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The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated.
Learn More >Touch and mechanical pain represent distinct, but interactive, modalities of mechanosensation. However, the molecular mechanisms underlying these mechanotransduction processes remain incompletely understood. Here, we show that deletion of the mechanically activated and rapidly adapting Piezo2 channel in a portion of the low-threshold mechanoreceptors and a majority of the IB4-positive nociceptors impairs touch but sensitizes mechanical pain in mice. Ectopic expression of the Piezo2 homolog, the intermediately adapting Piezo1 channel, in sensory neurons can sensitize touch in normal mice and rescue defective touch of the Piezo2-knockout mice. Broad expression of Piezo1 in sensory neurons decreases, rather than evokes, mechanical pain responses. Together, our data suggest that Piezo channels can mediate touch and indirectly suppress acute pain. Tuning Piezo-mediated touch sensitivity allows us to recapitulate the inhibitory effect of touch on acute pain in mouse models.
Learn More >The chronic pain syndrome inherited erythromelalgia (IEM) is attributed to mutations in the voltage-gated sodium channel (Nav) 1.7. Still, recent studies targeting Nav1.7 in clinical trials have provided conflicting results. Here, we differentiated induced pluripotent stem cells (iPS cells) from IEM patients with the Nav1.7/I848T mutation into sensory nociceptors. Action potentials in these IEM nociceptors displayed a decreased firing threshold, an enhanced upstroke and afterhyperpolarization, all of which may explain the increased pain experienced by patients. Subsequently, we investigated the voltage dependence of the tetrodotoxin-sensitive Nav activation in these human sensory neurons using a specific pre-pulse voltage protocol. The IEM mutation induced a hyperpolarizing shift of Nav activation which leads to activation of Nav1.7 at more negative potentials. Our results indicate that Nav1.7 is not active during subthreshold depolarizations, but that its activity defines the action potential threshold and contributes significantly to the action potential upstroke. Thus, our model system with iPS cell-derived sensory neurons provides a new rationale for Nav1.7 function and promises to be valuable as a translational tool to profile and develop more efficacious clinical analgesics.
Learn More >Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.
Learn More >Diabetic neuropathy is an incapacitating complication in diabetic patients. The cellular and molecular mechanisms involved in this pathology are poorly understood. Previous studies have suggested that the loss of spinal GABAergic inhibition participate in painful diabetic neuropathy. However, the role of extrasynaptic α5 subunit-containing GABAA (α5GABAA) receptors in this process is not known. The purpose of this study was to investigate the role of α5GABAA receptors in diabetes-induced tactile allodynia, loss of rate dependent depression (RDD) of the Hoffmann reflex (HR) and modulation of primary afferent excitability. Intraperitoneal administration of streptozotocin (STZ) induced tactile allodynia. Intrathecal injection of α5GABAA receptor inverse agonist, L-655,708, produced tactile allodynia in naïve rats whereas it reduced allodynia in diabetic rats. In healthy rats, electrical stimulation of the tibial nerve at 5 Hz induced RDD of the HR, although intrathecal treatment with L-655,708 (15 nmol) abolished RDD of the HR. STZ induced the loss of RDD of the HR, while intrathecal L-655,708 (15 nmol) restored RDD of the HR. L-655,708 (15 nmol) increased tonic excitability of the primary afferents without affecting the phasic excitability produced by the primary afferent depolarization. α5GABAA receptors were immunolocalized in superficial laminae of the dorsal horn and L4-L6 DRG. STZ increased mean fluorescence intensity and percentage of neurons expressing α5GABAA receptors in dorsal horn and L4-L6 DRGs in ten-weeks diabetic rats. Our results suggest that spinal α5GABAA receptors modulate the HR, play an antinociceptive and pronociceptive role in healthy and diabetic rats, respectively and are tonically active in primary afferents.
Learn More >The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8 T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In the present study, we demonstrate that CD8 T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intra-epidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2 mice that lack T and B cells. Reconstitution of Rag2 mice with CD8 T cells prior to cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8 T cells by cisplatin was necessary to induce resolution of CIPN in Rag2 mice because adoptive transfer of CD8 T cells from naïve WT mice to Rag2 mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8 T cell-dependent resolution of CIPN does not require epitope recognition by the T cell receptor (TCR). Moreover, adoptive transfer of cisplatin-educated CD8 T cells to Rag2 mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8 T is not cisplatin-specific.In conclusion, resolution of CIPN requires in vivo education of CD8 T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8 T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.
