies have documented that racial minorities and women receive poorer pain care than their demographic counterparts. Providers contribute to these disparities when their pain-related decision-making systematically varies across patient groups. Less is known about racial and gender disparities in children with pain or the extent to which providers contribute to these disparities. In a sample of 129 medical students (henceforth referred to as 'providers'), Virtual Human methodology and a pain-related version of the Implicit Association Test (IAT) were used to examine the effects of patient race/gender on providers' pain assessment/treatment decisions for pediatric chronic abdominal pain, as well as the moderating role of provider implicit pain-related race/gender attitudes. Findings indicated that providers rated Black patients as more distressed (mean difference [MD]=2.33, p<.01, SE=.71, 95% CI=.92, 3.73) and as experiencing more pain-related interference (MD=3.14, p<.01, SE=.76, 95% CI=1.63, 4.64) compared to White patients. Providers were more likely to recommend opioids for Black patients than White patients (MD=2.41, p<.01, SE=.58, 95% CI=1.05, 3.76). Female patients were perceived to be more distressed by their pain (MD=2.14, p<.01, SE=.79, 95% CI=.58, 3.70) than male patients, however there were no gender differences in treatment recommendations. IAT results indicated that providers held implicit attitudes that Black Americans (M=.19, SD=.29) and males (M=.38, SD=.29) were more pain-tolerant than their demographic counterparts; however, these implicit attitudes did not significantly moderate their pain assessment/treatment decisions. Future studies are needed to elucidate specific paths through which the pain experience and care of children differ across racial and gender groups. PERSPECTIVE: Providers' pain assessment (i.e., pain distress/pain interference) and treatment (i.e., opioids) of pediatric pain differs across patient race and to a lesser extent, patient gender. This study represents a critical step in research on pain-related disparities in pediatric pain.

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Repetitive transcranial magnetic stimulation of the primary motor cortex expedites recovery in the transition from acute to sustained experimental pain: a randomised, controlled study.

Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) is increasingly being investigated as a means of alleviating chronic pain. However, rTMS interventions are typically initiated once pain has already become chronic and maladaptive patterns of neural activity are likely to have been established. A critical question is whether M1 rTMS applied soon after pain onset can prevent the development of maladaptive neural activity and promote recovery. This study investigated the effect of 5 consecutive days of excitatory M1 rTMS on pain, functional limitation, mechanical hyperalgesia, descending inhibitory pain control, and M1 organisation in the transition from acute to sustained pain. Thirty healthy participants attended 8 sessions over a 16-day period. On Days 0, 2, and 4, nerve growth factor was injected into the right forearm to induce progressively developing muscle soreness and mechanical hyperalgesia. Active or sham excitatory rTMS was delivered on Days 4-8. Clinical and neurophysiological outcomes were recorded on Days 0, 2, 4, 6, 8, 11 and 14. Active rTMS promoted recovery of muscle soreness, pain, and mechanical hyperalgesia when compared to sham rTMS (all between-group p < 0.05). Corticomotor excitability and descending inhibitory pain control did not differ between groups. These findings suggest that active excitatory M1 rTMS promotes recovery of muscle soreness, pain, and mechanical hyperalgesia in the transition from acute to sustained experimental pain. The analgesic effects of M1 rTMS do not appear to be modulated by descending inhibitory pain control or local changes in corticomotor excitability.

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Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically exploited the potential of electroencephalography (EEG) to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4 – 8 Hz) and gamma (> 60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results suggest that increased theta and gamma synchrony in frontal brain areas are involved in the pathophysiology of chronic pain. While substantial challenges concerning the reproducibility of the findings and the accuracy, specificity and validity of potential EEG-based disease markers remain to be overcome, our study indicates that abnormal frontal synchrony at theta and gamma frequencies might be promising targets for non-invasive brain stimulation and/or neurofeedback approaches.

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Cell-specific role of HDAC6 in chemotherapy-induced mechanical allodynia and loss of intraepidermal nerve fibers.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of cancer treatment with no FDA-approved medication for its prevention or management. Using RNA sequencing analysis of dorsal root ganglia (DRG) we identify critical contributions of HDAC6 and mitochondrial damage to the establishment of CIPN in a mouse model of cisplatin-induced neuropathy. We show that pharmacological inhibition of HDAC6 using ACY-1215 or global deletion of HDAC6 is sufficient to prevent cisplatin-induced mechanical allodynia, loss of intraepidermal nerve fibers (IENFs), and mitochondrial bioenergetic deficits in DRG neurons and peripheral nerves in male and female mice. The bioenergetic deficits in the neuronal cell bodies in the DRG are characterized by reduced oxidative phosphorylation, whereas the mitochondrial deficits in the nerves are due to a reduction in axonal mitochondrial content. Notably, deleting HDAC6 in sensory neurons protects against the cisplatin-induced loss of IENFs and the reduction in mitochondrial bioenergetics and content in the peripheral nerve. In contrast, deletion of HDAC6 in sensory neurons only partially and transiently prevents cisplatin-induced mechanical allodynia and does not protect against impairment of mitochondrial function in DRG neurons. We further reveal a critical role of T cells in the protective effects of HDAC6 inhibition on these signs of CIPN. In summary, we show that cisplatin-induced mechanical allodynia is associated with mitochondrial damage in DRG neurons, while the loss of IENFs is related to bioenergetic deficits in peripheral nerves. Moreover, our findings identify cell-specific contributions of HDAC6 to mechanical allodynia and loss of IENFs that characterize cisplatin-induced peripheral neuropathy.

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A randomized controlled efficacy trial of Mindfulness-Based Stress Reduction compared to an active control group and usual care for fibromyalgia: the EUDAIMON study.