Learn More >Despite optimal medical management (OMM), low back pain (LBP) can be disabling, particularly after spinal surgery. Spinal cord stimulation (SCS) is effective in reducing neuropathic leg pain; however, evidence is limited for LBP.This prospective, open-label, parallel-group trial randomized (1:1) failed back surgery syndrome (FBSS) patients with predominant LBP to SCS plus OMM (SCS group) or OMM alone (OMM group) in 28 sites in Europe and the Americas. If trial stimulation was successful, a SCS system was implanted. Outcomes were assessed at baseline (pre-randomization) and 1, 3, 6, and 12 months post-randomization. Patients could change treatment groups at 6 months. The primary outcome was the proportion of patients with ≥50% reduction in LBP (responder) at 6 months. Secondary outcomes included change in pain intensity, functional disability and health-related quality of life (HRQoL). Results are posted at ClinicalTrials.gov registration number NCT01697358.In the intent-to-treat analysis, there were more responders in the SCS group than the OMM group (13.6%,15/110 versus 4.6%, 5/108, difference 9% with 95% CI 0.6-17.5%, P=0.036) at 6 months. The SCS group improved in all secondary outcomes compared to the OMM group. The OMM group only improved in HRQoL. In the SCS group, 17.6% (18/102) experienced SCS-related AEs through 6 months, with 11.8% (12/102) requiring surgical re-intervention.Adding multicolumn SCS to OMM improved pain relief, HRQoL and function in a traditionally difficult to treat population of FBSS patients with predominant LBP. Improvements were sustained at 12 months.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Learn More >Pain serves vital protective functions, which crucially depend on appropriate motor responses to noxious stimuli. Such responses not only depend on but can themselves shape the perception of pain. In chronic pain, perception is often decoupled from noxious stimuli and motor responses are no longer protective, which suggests that the relationships between noxious stimuli, pain perception, and behavior might be changed. We here performed a simple experiment to quantitatively assess the relationships between noxious stimuli, perception and behavior in 22 chronic pain patients and 22 age-matched healthy human participants. Brief noxious and tactile stimuli were applied to the participants' hands and participants performed speeded motor responses and provided perceptual ratings of the stimuli. Multi-level moderated mediation analyses assessed the relationships between stimulus intensity, perceptual ratings and reaction times for both stimulus types. The results revealed a significantly stronger involvement of motor responses in the translation of noxious stimuli into perception than in the translation of tactile stimuli into perception. This significant influence of motor responses on pain perception was found for both chronic pain patients and healthy participants. Thus, stimulus-perception-behavior relationships appear to be at least partially preserved in chronic pain patients and motor-related as well as behavioral interventions might harness these functional relationships to modulate pain perception.
Learn More >The effectiveness of cognitive strategies to attenuate pain has been reported in various behavioural studies, however the underlying neuronal mechanisms are only now beginning to be understood. Using a 7 T fMRI, we investigated three different pain attenuation strategies in 20 healthy subjects via: (a) non-imaginal distraction by counting backwards in steps of seven; (b) imaginal distraction by imagining a safe place; and (c) reinterpretation of the pain valence (reappraisal). Although we found considerable variability in the performances, all strategies exhibited a significant relief of pain compared to an unmodulated pain condition. Our finding argues against a subject's potential predisposition for a certain attenuation approach, as some of the subjects performed well on all attenuation tasks yet others performed low on all attenuation tasks. We further investigated the variability of performance within-subjects and explored the cortical regions that contribute to successful single attempts of pain attenuation at trial level. For each of the three tasks, we found a different pattern of brain activity that reflects the performance of pain attenuation. The more successful trials are related to reduced activity of different parts of the insular cortex. Behavioural data suggest that distraction is the preferable cognitive strategy to modulate pain perception. For three different cognitive strategies we revealed brain regions that are suggested to reliably modulate the perception of pain. The findings could be of utmost benefit for future attempts to integrate neuroscientific techniques into the treatment of pain. Further studies are necessary to investigate whether the present results are transferable to patients as an essential part of the multimodal therapy for chronic pain. These patients may also benefit from additional neurofeedback techniques by combining the strategies with the cortical feedback in order to modulate pain-related brain activity.
Learn More >To study iron deposition in red nucleus (RN), globus pallidus (GP), and periaqueductal gray matter (PAG) as a potential biomarker of chronic migraine (CM) and its association with levels of biomarkers related to migraine pathophysiology.
Learn More >This review compares mindfulness-based stress reduction (MBSR) to cognitive-behavioural therapy (CBT) in its ability to improve physical functioning and reduce pain intensity and distress in patients with chronic pain (CP), when evaluated against control conditions.
Learn More >Deaths due to opioid overdose have tripled in the last decade. Efforts to curb this trend have focused on restricting the prescription opioid supply; however, the near-term effects of such efforts are unknown.
Learn More >Neuropeptides are peptide neuromodulators that are expressed by neurons and act on neural targets by activating neuropeptide receptors1. These receptors serve as therapeutic targets for the treatment of a number of pathophysiological conditions, including obesity, pain and addiction2-6. Major technological advances in the 1980s involving improved sensitivity of peptide purification methods and single neuron mRNA sequencing techniques have led to an explosion in the number of newly discovered neuropeptides7. However, to date, receptors for many of these neuropeptides remain largely unknown. In addition, currently there are a number of "orphan" G-protein-coupled receptors (GPCRs) for which endogenous ligands or function are yet to be identified8, 9.These "orphan" neuropeptides and GPCRs represent an untapped resource for the development of therapeutics to treat chronic diseases including drug abuse disorders, obesity and neuropathic pain. With this in mind much effort has been put towards deorphanizing these "orphan" peptides/GPCRs. Here, we summarize current insights into one such relationship: that between the neuropeptide PEN and the GPCR named GPR83. This intriguing system promises to deepen our current understanding of neuropeptide/GPCR systems, but also highlights the necessity for further technological advances in order to fully understand its complexity.
Learn More >Migraine is a common neurological disorder that afflicts up to 15% of the adult population in most countries, with predominance in females. It is characterized by episodic, often disabling headache, photophobia and phonophobia, autonomic symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of the attack. Although still debated, many researchers consider migraine to be a disorder in which CNS dysfunction plays a pivotal role while various parts of the trigeminal system are necessary for the expression of associated symptoms.Treatment of migraine has in recent years seen the development of drugs that target the trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. Several of these drugs are now approved for use in frequent episodic and in chronic migraine. CGRP-related therapies offer considerable improvements over existing drugs, as they are the first to be designed specifically to act on the trigeminal pain system: they are more specific and have little or no adverse effects. Small molecule CGRP receptor antagonists, gepants, are effective for acute relief of migraine headache, whereas monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and Galcanezumab) or the CGRP receptor (Erenumab) effectively prevent migraine attacks. The neurobiology of CGRP signaling is briefly summarized together with key clinical evidence for the role of CGRP in migraine headache, including the efficacy of CGRP-targeted treatments.
Learn More >The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. , , , , , and gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1⁻DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1⁻DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1⁻DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1⁻DNA binding was positively associated with and gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients.
Learn More >"Congenital insensitivity to pain (CIP)" is an umbrella term used to describe a group of rare genetic diseases also classified as "Hereditary Sensory Autonomic Neuropathies (HSAN)". These are intriguing conditions with potential to shed light on the poorly understood relationship concerning nociception and the experience of pain. However, the term CIP is epistemologically incorrect and is the product of historical circumstances. The term conflates pain and nociception and thus prevents researchers and caregivers from grasping the full dimensions of these conditions. The aims of this article are to review the epistemological problems surrounding the term, to demonstrate why the term is inaccurate and to suggest a new term: "Congenital Nociceptor Deficiency". The suggested term better reflects the nature of the conditions, and incorporates current understandings of nociception. Perspective: The umbrella term "Congenital Insensitivity to Pain" conflates pain and nociception, which is epistemologically unacceptable. We suggest a new term – Congenital Nociceptor Deficiency – that overcomes this problem and is concordant with current neurobiological knowledge.
Learn More >Spatial integration of parts of the body is impaired in patients with complex regional pain syndrome (CRPS). Since the training of mental rotation (MR) has been shown to be among the effective therapy strategies for CRPS, impairment of MR is also important for the pathophysiological understanding of CRPS. The aim of this study was to evaluate whether differences in neural representation of MR occur between CRPS patients and healthy controls. Therefore we included 15 chronic CRPS patients and 15 age-/gender matched healthy controls. We assessed behavioral (accuracy and reaction time for MR of both hands), clinical (DASH) and MRI (T1, fMRI during MR) data. Reaction times in the patient group were delayed compared to healthy controls without a lateralization effect for affected hand side. Although both groups showed an activation pattern typical for MR, only HC showed a highly significant contrast for the rotated versus unrotated hands in the right intraparietal sulcus. CRPS patients showed a reduction of fMRI activation in areas including subthalamic nucleus, nucleus accumbens and putamen. Regression analysis for the CRPS group emphasized the importance of putamen and n. accumbens activation for MR performance. This study highlights the reduced access of CRPS patients for mental resources modulating arousal, emotional response and subcortical sensorimotor integration. PERSPECTIVE: This study localized the underlying neural responses for impaired mental rotation (MR) in patients with complex regional pain syndrome (CRPS) as a decrease in basal ganglia (putamen) and nucleus accumbens activation.
Learn More >κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in Phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.
Learn More >The present study investigated the role of the amygdala NMDA receptors/NOS pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala (CeA), chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was intraperitoneally administered to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (0.05-0.1 µg/rat) or L-NAME, the NO synthase inhibitor, (0.1-0.5 µg/rat) were microinjected into the CeA, the higher doses potentiated an ineffective dose of morphine (3 mg/kg). Microinjection of the same doses of D-AP5 and L-NAME without morphine had no effect. Co-microinjection of the ineffective doses of L-NAME (0.1 µg/rat) and D-AP5 (0.05 µg/rat) with a 5-min interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cAMP-response element-binding protein (CREB) and phosphorylated CREB (pCREB) in the amygdala tissues. Our results showed that neuropathic pain increased the pCREB/CREB ratio in the amygdala, while this ratio was decreased following morphine-induced anti-allodynia. The potentiative effect of the co-administration of D-AP5/L-NAME on an ineffective dose of morphine also decreased the amygdala pCREB/CREB levels. Therefore, it seems that the amygdala pCREB/CREB signaling pathway plays a critical role in processing neuropathic pain. Moreover, the glutamate NMDA receptors and NO system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is hard to treat and the exact mechanisms are still unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. The findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.
Learn More >This topical review outlines the resilience pathway to adaptive functioning in pediatric pain within a developmental perspective. Self-Determination Theory proposes that the satisfaction of one's basic psychological needs (for autonomy, relatedness, and competence) is crucial for understanding human flourishing and healthy development. However, the role of the basic psychological needs received little attention in a pediatric-pain population. Yet, we propose that need satisfaction may be a resilience factor and need frustration a risk factor, for living with chronic pain. In this topical review, we first discuss two major models that have been developed to understand pain-related disability: the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain. Both models have been used with children and adolescents but do not include a developmental perspective. Therefore, we introduce Self-Determination Theory and highlight the potentially moderating and mediating role of the basic needs on pain-related disability in children and adolescents. Taken together, we believe that Self-Determination Theory is compatible with the fear-avoidance model of pain and the ecological resilience-risk model in pediatric chronic pain and may deepen our understanding of why some adolescents are able to live adaptively in spite of chronic pain.