Fibromyalgia syndrome (FM) represents a great challenge for clinicians and researchers because the efficacy of currently available treatments is limited. The present study examined the efficacy of Mindfulness-Based Stress Reduction (MBSR) for reducing functional impairment as well as the role of mindfulness-related constructs as mediators of treatment outcomes for people with FM. 225 participants with FM were randomized into three study arms: MBSR plus treatment-as-usual (TAU), FibroQoL (multicomponent intervention for FM) plus TAU, and TAU alone. The primary endpoint was functional impact (measured with the Fibromyalgia Impact Questionnaire Revised), and secondary outcomes included "fibromyalginess", anxiety and depression, pain catastrophising, perceived stress and cognitive dysfunction. The differences in outcomes between groups at post-treatment assessment (primary endpoint) and 12-month follow-up were analyzed using linear mixed-effects models and mediational models through path analyses. MBSR was superior to TAU both at post-treatment (large effect sizes) and at follow-up (medium to large effect sizes), and MBSR was also superior to FibroQoL post-treatment (medium to large effect sizes), but long-term it was only modestly better (significant differences only in pain catastrophising and fibromyalginess). Immediately post-treatment, the NNT for 20% improvement in MBSR versus TAU and FibroQoL was 4.0 (95%CI= 2.1-6.5) and 5.0 (95%CI= 2.7-37.3). An unreliable NNT value of 9 (not computable 95%CI) was found for FibroQoL vs. TAU. Changes produced by MBSR in functional impact were mediated by psychological inflexibility and the mindfulness facet Acting with awareness. These findings are discussed in relation to previous studies of psychological treatments for FM.

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Trigeminal Aδ- and C-afferent supply of lamina I neurons in the trigeminocervical complex.

Nociceptive trigeminal afferents innervating craniofacial area, e.g. facial skin and cranial meninges, project to a broad region in the medullary and upper cervical dorsal horn designated as the trigeminocervical complex. Lamina I neurons in the trigeminocervical complex integrate and relay peripheral inputs, thus playing a key role in both cranial nociception and primary headache syndromes. Because of the technically challenging nature of recording, the long-range trigeminal afferent inputs to the medullary and cervical lamina I neurons were not intensively studied so far. Therefore, we have developed an ex vivo brainstem-cervical cord preparation with attached trigeminal nerve for the visually-guided whole-cell recordings from the medullary and cervical lamina I neurons. Two-thirds of recorded neurons generated intrinsic rhythmic discharges. The stimulation of the trigeminal nerve produced a complex effect; it interrupted the rhythmic discharge for hundreds of milliseconds but, if the neuron was silenced by a hyperpolarizing current injection, could elicit a discharge. The monosynaptic inputs from the trigeminal Aδ-, high-threshold-Aδ-, low-threshold-C- and C-afferents were recorded in the medullary neurons, as well as in the cervical neurons located in the segments C1-C2 and, to lesser degree, in C3-C4. This pattern of supply was consistent with our labelling experiments showing extensive cervical projections of trigeminal afferents. Excitatory inputs were mediated, although not exclusively, via AMPA/kainate and NMDA receptors, while inhibitory inputs via both GABA and glycine receptors. In conclusion, the trigeminocervical lamina I neurons receive a complex pattern of long-range mono- and polysynaptic inputs from a variety of the trigeminal nociceptive afferents.

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Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn.

Tissue injury produces a delicate balance between latent pain sensitization (LS) and compensatory endogenous opioid receptor analgesia that continues for months, even after re-establishment of normal pain thresholds. To evaluate the contribution of mu (MOR), delta (DOR), and/or kappa (KOR) opioid receptors to the silencing of chronic postoperative pain, we performed plantar incision at the hindpaw, waited 21 days for the resolution of hyperalgesia, and then intrathecally injected subtype-selective ligands. We found that the MOR-selective inhibitor CTOP (1-1000 ng) dose-dependently reinstated mechanical hyperalgesia. Two DOR-selective inhibitors naltrindole (1-10 μg) and TIPP[Ψ] (1-20 μg) reinstated mechanical hyperalgesia, but only at the highest dose that also produced itching, licking, and tail biting. Both the prototypical KOR-selective inhibitors nor-BNI (0.1-10 μg) and the newer KOR inhibitor with more canonical pharmocodynamic effects, LY2456302 (0.1-10 μg), reinstated mechanical hyperalgesia. Furthermore, LY2456302 (10 μg) increased the expression of phosphorylated signal-regulated kinase (pERK), a marker of central sensitization, in dorsal horn neurons but not glia. Sex studies revealed that LY2456302 (0.3 μg) reinstated hyperalgesia and pERK expression to a greater degree in female as compared to male mice. Our results suggest that spinal MOR and KOR, but not DOR, maintain LS within a state of remission to reduce the intensity and duration of postoperative pain, and that endogenous KOR but not MOR analgesia is greater in female mice.

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Increased expression of fibronectin leucine-rich transmembrane protein 3 in the dorsal root ganglion induces neuropathic pain in rats.

Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the dorsal root ganglion (DRG), FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated transcription in the DRG, but not in the spinal cord. Intrathecal administration of FLRT3 protein to naïve rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia.Neuropathic pain occurs frequently after nerve injury and is associated with abnormal neuronal excitability in the spinal cord. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) regulates neurite outgrowth and cell adhesion. Here, nerve injury increased FLRT3 protein levels in the spinal cord dorsal root, despite the fact that transcripts were only induced in the dorsal root ganglion (DRG). FLRT3 protein injection into the rat spinal cord induced mechanical hypersensitivity, as did virus-mediated FLRT3 overexpression in DRG. Conversely, FLRT3 inhibition with antibodies attenuated mechanically induced pain after nerve damage. These findings suggest that FLRT3 is produced by injured DRG neurons and increases neuronal excitability in the dorsal horn, leading to pain sensitization. Neuropathic pain induction is a novel function of FLRT3.

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Toward a Multimodal Framework of Brainstem Pain-Modulation Circuits in Migraine.