Learn More >Glycine receptors (GlyRs) are pentameric proteins that consist of α (α1-α4) subunits and/or β subunit. In the spinal cord of adult animals, the majority of inhibitory glycinergic neurotransmission is mediated by α1 subunit-containing GlyRs. The reduced glycinergic inhibition (disinhibition) is proposed to increase the excitabilities and spontaneous activities of spinal nociceptive neurons during pathological pain. However, the molecular mechanisms by which peripheral lesions impair GlyRs-α1-mediated synaptic inhibition remain largely unknown. Here we found that activity-dependent ubiquitination of GlyRs-α1 subunit might contribute to glycinergic disinhibition after peripheral inflammation. Our data showed that HUWE1 (HECT, UBA, WWE domain containing 1), an E3 ubiquitin ligase, located at spinal synapses and specifically interacted with GlyRs-α1 subunit. By ubiquitinating GlyRs-α1, HUWE1 reduced the surface expression of GlyRs-α1 through endocytic pathway. In the dorsal horn of Complete Freund's Adjuvant-injected mice, shRNA-mediated knockdown of HUWE1 blunted GlyRs-α1 ubiquitination, potentiated glycinergic synaptic transmission and attenuated inflammatory pain. These data implicated that ubiquitin modification of GlyRs-α1 represented an important way for peripheral inflammation to reduce spinal glycinergic inhibition and that interference with HUWE1 activity generated analgesic action by resuming GlyRs-α1-mediated synaptic transmission.
Learn More >Nociceptors, sensory neurons that detect damage or potential damage to the body, are the first stage of communicating noxious stimuli from the periphery to central nervous system (CNS). In this study, long-term potentiation (LTP) in the CNS of the medicinal leech, Hirudo verbana, was examined, taking advantage of the ability to selectively record from nociceptive synapses in this model organism. High frequency stimulation (HFS) of nociceptors produced a persistent increase in synaptic transmission and this LTP was both NMDA receptor-mediated and synapse-specific. Surprisingly, inhibition of NMDA receptors during HFS "uncovered" a persistent form of depression. This long-term depression (LTD) was mediated by the endocannabinoid 2-arachidonoyl glycerol (2-AG) acting on a TRPV (transient receptor potential vanilloid) -like channel. These observations suggest that (1) NMDA receptor mediated LTP is observed in nociceptors across both vertebrate and invertebrate phyla and (2) there may be an interaction between NMDA receptor-mediated and endocannabinoid-mediated forms of synaptic plasticity in nociceptors. Specifically, the NMDA receptor mediated processes may suppress endocannabinoid signaling. Such findings could be significant for understanding cellular mechanisms behind nociceptive sensitization and perhaps their contribution to chronic pain.
Learn More >Anti-citrullinated protein antibodies (ACPA) have been suggested to have a potential role in both bone loss and pain in rheumatoid arthritis (RA), based on studies in vitro and in animal models. Here we addressed if anti-cyclic citrullinated (anti-CCP) antibodies were associated with osteopenia or pain in patients with RA, at the time for diagnosis.
Learn More >Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesising lipid analogues with a range of amino acid head groups in both L- and D- configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl- D-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).
Learn More >Although recent scientific advances have improved our understanding of basic biological mechanisms underlying chemotherapy-induced peripheral neuropathy (CIPN), few interventions are available to prevent or treat CIPN. While some biological targets from preclinical studies show promise in non-human animal models, few targets have been translated to successful clinical trials. To address this problem, the National Cancer Institute's (NCI's) Symptom Management and Health-Related Quality of Life Steering Committee convened a meeting of experts in the CIPN and oncology symptom management fields to participate in a Clinical Trials Planning Meeting (CTPM). Investigators presented data from preclinical and translational studies for possible CIPN interventions; these were evaluated for readiness of randomized clinical trial testing by experts, and recommendations were provided. Breakout sessions were convened to discuss and develop future studies. The CTPM experts concluded that there is compelling evidence to move forward with selected pharmacological and non-pharmacological clinical trials for the prevention and treatment of CIPN. Several key feasibility issues need to be addressed, however. These include: identification of optimal outcome measures to define the CIPN phenotype, establishment of parameters that guide the evaluation of clinically meaningful effects, and adoption of approaches for inclusion of translational and biomarker/genetic measures. The results of the CTPM provide support for conducting clinical trials that include both pharmacological and non-pharmacological approaches, alone or in combination, with biomarkers, genetics or other measures designed to inform underlying CIPN mechanisms. Several working groups were formed to design rigorous CIPN clinical trials, the results of which are ongoing.
Learn More >Parental migraine in relation to migraine in offspring: Family linkage analyses from the HUNT Study.
Migraine is known to run in families. While some clinical studies have indicated that migraine is disproportionally transmitted through the maternal line, this has not been examined in a population-based setting.
Learn More >The delta opioid receptor (DOPr) is an emerging target for the management of chronic pain and depression. Studies have highlighted the potential of biased signaling, the preferential activation of one signaling pathway over another downstream of DOPr, to generate a better therapeutic profile. BMS 986187 is a recently discovered positive allosteric modulator (PAM) of the DOPr. Here we ask if BMS 986187 can directly activate the receptor from an allosteric site in the absence of orthosteric ligand and if a signaling bias is generated.
Learn More >Opioid and neurotensin (NT) receptors are expressed in both central and peripheral nervous systems where they modulate nociceptive responses. Nowadays, opioid analgesics like morphine remain the most prescribed drugs for the treatment of moderate to severe pain. However, despite their daily used, opioids can produce life-threatening side effects, such as constipation or respiratory depression. Besides, NT analogs exert strong opioid-independent analgesia. Here, we thus hypothesized that the combined use of opioid and NT agonists would require lower doses to produce significant analgesic effects, hence decreasing opioid-induced adverse effects. We used isobologram analyses to determine if the combination of a NT brain-penetrant analog, An2-NT(8-13) with morphine results in an inhibitory, synergistic or additive analgesic response. We found that intravenous administration of An2-NT(8-13) reduced by 90% the nocifensive behaviors induced by formalin injection, at the dose of 0.018mg/kg. Likewise, subcutaneous morphine reduced pain by 90% at 1.8mg/kg. Importantly, isobologram analyses revealed that the co-injection of An2-NT(8-13) with morphine induced an additive analgesic response. We finally assessed the effects of morphine and An2-NT(8-13) on the gastrointestinal tract motility using the charcoal meal test. As opposed to morphine which significantly reduced the intestinal motility at the analgesic effective dose of 1.8mg/kg, An2-NT(8-13) did not affect the charcoal meal intestinal transit at 0.018mg/kg. Interestingly, at the dose providing 90% pain relief, the co-administration of morphine with An2-NT(8-13) had a reduced effect on constipation. Altogether, these results suggest that combining NT agonists with morphine may improve its analgesic/adverse effect ratio.