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Erenumab (AMG 334), a monoclonal antagonist antibody against the canonical CGRP receptor, does not impair vasodilatory or contractile responses to other vasoactive agents in human isolated cranial arteries.

Calcitonin gene-related peptide (CGRP) is a neuronal transmitter present in intracranial sensory nerves, where it is involved in migraine pathophysiology as well as other biological functions. Recently, the fully human monoclonal antibody erenumab (AMG 334), which targets the canonical calcitonin gene-related peptide receptor, showed significant prophylactic efficacy and favourable safety in phase II and III clinical trials for episodic and chronic migraine and is now approved for migraine prevention in several countries.

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PI16 is a non-neuronal regulator of neuropathic pain.

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Comparison of Chemotherapy Effects on Mechanical Sensitivity and Food-Maintained Operant Responding in Male and Female Rats.

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Passive transfer of fibromyalgia pain from patients to mice.

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Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7.

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Resolvin D3 controls mouse and human nociceptive functions and preclinical progression of psoriasis.

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Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation.

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The Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Fenobam: Pharmacokinetics, Side Effects, and Analgesic Effects in Healthy Human Subjects.

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Altered synaptic adaptation and gain in sensory circuits of the casein kinase 1 delta (CK1dT44A) mouse model of migraine.

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Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in C. elegans

Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of mutants. mutants display increased cholinergic- and decreased GABAergic-transmission. Moreover, increased cholinergic transmission in mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

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Longitudinal follow-up of biopsy-proven small fiber neuropathy.

Little is published on the prognosis of small fiber neuropathy (SFN).

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World Brain Day 2019: migraine, the painful truth.

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KCNMB3 in spinal microglia contributes to the generation and maintenance of neuropathic pain in mice.

Neuropathic pain is one of most intense types of chronic pain. Numerous studies investigating neuropathic pain have described the critical involvement of microglia in the spinal cord. Previous studies have indicated that activation of large conductance Ca2+‑activated K+ (BK) channels contributes to microglial activation in the spinal dorsal horn (SDH) and the generation of neuropathic pain. However, the specific role of BK channels in spinal microglia in neuropathic pain has not been fully addressed in previous studies, as BK channel inhibitors were used to inhibit microglial BK channel based on their inhibitory kinetics. We previously identified that Ca2+‑activated K+ channel β3 auxiliary subunit (KCNMB3), which is an auxiliary subunit of BK channels and regulates gating properties of the channel, is exclusively expressed in microglia in the spinal cord. The present study analyzed the role of BK channels in spinal microglia in neuropathic pain using a spinal microglia‑specific BK channel knockdown method, with intrathecal injection of KCNMB3 small interfering RNA. Neuropathic pain was significantly attenuated in KCNMB3 knockdown mice. Increases in the number of microglia in the SDH following nerve injury were attenuated by KCNMB3 knockdown. Furthermore, increased levels of pain‑associated molecules in the SDH were attenuated in KCNMB3 knockdown mice. Attempts were also made to analyze the effects of KCNMB3 knockdown on chronic pain. KCNMB3 knockdown ameliorated chronic pain and inhibited the expression levels of pain‑associated molecules in the SDH. The results from the present study suggested that BK channels modulated the activation state of spinal microglia, and that KCNMB3 is a potential therapeutic target for neuropathic pain.

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The IL-6/p-BTK/p-ERK signaling mediates the calcium phosphate-induced pruritus.

Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice-triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERKs in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed a higher mRNA expression of Bruton's tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably diminish the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.-Keshari, S., Sipayung, A. D., Hsieh, C.-C., Su, L.-J., Chiang, Y.-R., Chang, H.-C., Yang, W.-C., Chuang, T.-H., Chen, C.-L., Huang, C.-M. The IL-6/p-BTK/p-ERK signaling mediates the calcium phosphate-induced pruritus.

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Cannabis for Chronic Pain: We Simply Don’t Know.

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Long-term Safety and Tolerability of NKTR-181 in Patients with Moderate to Severe Chronic Low Back Pain or Chronic Noncancer Pain: A Phase 3 Multicenter, Open-Label, 52-Week Study (SUMMIT-08 LTS).

To evaluate the long-term safety of NKTR-181, a novel mu-opioid receptor agonist that may have reduced human abuse potential, in patients with moderate to severe chronic low back pain (CLBP) or other chronic noncancer pain (CNP).

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Recent advances in understanding and managing phantom limb pain.

Post-amputation phantom limb pain (PLP) is highly prevalent and very difficult to treat. The high-prevalence, high-pain intensity levels, and decreased quality of life associated with PLP compel us to explore novel avenues to prevent, manage, and reverse this chronic pain condition. This narrative review focuses on recent advances in the treatment of PLP and reviews evidence of mechanism-based treatments from randomized controlled trials published over the past 5 years. We review recent evidence for the efficacy of targeted muscle reinnervation, repetitive transcranial magnetic stimulation, imaginal phantom limb exercises, mirror therapy, virtual and augmented reality, and eye movement desensitization and reprocessing therapy. The results indicate that not one of the above treatments is consistently better than a control condition. The challenge remains that there is little level 1 evidence of efficacy for PLP treatments and most treatment trials are underpowered (small sample sizes). The lack of efficacy likely speaks to the multiple mechanisms that contribute to PLP both between and within individuals who have sustained an amputation. Research approaches are called for to classify patients according to shared factors and evaluate treatment efficacy within classes. Subgroup analyses examining sex effects are recommended given the clear differences between males and females in pain mechanisms and outcomes. Use of novel data analytical approaches such as growth mixture modeling for multivariate latent classes may help to identify sub-clusters of patients with common outcome trajectories over time.

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Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study.

This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA).

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Sepiapterin reductase inhibition selectively reduces inflammatory joint pain and increases urinary sepiapterin.