Learn More >Patients with chronic neuropathic pain frequently suffer from symptoms of anhedonia, which is a core symptom of depression. Accumulating studies suggest that gut microbiota may play a role in depression via gut-microbiota-brain axis. However, it is unknown whether gut microbiota plays a role in neuropathic pain-associated anhedonia. Here, we used a rat model of spared nerve injury (SNI). Hierarchical cluster analysis of sucrose preference test (SPT) results was used to classify the SNI rats with or without anhedonia-like phenotype. The 16S ribosomal RNA sequencing analysis showed abnormal composition of gut microbiota in the anhedonia susceptible compared to sham-operated rats and resilient rats. Furthermore, antibiotics-treated mice showed pain as well as depression-like and anhedonia-like phenotypes, suggesting a role of gut microbiota in these abnormal behaviors. Transplantation of fecal microbiota from anhedonia susceptible rats into antibiotics-treated pseudo-germ-free mice significantly exaggerated pain and depression-like phenotypes, including anhedonia. In contrast, transplantation of fecal microbiota from resilient rats into antibiotics-treated pseudo-germ-free mice significantly improved pain and depression-like phenotypes, including anhedonia. In conclusion, this study suggests that abnormal composition of gut microbiota may contribute to anhedonia susceptibility post SNI surgery, and that gut microbiota also plays a role in the pain as well as depression-like phenotypes. Interestingly, fecal microbiota transplantation from SNI rats with or without anhedonia can alter pain, depression-like and anhedonia-like phenotypes in the pseudo-germ-free mice. Therefore, it is likely that gut microbiota plays a key role in the pain as well as depression-like phenotypes including anhedonia in rodents with neuropathic pain.
Learn More >Animal models have provided a growing body of information about the pathophysiology of headaches and novel therapeutic targets. In recent years, experiments in awake animals have gained attention as more relevant headache models. Pain can be assessed in animals using behavioral alterations, which includes sensory-discriminative, affective-emotional and cognitive aspects. Spontaneous behavioral alterations such as increased grooming, freezing, eye blinking, wet dog shake and head shake and decreased locomotion, rearing, food or water consumption observed during pain episodes are oftentimes easy to translate into clinical outcomes, but are giving little information about the localization and modality of the pain. Evoked pain response such as tactile and thermal hypersensitivity measures are less translatable but gives more insight into mechanisms of action. Mechanical allodynia is usually assessed with von Frey monofilaments and dynamic aesthesiometer, and thermal allodynia can be evaluated with acetone evaporation test and Hargreaves' test in animal models. Anxiety and depression are the most frequent comorbid diseases in headache disorders. Anxiety-like behaviors are evaluated with the open-field, elevated plus-maze or light/dark box tests. Interpretation of the latter test is challenging in migraine models, as presence of photophobia or photosensitivity can also be measured in light/dark boxes. Depressive behavior is assessed with the forced-swim or tail suspension tests. The majority of headache patients complain of cognitive symptoms and migraine is associated with poor cognitive performance in clinic-based studies. Cluster headache and tension type headache patients also exhibit a reversible cognitive dysfunction during the headache attacks. However, only a limited number of animal studies have investigated cognitive aspects of headache disorders, which remains a relatively unexplored aspect of these pathologies. Thus, the headache field has an excellent and growing selection of model systems that are likely to yield exciting advances in the future.
Learn More >Virtual and augmented imagery are emerging technologies with potential to reduce the severity and impact of neuropathic pain in people with spinal cord injury (SCI).
Learn More >To describe contextual factors (CFs) used by nurses to increase placebo and to prevent nocebo effects.
Learn More >Pain which persists after thoracotomy is well recognized, and activation of the N-methyl-d-aspartate (NMDA) receptor could be a contributing factor. This study sought to establish whether ketamine given peri-operatively could reduce persistent post-surgical pain.
Learn More >Spinal cord lamina I neurons receiving dense input from nociceptors, and projecting to the parabrachial area at the ponto-mesencephalic junction form the major ascending pain-related pathway in rodents. Lamina I spinoparabrachial neurons have never been characterised in mice, despite the growing and extensive use of this species to understand the contribution of lamina I spinoparabrachial neurons in chronic pain. The electrophysiological properties of lamina I spinoparabrachial neurons recorded here in the anaesthetized mice are comparable to those of rat or cat, forming a nociceptive and thermoreceptive pathway. It was confirmed "on line" that lamina I spinoparabrachial neurons that normally encode noxious stimuli can receive input from low threshold mechanoreceptors in certain conditions. The present work indicates that the study of lamina I spinoparabrachial neurons in vivo could take advantage of the use of genetically modified mice.