To evaluate the anti-inflammatory and analgesic effect of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease and to evaluate sepiapterin as a non-invasive, translational biomarker of SPR inhibition/target engagement in mice and healthy human volunteers.

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When therapeutic expectancies are violated: An fMRI study.

Positive and negative expectancies drive behavioral and neurobiological placebo and nocebo effects which in turn can have profound effects on patient improvement or worsening. However, expectations of events and outcomes are often not met in daily life and clinical practice. It is currently unknown how this affects placebo and nocebo effects. We have demonstrated that the violation of expectancies, such as when a discrepancy between what is expected and what is actually presented, reduces both placebo and nocebo effects while causing an extinction of placebo effects. The reduction of placebo and nocebo effects was paralleled by an activation of the left inferior parietal cortex, a brain region that redirects attention when discrepancies between sensory and cognitive events occur. Our findings highlight the importance of expectancy violation in shaping placebo and nocebo effects and open up new avenues for managing positive and negative expectations in clinical trials and practices. This article is protected by copyright. All rights reserved.

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BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus.

Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8-22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.

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The role of dorsal root ganglia PIM1 in peripheral nerve injury-induced neuropathic pain.

Neuropathic pain induced by peripheral nerve injury is a complex and chronic state that is accompanied by poor quality of life. However, whether PIM1 (proviral integration site 1) contributes to the development of nociceptive hypersensitivity induced by nerve injury remains unknown. The present study was designed to investigate the effects of PIM1 on spinal nerve ligation (SNL) induced pain hypersensitivity. Here, we found that PIM1 positive neurons in the dorsal root ganglion (DRG) were colocalized with nociceptive neuronal markers CGRP, IB4 and substance P and were upregulated after SNL surgery. Knockdown PIM1 in the DRG by AAV5-shPIM1 alleviated SNL-induced pain hypersensitivity. In neuroblastoma cells (neuro-2a), PIM1 regulated the expression of CXCR4 phosphorylated at ser339 (pCXCR4) as well as the CXCL12/CXCR4 pathway. In the DRG tissues, we found that PIM1 was co-expressed with CXCR4, and knockdown of PIM1 attenuated pCXCR4 (ser339) protein expression but had little effect on total CXCR4 protein expression after SNL surgery. These findings suggest that PIM1 contributes to nerve injury-induced nociceptive hypersensitivity. Based on these findings and the characteristics of PIM1, we speculate that PIM1 might be a viable therapeutic target for the treatment of neuropathic pain in the near future.

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Itch induction by audiovisual stimuli and histamine iontophoresis: a randomised, controlled non-inferiority study.

Previous research mainly uses skin-manipulating methods to induce itch. In comparison to these methods, itch induced by audiovisual stimuli lacks a direct skin manipulation.

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μ Opioid Receptor-Triggered Notch-1 Activation Contributes to Morphine Tolerance: Role of Neuron-Glia Communication.

The development of analgesic tolerance to opioids is an important limitation in the management of chronic pain. Spinal cord glial cell activation appears to play a pivotal role in the development and maintenance of opioid tolerance, indicating the presence of an opioid-induced neuronal-glial interaction; however, how opioids drive this cross-talk is still elusive. In search of treatments to attenuate morphine analgesic tolerance, our research focused on the role of Notch signaling pathway, one of the most important mechanisms of cell-to-cell interactions, in the spinal dorsal horn after morphine repeated exposure and whether Notch inhibition attenuates morphine analgesic tolerance. Double immunofluorescence experiments on spinal sections from morphine-tolerant mice showed a neuronal localization of Notch-1 receptor whereas the Notch ligand Jagged was localized on neighboring astrocytes. Morphine-induced μ opioid receptor (MOR) stimulation triggered Notch-1 signaling activation and this event was mediated by astrocyte JNK activation. Notch-1 activation selectively reduced the expression of histone deacetylase (HDAC)-1, resulting in an overphosphorylation of PKC and ERK, kinases involved in MOR phosphorylation and internalization after repeated morphine exposure. Notch-1 signaling inhibition, through intrathecal administration of the γ-secretase inhibitor, DAPT, counteracted PKC and ERK overphosphorylation, MOR internalization, and analgesic tolerance. Conversely, the HDAC-1 inhibitor, LG325, further aggravated MOR internalization, PKC overphosphorylation, and analgesic tolerance.Our findings implicate the MOR-triggered Notch-1 signaling in promoting MOR internalization and morphine analgesic tolerance by epigenetic regulation mechanisms. These data suggest that Notch-1 inhibitors could represent an innovative therapeutic perspective for the management of opioid tolerance in chronic pain therapy.

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Can quantitative sensory tests predict failed back surgery?: A prospective cohort study.

Failed back surgery syndrome (FBSS) is a pain condition refractory to therapy, and is characterised by persistent low back pain after spinal surgery. FBSS is associated with severe disability, low quality of life and high unemployment. We are currently unable to identify patients who are at risk of developing FBSS. Patients with chronic low back pain may display signs of central hypersensitivity as assessed by quantitative sensory tests (QST). This can contribute to the risk of developing persistent pain after surgery.

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Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain.

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Distinct roles for innexin gap junctions and hemichannels in mechanosensation.

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Interaction of peripheral nerves and mast cells, eosinophils, and basophils in the development of pruritus.

Mast cells, eosinophils, and basophils are central effector immune cells in allergic skin inflammation including atopic dermatitis (AD). Recent studies revealed that the bidirectional interaction between these three immune cell types (mast cells, eosinophils, and basophils) and the nervous system is involved in the pathogenesis of neurogenic inflammation, pain, and pruritus. Emerging evidence shows that these cells are the main source of pruritogens such as histamine, neuropeptides, cytokines, which are potential new therapeutic targets for drug development in chronic pruritus. For instance, many Th2 cytokines including interleukin (IL)-4, 13, and 31 have been recognized as some of the most promising targets for the treatment of chronic pruritus in AD. In this review, we highlight the link between these three immune cell subsets and peripheral nerves, with emphasis on the development of chronic pruritus such as AD. We present cytokines and receptors of these three immune cells and peripheral nerves, and discuss the therapeutic potential of targeting these neuro-immunological processes. This article is protected by copyright. All rights reserved.

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New and Emerging Treatments for Vaso-Occlusive Pain in Sickle Cell Disease.

Acute pain from episodic vaso-occlusion (VOC) spans the lifespan of almost everyone with sickle cell disease (SCD), while additional chronic pain develops in susceptible individuals in early adolescences. Frequent acute pain with chronic pain causes significant physical and psychological morbidity, and frequent healthcare utilization. Available pharmacologic therapies reduce acute pain frequency but few evidence-based therapies are available for chronic pain. An extensive PubMed literature search was performed with appropriate search criteria. The pathophysiology of acute pain from VOC in SCD is very complex with many events subsequent to sickle polymer formation. Sensitization of pain pathways and alterations of brain networks contributes to the experience of chronic pain. Numerous therapies targeting putative VOC mechanisms are in clinical trials, and show considerable promise. Alternative analgesic treatments for acute and chronic pain have been examined in small patient cohorts, but formal clinical trials are lacking. Childhood is likely a critical window for prevention of acute and later chronic pain. New multimodal analgesic therapies are needed, particularly for chronic pain, and should be examined in clinical trials. Given the multifactorial nature of both pain and VOC, simultaneously targeting multiple mechanisms may be the optimal approach for effective preventive therapies.

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Functional selection of protease inhibitory antibodies.

Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibitory mAbs by coexpressing 3 recombinant proteins in the periplasmic space of -an antibody clone, a protease of interest, and a β-lactamase modified by insertion of a protease cleavable peptide sequence. During functional selection, inhibitory antibodies prevent the protease from cleaving the modified β-lactamase, thereby allowing the cell to survive in the presence of ampicillin. Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), β-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in cancer), and Alp2 (a serine protease in aspergillosis). Notably, 37 of 41 identified binders were inhibitory. Isolated mAb inhibitors exhibited nanomolar potency, exclusive selectivity, excellent proteolytic stability, and desired biological functions. Particularly, anti-Alp2 Fab A4A1 had a binding affinity of 11 nM and inhibition potency of 14 nM, anti-BACE1 IgG B2B2 reduced amyloid beta (Aβ) production by 80% in cellular assays, and IgG L13 inhibited MMP-9 but not MMP-2/-12/-14 and significantly relieved neuropathic pain development in mice.

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Spotlight on headache.

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Pilot Study of Injection of OnabotulinumtoxinA Toward the Sphenopalatine Ganglion for the Treatment of Classical Trigeminal Neuralgia.

The sphenopalatine ganglion (SPG) has previously been targeted in trigeminal neuralgia (TN), but its role in this condition has not been established.

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Treatment Strategies and Effective Management of Phantom Limb-Associated Pain.

Phantom sensations are incompletely understood phenomena which take place following an amputation or deafferentation of a limb. They can present as kinetic, kinesthetic, or exteroceptive perceptions. It is estimated that phantom limb pain (PLP) affects anywhere from 40 to 80% of amputees.

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Stem Cell Therapies for Treatment of Discogenic Low Back Pain: a Comprehensive Review.

Discogenic low back pain (DLBP) stems from pathology in one or more intervertebral discs identified as the root cause of the pain. It is the most common type of chronic low back pain (LBP), representing 26-42% of attributable cases.

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Cannabis-based medicines for chronic pain management: current and future prospects.

The medicinal use of cannabis has recently become the focus of much medical, as well as political, attention. This reality of growing use but limited evidence creates unique dilemmas for the prescribing clinician. The purpose of this review is to explore current evidence and gaps in knowledge and offer some practical considerations.

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Neuropsychological functions of verbal recall and psychomotor speed significantly affect pain tolerance.

Effects from cognitive performance on pain tolerance have been documented, however, sample sizes are small and confounders often overlooked. We aimed to establish that performance on neuropsychological tests was associated with pain tolerance, controlling for salient confounders.

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Phα1β Spider Toxin Reverses Glial Structural Plasticity Upon Peripheral Inflammation.

The incoming signals from injured sensory neurons upon peripheral inflammation are processed in the dorsal horn of spinal cord, where glial cells accumulate and play a critical role in initiating allodynia (increased pain in response to light-touch). However, how painful stimuli in the periphery engage glial reactivity in the spinal cord remains unclear. Here, we found that a hind paw inflammation induced by CFA produces robust morphological changes in spinal astrocytes and microglia compatible with the reactive phenotype. Strikingly, we discovered that a single intrathecal injection with venom peptides that inhibit calcium channels reversed all the glial pathological features of the peripheral inflammation. These effects were more apparent in rats treated with the Phα1β spider toxin (non-specific calcium channel antagonist) than ω-MVIIA cone snail toxin (selective N-type calcium channel antagonist). These data reveal for the first time a venom peptide acting on glial structural remodeling . We, therefore, suggest that calcium-dependent plasticity is an essential trigger for glial cells to initiate reactivity, which may represent a new target for the antinociceptive effects of Phα1β and ω-MVIIA toxins in inflammatory pain conditions.

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Network Meta-Analysis of Calcitonin Gene-Related Peptide Receptor Antagonists for the Acute Treatment of Migraine.