Learn More >Cannabis users have long reported therapeutic properties of the plant for a variety of conditions, some of which include nausea, emesis, seizures, cancer, neurogenic diseases and pain control. Research has elucidated many cannabinoid pharmacodynamic and pharmacokinetic properties, expanding the potential use of cannabinoids as a medical therapy. Due to the inconsistent delivery and control of the active components involved with smoking, pharmaceutical companies are investigating and prioritizing routes other than smoke inhalation for therapeutic use of cannabinoids. In this relatively new field of pharmaceutical development, ongoing drug development promises great benefit from targeted endocannabinoid receptor agonism. Available in Canada and Europe, nabiximols, a specific extract from the Cannabis plant, has demonstrated great benefit in the treatment of pain related to spasticity in multiple sclerosis, cancer and otherwise chronic pain conditions. The cannabidiol oral solution Epidiolex®, which is available in the USA, is indicated for management of refractory epilepsy but may offer therapeutic relief to chronic pain conditions as well. Current investigative drugs, such as those developed by Cara Therapeutics and Zynerba Pharmaceuticals, are synthetic cannabinoids which show promise to specifically target neuropsychiatric conditions and chronic pain symptoms such as neuropathy and allodynia. The objective of this review is to provide clinicians with an update of currently available and promising developmental cannabis pharmaceutical derivatives which may stand to greatly benefit patients with otherwise difficult-to-treat chronic conditions.
Learn More >Postherpetic neuralgia (PHN) is the most common complication of varicella zoster virus (VZV) reactivation and a cause of considerable physical and psychosocial morbidity. No known treatment effectively prevents the development of PHN in patients with VZV reactivation. In this study, our objective was to evaluate the efficacy of premedication with gabapentin for reducing the risk of PHN in patients with diabetic and nondiabetic neuropathy. We retrospectively searched the electronic health records of patients with diabetic and nondiabetic neuropathy treated with gabapentin at Mayo Clinic before diagnosis of VZV reactivation. In total, PHN developed in 7 patients with diabetic neuropathy receiving gabapentin (n=62 [11.3%]) compared with 26 not receiving premedication with gabapentin (n=50 [52.0%]) (odds ratio, 0.12; 95% CI, 0.05-0.31; P<.001); PHN developed in 11 patients with nondiabetic neuropathy receiving gabapentin (n=109 [10.1%]) compared with 108 not receiving premedication with gabapentin (n=217 [49.8%]) (odds ratio, 0.11; 95% CI, 0.06-0.22; P<.001). In this cohort of patients with neuropathy, gabapentin administration before the onset of VZV reactivation significantly reduced the risk of PHN.
Learn More >The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception related prefrontal anterior cingulate cortex (ACC). However, less information is available for the functional roles of CGRP in cortical regions such as the ACC. Recent studies have consistently demonstrated that long-term potentiation (LTP) is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical LTP and the recruitment of inactive channels. CGRP-induced LTP was also blocked by NMDA receptor antagonist AP-5. Consistently, application of CGRP increased NMDA receptor mediated excitatory postsynaptic currents (EPSCs). Finally, we found that CGRP-induced LTP requires activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and PKA. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a PKA inhibitor KT5720 all reduced or blocked CGRP induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.
Learn More >Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public presentation and promises as well as in its use.
Learn More >Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer; however, the mechanisms responsible for hyperalgesia are not well understood. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, in this study we examined the role for pro-inflammatory cytokines (PICs) of the PAG in regulating mechanical and thermal hyperalgesia evoked by bone cancer via PI3K-mTOR signals. Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. Western blot analysis and ELISA were used to examine PI3K/Akt/mTOR and PIC receptors and the levels of IL-1β, IL-6 and TNF-α. Protein expression levels of p-PI3K/p-Akt/p-mTOR were amplified in the PAG of bone cancer rats; and blocking PI3K-mTOR pathways in the PAG attenuated hyperalgesia responses. In addition, IL-1β, IL-6 and TNF-α were elevated in the PAG of bone cancer rats and expression of their respective receptors (namely, IL-1R, IL-6R and TNFR subtype TNFR1) was upregulated. Inhibition of IL-1R, IL-6R and TNFR1 alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated PI3K-mTOR. Our data suggest that upregulation of PIC signal in the PAG of cancer rats amplifies PI3K-mTOR signal in this brain region and alters the descending pathways in regulating pain transmission; and this thereby contributes to the development of bone cancer-induced pain.
Learn More >Inflammatory pain is associated with peripheral and central sensitization, but the underlying synaptic plasticity at the spinal cord level is poorly understood. Transient receptor potential (TRP) channels expressed at peripheral nerve endings, including TRPA1 and TRPV1, can detect nociceptive stimuli. In this study, we determined the contribution of presynaptic TRPA1 and TRPV1 at the spinal cord level to regulating nociceptive drive in chronic inflammatory pain induced by treatment with complete Freund's adjuvant (CFA) in rats. CFA treatment caused a large increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in lamina I, but not lamina II outer zone, dorsal horn neurons. However, blocking NMDA receptors had no effect on spontaneous EPSCs in lamina I neurons of CFA-treated rats. Application of a specific TRPA1 antagonist, AM-0902, or of a specific TRPV1 antagonist, 5'-iodoresiniferatoxin, significantly attenuated the elevated frequency of spontaneous EPSCs and miniature EPSCs, the amplitude of monosynaptic EPSCs evoked from the dorsal root in lamina I neurons of CFA-treated rats. AM-0902 and 5'-iodoresiniferatoxin had no effect on evoked or miniature EPSCs in lamina I neurons of vehicle-treated rats. In addition, intrathecal injection of AM-0902 or 5'-iodoresiniferatoxin significantly reduced pain hypersensitivity in CFA-treated rats but had no effect on acute nociception in vehicle-treated rats. These findings suggest that chronic inflammatory pain is associated with NMDA receptor-independent potentiation in glutamatergic drive to spinal lamina I neurons. Endogenous presynaptic TRPA1 and TRPV1 activity at the spinal level contributes to increased nociceptive input from primary sensory nerves to dorsal horn neurons in inflammatory pain. This article is protected by copyright. All rights reserved.