Research has indicated that calcitonin gene-related peptide (CGRP) receptor antagonists can be effective in the acute treatment of migraine. Six major drugs are included within this category: telcagepant, olcegepant, BI 44370, rimegepant (BMS-927711), MK3207, and ubrogepant. However, no previous studies have performed network meta-analyses to directly compare the effects of these drugs. In the present study, we assessed the therapeutic qualities of these six different drugs to inform further clinical research. We searched PubMed, Embase, Ovid MEDLINE, Web of Science, and the Cochrane Central Register for Controlled Trials for relevant randomized controlled trials (RCTs) published through to October 2018. Two reviewers performed a network meta-analysis of efficacy and toxicity on the basis of odds ratios (ORs). Ten randomized controlled trials involving 8,174 patients were included in our analysis. Olcegepant (OR: 4.09; CI: 1.81, 9.25), ubrogepant (OR: 2.11; CI: 1.10, 4.05), and BI 44370 (OR: 3.36; CI: 2.24, 5.04) were more effective in ensuring pain relief 2 h after treatment than was placebo treatment. BI 44370 was associated with an increased risk of adverse events when compared with placebo treatment (OR: 1.57; CI: 1.32, 1.88). Surface under the cumulative ranking curve analysis revealed that olcegepant was most effective and ubrogepant was associated with the lowest risk of adverse events among the six treatment options. Olcegepant was more effective, and ubrogepant had lower toxicity than the remaining treatments. CGRP antagonists are promising for the acute treatment of migraine, especially among patients who are unable to take triptans.

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High Temporal Summation of Pain Predicts Immediate Analgesic Effect of Acupuncture in Chronic Pain Patients-A Prospective Cohort Study.

This prospective cohort study explored whether two distinguished sensory parameters predicted acupuncture effects in chronic pain patients; namely high temporal summation of pain (TS) indicating spinal synaptic facilitation as well as a low vibration detection threshold (VDT) indicating a loss of Aβ-fiber function. Pinprick induced TS and VDT were assessed by standardized, validated methods at the most painful body site and a pain free control site in 100 chronic pain patients receiving six acupuncture sessions as part of an interdisciplinary multimodal pain treatment (IMPT). Immediate change in pain intensity after the first acupuncture session (first treatment on the first day of IMPT) was assessed by the verbal rating scale (VRS, 0-100). After 4 weeks of treatment, patients indicated in a questionnaire whether acupuncture had relieved pain immediately and whether it had contributed to overall pain reduction and well-being after IMPT. Logistic regression analysis revealed an association between high TS at the control site and a reduction in pain intensity of at least 30% (VRS) after the first acupuncture (OR [95%-CI] 4.3 [1.6-11.8]). Questionnaire ratings of immediate pain relief after acupuncture were associated with high TS at the control site (OR [95%-CI] 3.8 [1.4-10.2] any pain relief, OR [95%-CI] 5.5 [1.7-17.1] over 50% pain reduction) and at the pain site (OR [95%-CI] 3.2 [1.2-8.9] any pain relief). Appraisals of the contribution of acupuncture to overall pain reduction and well-being after IMPT were not associated with TS. The VDT was not associated with any outcome. This explorative study provides first-time evidence that high TS, especially at a pain free control site, but not VDT, might predict immediate analgesic response to acupuncture in chronic pain patients. Thus, highly centrally sensitized chronic pain patients might respond particularly well to acupuncture.

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Patterns of opioid use (codeine, morphine or meperidine) in the Canadian population over time: analysis of the Longitudinal National Population Health Survey 1994-2011.

This study aimed to investigate cohort effects in selected opioids use and determine whether cohort differences were associated with changes in risk factors for use over time.

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Glia to neuron ratio in the posterior aspect of the human spinal cord at thoracic segments relevant to spinal cord stimulation.

Spinal cord stimulation (SCS) applied between T8 and T11 segments has been shown to be effective for the treatment of chronic pain of the lower back and limbs. However, the mechanism of the analgesic effect at these medullary levels remains unclear. Numerous studies relate glial cells with development and maintenance of chronic neuropathic pain. Glial cells are electrically excitable, which makes them a potential therapeutic target using SCS. The aim of this study is to report glia to neuron ratio in thoracic segments relevant to SCS, as well as to characterize the glia cell population at these levels. Dissections from gray and white matter of posterior spinal cord segments (T8, T9, intersection T9/T10, T10 and T11) were obtained from 11 human cadavers for histological analyses. Neuronal bodies and glial cells (microglia, astrocytes and oligodendrocytes) were immunostained, microphotographed and counted using image analysis software. Statistical analyses were carried out to establish significant differences of neuronal and glial populations among the selected segments, between the glial cells in a segment, and glial cells in white and gray matter. Results show that glia to neuron ratio in the posterior gray matter of the human spinal cord within the T8-T11 vertebral region is in the range 11 : 1 to 13 : 1, although not significantly different among vertebral segments. Glia cells are more abundant in gray matter than in white matter, whereas astrocytes and oligodendrocytes are more abundant than microglia (40 : 40 : 20). Interestingly, the population of oligodendrocytes in the T9/T10 intersection is significantly larger than in any other segment. In conclusion, glial cells are the predominant bodies in the posterior gray and white matter of the T8-T11 segments of the human spinal cord. Given the crucial role of glial cells in the development and maintenance of neuropathic pain, and their electrophysiological characteristics, anatomical determination of the ratio of different cell populations in spinal segments commonly exposed to SCS is fundamental to understand fully the biological effects observed with this therapy.

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Evidence that the TRPV1 S1-S4 Membrane Domain Contributes to Thermosensing.

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Waves of Pain Relief: A Systematic Review of Clinical Trials in Spinal Cord Stimulation Waveforms for the Treatment of Chronic Neuropathic Low-Back and Leg Pain.

In the United States, chronic low-back pain affects up to 37% of adults and is a multi-billion dollar healthcare market. Spinal Cord Simulation (SCS) has been established as an effective treatment alternative for chronic neuropathic low-back and leg pain especially for patients suffering from Failed Back Surgery Syndrome (FBSS) or Chronic Regional Pain Syndrome (CRPS). The field of SCS has rapidly advanced such that analgesia can now be achieved through numerous different waveforms, each claiming to offer improved outcomes. These waveforms include traditional paresthesia-based stimulation (PB-SCS; <100 Hz), paresthesia-free high-frequency stimulation (HF-SCS; 5-10 kHz), burst stimulation, and sub-perception stimulation (SP-SCS; 1-5 kHz). Level 1 evidence critically evaluating the efficacy of these different waveforms is lacking. We conducted a systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines to identify all randomized controlled trials (RCTs) of SCS in the treatment of chronic neuropathic low-back and leg pain, FBSS, or CRPS. A total of 38 eligible studies were reviewed to yield a final 13 RCTs that were included in our systematic review. We review the evidence from RCTs in the field of SCS that have established PB-SCS, HF-SCS, Burst, and SP-SCS as viable treatment options for chronic neuropathic low-back and leg pain. We critically evaluate the evidence that claims to support the use of one waveform over the other and review the literature on patient preference for different waveforms.

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Pharmacological inhibition of NPY receptors illustrates dissociable features of experimental colitis in the mouse DSS model: Implications for preclinical evaluation of efficacy in an inflammatory bowel disease model.

Administration of dextran sodium sulfate (DSS) to rodents at varying concentrations and exposure times is commonly used to model human inflammatory bowel disease (IBD). Currently, the criteria used to assess IBD-like pathology seldom include surrogate measures of visceral pain. Thus, we sought to standardize the model and then identify surrogate measures to assess effects on visceral pain. We used various 4% DSS protocols and evaluated effects on weight loss, colon pathology, biochemistry, RNA signature, and open field behavior. We then tested the therapeutic potential of NPY Y1 and/or Y2 receptor inhibition for the treatment of IBD pathology using this expanded panel of outcome measures. DSS caused weight loss and colon shrinkage, increased colon NPY and inflammatory cytokine expression, altered behaviors in the open field and induced a distinct gene metasignature that significantly overlapped with that of human IBD patients. Inhibition of Y1 and/or Y2 receptors failed to improve gross colon pathology. Y1 antagonism significantly attenuated colon inflammatory cytokine expression without altering pain-associated behaviors while Y2 antagonism significantly inhibited pain-associated behaviors in spite of a limited effect on inflammatory markers. A protocol using 7 days of 4% DSS most closely modeled human IBD pathology. In this model, rearing behavior potentially represents a tool for evaluating visceral pain/discomfort that may be pharmacologically dissociable from other features of pathology. The finding that two different NPY receptor antagonists exhibited different efficacy profiles highlights the benefit of including a variety of outcome measures in IBD efficacy studies to most fully evaluate the therapeutic potential of experimental treatments.

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Chronic Headache: a Review of Interventional Treatment Strategies in Headache Management.

To provide an overview of current interventional pain management techniques for primary headaches with a focus on peripheral nerve stimulation and nerve blocks.

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Virtual reality exposure before elective day care surgery to reduce anxiety and pain in children: A randomised controlled trial.

Pre-operative anxiety in children is very common and is associated with adverse outcomes.

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Predicting treatment adherence and outcome to outpatient multimodal rehabilitation in chronic low back pain.

There is a growing need to identify patient pre-treatment characteristics that could predict adherence and outcome following specific interventions.

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Opioids Are Not Better than Non-opioid Pain Medications for Chronic Back, Hip, or Knee Pain.

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Classism in Pain Care: The Role of Patient Socioeconomic Status on Nurses’ Pain Assessment and Management Practices.

Research on social disparities in pain care has been mainly focused on the role of race/racism and sex/sexism. Classism in pain assessment and management practices has been much less investigated. We aimed to test the effect of patient socioeconomic status (SES; a proxy of social class) on nurses' pain assessment and management practices and whether patient SES modulated the effects of patient distress and evidence of pathology on such practices.

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Off-label Antidepressant Use for Treatment and Management of Chronic Pain: Evolving Understanding and Comprehensive Review.

While clinicians have been using antidepressants for off-label indications in the treatment of chronic pain in recent years, newer studies have proven effectiveness and provided additional mechanistic understanding and defined potential adverse effects. As depression and chronic pain are frequently comorbid conditions, the use of antidepressants has allowed for treatment of both conditions concomitantly in the same patient population.

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Linking Traumatic Brain Injury, Sleep Disruption and Post-Traumatic Headache: a Potential Role for Glymphatic Pathway Dysfunction.

Traumatic brain injury (TBI) is a major public health concern in the USA and worldwide. Sleep disruption and headaches are two of the most common problems reported by patients after TBI. In this manuscript, we review the current knowledge regarding the relation between post-traumatic sleep disruption and headaches. We also describe the role of the glymphatic system as a potential link between TBI, sleep, and headaches.

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Bidirectional optogenetic modulation of prefrontal-hippocampal connectivity in pain-related working memory deficits.

Dysfunction of the prefrontal-hippocampal circuit has been identified as a leading cause to pain-related working-memory (WM) deficits. However, the underlying mechanisms remain poorly determined. To address this issue, we implanted multichannel arrays of electrodes in the prelimbic cortex (PL-mPFC), and in the dorsal hippocampal CA1 field (dCA1) to record the neural activity during the performance of a delayed non-match to sample (DNMS) task. The prefrontal-hippocampal connectivity was selectively modulated by bidirectional optogenetic inhibition or stimulation of local PL-mPFC glutamatergic calcium/calmodulin-dependent protein kinase-II alpha (CaMKIIα) expressing neurons during the DNMS task delay-period. The within-subject behavioral performance was assessed using a persistent neuropathic pain model – spared nerve injury (SNI). Our results showed that the induction of the neuropathic pain condition affects the interplay between PL-mPFC and dCA1 regions in a frequency-dependent manner, and that occurs particularly across theta oscillations while rats performed the task. In SNI-treated rats, this disruption was reversed by the selective optogenetic inhibition of PL-mPFC CaMKIIα-expressing neurons during the last portion of the delay-period, but without any significant effect on pain responses. Finally, we found that prefrontal-hippocampal theta connectivity is strictly associated with higher performance levels. Together, our findings suggest that PL-mPFC CaMKIIα-expressing neurons could be modulated by painful conditions and their activity may be critical for prefrontal-hippocampal connectivity during WM processing.