Learn More >Abdominal pain associated with low-grade inflammation is frequently encountered in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) during the remission phase. Current treatments are generally weakly effective. Therefore, new therapeutic approaches are needed. The role of Cav3.2 voltage-dependent calcium channels, which have been shown to be important in other chronic pain contexts, was investigated in a murine model of colonic hypersensitivity (CHS) associated with low-grade inflammation.
Learn More >Neuromodulation is nowadays investigated as a promising method for pain relief. Research indicates that a single 30-minute stimulation with transcranial pulsed electromagnetic fields (tPEMF) can induce analgesic effects. However, it is unknown whether tPEMF can induce analgesia in neuropathic pain patients.
Learn More >OnabotulinumtoxinA is effective in preventing chronic migraine (CM); however, the benefit of onabotulinumtoxinA in patients with CM with daily headache is unknown because these patients are typically excluded from clinical trials. This subanalysis of the COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without daily headache.
Learn More >Repeated intravesical PAR4 (protease activated receptor 4) activation elicits persistent bladder pain lasting 5 days after the last treatment. Persistent bladder pain was fully reversed by a systemic HMGB1 (high mobility box 1) inhibitor while a MIF (macrophage migration inhibitory factor) antagonist partly reversed it. Since there is growing evidence that spinal MIF and HMGB1 mediate inflammatory and neuropathic pain we examined whether there were spinal changes occurring during persistent bladder pain that may be responsible for maintaining bladder pain. In addition, we tested whether we could modulate persistent bladder pain with spinal MIF or HMGB1 antagonists. Persistent bladder pain was elicited in female C57 mice by repeated (3x) intravesical instillation of PAR4-activating peptide while control animals received scramble peptide treatment. On day 4, spinal cord (L6-S1) changes in c-fos (non-specific marker of spinal activation) was assessed with immunofluorescence while MIF and HMGB1 were assessed with immunofluorescence, western blotting and real-time PCR. On day 7, mice received an intrathecal injection of a neutralizing MIF monoclonal antibody (15 µg in 5 µl PBS) or a HMGB1 inhibitor glycyrrhizin (25 µg in 5 µl of 5 % alcohol in PBS) and abdominal mechanical threshold was tested. On day 9, mice were treated with vehicle or control and abdominal mechanical threshold was tested. Immunofluorescence showed that c-fos and MIF in the dorsal horn, dorsal grey commissure and intermediolateral areas significantly increased in PAR4-treated mice while HMGB1 was decreased. In addition, intrathecal treatment with MIF neutralizing mAb or glycyrrhizin significantly alleviated abdominal mechanical hypersensitivity at 1 and 2 hours and the analgesic effect diminished at 6 hours. Vehicle or control treatment had no effect. Persistent bladder pain is associated with spinal changes in MIF and HMGB1 levels. Furthermore, spinal treatment with MIF monoclonal antibody and HMGB1 inhibitor temporarily reversed bladder pain. Our findings suggest that spinal MIF and HMGB1 participate in persistent bladder pain induced by repeated intravesical PAR4 and may be potential therapeutic targets in chronic bladder pain conditions.
Learn More >Testing of exteroceptive electromyographic modulation of ongoing voluntary muscle activity is of increasing interest as a diagnostic tool in clinical neurophysiology. The cutaneous silent period (CSP) is a robust and reproducible nociceptive EMG suppression, mediated at the spinal level by small-diameter A-delta afferents. The techniques and physiological principles of CSP testing, which are a fundamental prerequisite for a valid and thoughtful clinical application, are reviewed separately in part 1 (Kofler et al., 2019). This comprehensive review surveys the literature on pathophysiological conditions in which CSPs have been reported, and aims at a critical overview on the clinical utility of CSP testing. The most useful clinical applications seem to be the functional diagnostics of intramedullary, in particular centromedullary, dysfunctions, and the assessment of small fiber neuropathies, in particular those affecting A-delta fibers. CSPs have in addition been studied in a variety of movement disorders and in neuropathic pain and other painful conditions, including fibromyalgia.
Learn More >The vast majority of headache patients encountered in the outpatient general medicine setting will be diagnosed with a primary headache disorder, mostly migraine or tension-type headache. Other less common primary headaches and secondary headaches, related to or caused by another condition, are the topic of this article. Nonmigraine primary headaches include trigeminal autonomic cephalalgias, primarily cluster headache; facial pain, primarily trigeminal neuralgia; and miscellaneous headache syndromes, such as hemicrania continua and new daily persistent headache. Selected secondary headaches related to vascular disease, cerebrospinal fluid dynamics, and inflammatory conditions are also reviewed.
Learn More >Migraine and tension-type headache are highly prevalent. Migraine is associated with significant work- and family-related disability. Migraine is underdiagnosed; it reasonable to err on the side of migraine when choosing between primary headaches. Barriers to appropriate treatment of migraine include lack of access to providers, misdiagnosis, and acute and preventive therapies not being prescribed. Acute, rescue, and preventive treatment options are extensive, and new classes of treatments are either available or in development. This review addresses diagnostic challenges including recognizing migraine with aura. It also summarizes nonpharmacologic, acute, rescue, and preventive treatment options for migraine and treatment of tension-type headache.