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Treatment of central sensitization in patients with chronic pain: time for change?

: Given our improved understanding of the role of central sensitization (CS) in many patients with chronic pain, it seems rational to account for CS during treatment. : First, the treatment rationale based on the complex mechanisms underlying CS in patients having chronic pain is presented. Second, emphasis is given to explaining the concept of CS when providing treatment, as well as why patients and clinicians should focus on long-term rather than short-term treatment effects. Third, possible pharmacological and non-pharmacological treatment options are discussed. : Centrally acting drugs such as tricyclic compounds, serotonin-norepinephrine reuptake inhibitors, and αδ ligands each target mechanisms that are often dysfunctional in patients having chronic pain and CS, but decades of clinical practice and clinical trials have not resulted in satisfactory outcomes. This comes as no surprise; CS comprises complex psycho-neuro-immunological interactions, while each of the tested drugs targets one or two of those mechanisms from a purely biomedical viewpoint. Clinicians willing to take CS into account should design an individually tailored multimodal treatment plan comprising pain neuroscience education, cognition-targeted exercise therapy, sleep management, stress management, and/or dietary intervention.

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How does reduction in pain lead to reduction in disability in patients with musculoskeletal pain?

Reduction in pain following multidisciplinary treatment is most often associated with a reduction in disability. To further elaborate the relationship between pain intensity and disability, the present study investigated three main questions: first, whether multidisciplinary treatment leads to a significant improvement in pain, disability and psychological variables (depression, pain acceptance and catastrophizing). Second, it was examined whether pain reduction may account for significant changes in the psychological variables (pre- to follow-up change scores). Finally, it was analyzed whether the psychological changes mediate the association between reduction in pain and in disability after controlling for age, sex and pain history.

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The World Health Organization Disability Assessment Schedule-2.0 (WHODAS 2.0) in a chronic pain population being considered for chronic opioid therapy.

To examine the validity of the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) for the assessment of function in a community-based sample of patients with chronic pain conditions undergoing evaluation for chronic opioid therapy.

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Response Predictors in Chronic Migraine: Medication Overuse and Depressive Symptoms Negatively Impact Onabotulinumtoxin-A Treatment.

Despite numerous studies that have investigated clinical, radiological, and biochemical response predictors, the clinical profile of those patients who might benefit from OnabotulinumtoxinA is still missing. The aim of the present study was to identify potential OnabotulinumtoxinA response predictors among several clinical characteristics and confirm OnabotulinumtoxinA efficacy and safety in chronic migraine (CM) prevention. The study was conducted at the Headache Center-Neurology Clinic-Spedali Civili Hospital of Brescia. Eighty-four consecutive CM patients were enrolled, with a mean age of 48 years (SD 9.7) and a mean disease duration of 10.1 years (SD 6.6). The mean reported headache-days frequency was 22.5 (SD 5.9) per month, while the mean number of severe headache-days was 15.2 (SD 8.9) with a mean monthly medication intake of 33.2 (SD 5.6). The clinical characteristics analyzed as potential response predictors were: gender, disease duration, migraine characteristics (location, side constancy, unilateral autonomic and neurovegetative symptoms), previous prophylactic treatments, add-on therapies, withdrawal therapies, psychiatric (anxiety and depression symptoms) comorbidities and medication overuse. A significant reduction from baseline to 3, 6, 9, and 12 month treatment cycles in total headache days, high intensity headache days and triptans consumption per month was found. Depressive symptoms and medication overuse negatively predicted OnabotulinumtoxinA outcome. Our results confirm the efficacy and safety of OnabotulinumtoxinA in CM. Depressive comorbidity and medication overuse, among all clinical variables, were the only significant response predictors. Such findings provide interesting insights regarding patients selection for OnabotulinumtoxinA treatment as, with the introduction of anti calcitonin gene-related (CGRP) monoclonal antibodies, clinicians will have to thoroughly judge and tailor among the many available therapeutic options now available. Future research might be needed to confirm our findings, in particular for its therapeutic implications.

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Associations Between Headache-Free Days and Patient-Reported Outcomes Among Migraine Patients: A Cross-Sectional Analysis of Survey Data in Europe.

Migraine imposes a substantial burden on patients, society, and healthcare systems. This study aimed to assess the associations between the number of headache-free days (HFDs) and health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), and healthcare resource utilization (HRU) in patients with migraine in the EU5 (France, Germany, Italy, Spain, and the United Kingdom).

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New persistent opioid use among older patients following surgery: A Medicare claims analysis.

Although new persistent opioid use and high-risk prescribing have been recognized as important postoperative complications among younger patients (18-64 years of age), little is known about the incidence for postoperative opioid use among older patients (>65 years of age).

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Demographic, clinical, and treatment characteristics of the juvenile primary fibromyalgia syndrome cohort enrolled in the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry.

To describe the demographic, clinical, and treatment characteristics of youth diagnosed with juvenile primary fibromyalgia syndrome (JPFS) who are seen in pediatric rheumatology clinics.

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Advances in the Understanding and Management of Chronic Pain in Multiple Sclerosis: a Comprehensive Review.

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system that can lead to severe physical, cognitive, and neurological deficits that often manifest in young adults. Central neuropathic pain is a common presenting symptom, often prompting patients to seek treatment with opioids, NSAIDS, antiepileptics, and antidepressants despite minimal effectiveness and alarming side-effect profiles. Additionally, spasticity occurs in more than 80% of MS patients and is an important consideration for further study in treatment.

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