Learn More >The addictive potential of clinically-used opioids due to their direct action on the dopaminergic reward system in the brain has limited their application. In an attempt to reduce negative side effects as well as to improve the overall effectiveness of these analgesics, we have designed, synthesized, and evaluated an N-(2-hydroxypropyl)methacrylamide (HPMA)-based macromolecular prodrug of hydromorphone (HMP), a commonly used opioid. To this end, P-HMP was synthesized via RAFT polymerization and a subsequent polymer analogous reaction. Its interaction with inflammatory cells in arthritic joints was evaluated in vitro using a RAW264.7 cell culture, and subsequent confocal microscopy analysis confirmed that P-HMP could be internalized by the cells via endocytosis. In vivo imaging studies indicated that the prodrug can passively target to the arthritic joint after systemic administration in a rodent model of monoarticular adjuvant-induced arthritis (MAA). The inflammatory pain-alleviating properties of the prodrug were assessed in MAA rats using the incapacitance test, and were observed to be similar to dose-equivalent HMP. Analgesia through mechanisms at the spinal cord level was further measured using the tail flick test and it was determined that the prodrug significantly reduced spinal cord analgesia versus free HMP, further validating the peripheral restriction of the macromolecular prodrug. Immunohistochemical analysis of cellular uptake of the P-HMP within the MAA knee joint proved the internalization of the prodrug by phagocytic synoviocytes, co-localized with HMP's target receptor as well as with pain-modulating ion channels. Therefore, it can be concluded that the novel inflammation-targeting polymeric prodrug of HMP (P-HMP) has the potential to be developed as an effective and safe analgesic agent for musculoskeletal pain.
Learn More >There are few prospective studies providing comprehensive assessment of risk factors for acute and persistent pain after breast surgery. This prospective observational study assessed patient-related, perioperative, and genetic risk factors for severe acute pain and persistent pain following breast cancer surgery.
Learn More >Spinal cord stimulation (SCS) relieves pain by delivering doses of electric current to the dorsal column of the spinal cord and has been found to be most effective in the treatment of neuropathic pain. Psychological distress is a significant risk factor for the development of chronic pain and has been found to affect the outcome of SCS. Childhood trauma is a risk factor for chronic pain, but has not previously been studied in SCS patients.
Learn More >To determine whether patients with painful myofascial temporomandibular disorders (TMD) demonstrate facilitated temporal summation (TS) responses to painful heat stimuli applied to the painful trigeminal and extratrigeminal regions and whether there is a side difference in the trigeminal region for myofascial TMD pain patients compared to healthy controls.
Learn More >Medication-overuse headache (MOH) is a common chronic headache caused by overuse of headache analgesics. It has similarities with substance dependence disorders. The treatment of choice for MOH is withdrawal of the offending analgesics. Behavioral brief intervention treatment using methods adapted from substance misuse settings is effective. Here we investigate the severity of analgesics dependence in MOH using the Severity of Dependence Scale (SDS), validate the SDS score against formal substance dependence diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and examine whether the SDS predicts successful withdrawal.
Learn More >Ecological momentary assessment (EMA) involves repeated sampling of people's current experiences in real time in their natural environments, which offers a granular perspective on patients' experience of pain and other symptoms. However, EMA can be burdensome to patients, and its benefits depend upon patients' engagement in the assessments.
Learn More >Many neuropsychological theories agree that the brain maintains a relatively persistent representation of one's own body, as indicated by vivid "phantom" experiences. It remains unclear how the loss of sensory and motor information contributes to the presence of this representation. Here, we focus on new empirical and theoretical evidence of phantom sensations following damage to or an anesthetic block of the brachial plexus. We suggest a crucial role of this structure in understanding the interaction between peripheral and central mechanisms in health and in pathology. Studies of brachial plexus function have shed new light on how neuroplasticity enables "somatotopic interferences", including pain and body awareness. Understanding the relations among clinical disorders, their neural substrate, and behavioral outcomes may enhance methods of sensory rehabilitation for phantom limbs.
Learn More >Reduced blood flow in the skin is observed in patients with neuropathic pain and in animal models. The aim of the present study was to elucidate the relationship between reduced skin blood flow and neuropathic pain in mice with a chronic constriction injury (CCI). Noradrenaline-induced contraction was enhanced in isolated plantar arteries ipsilateral to the CCI surgery compared to the contralateral arteries. Ten μM hydralazine, a peripheral vasodilator, at improved the enhanced contractile response in the ipsilateral arteries. The plantar blood flow in vivo was lower on the ipsilateral side of the CCI mice than on the contralateral side, and a 50% paw withdrawal threshold, as measured using the von Frey filament test, was lower on the former than on the latter side. An intraperitoneal injection (i.p.) of hydralazine (1 mg/kg) or phentolamine (5 mg/kg) improved blood flow in the skin and hyperalgesia in the ipsilateral plantar. In adrenalectomized CCI mice, plantar blood flow in the skin on the ipsilateral side was increased compared to in sham-operated mice, which was accompanied by alleviation of hyperalgesia. Moreover, the enhanced contractile response to noradrenaline was also observed in the ipsilateral plantar arteries isolated from the adrenalectomized CCI mice. Either hydralazine (1 mg/kg, i.p.) or an adrenalectomy barely affected mean arterial pressure in the CCI mice, whereas phentolamine (5 mg/kg, i.p.) lowered it. These results suggest that reduced blood flow in the skin contributes to neuropathic pain and that improving that blood flow with peripheral vasodilators, such as hydralazine, can alleviate it.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) affects 30% to 40% of patients with cancer with long-lasting disability. Scrambler therapy (ST) appeared to benefit patients in uncontrolled trials, so we performed a randomized sham-controlled Phase II trial of ST.
Learn More >Recommended medications for the acute treatment of migraine encompass triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. While it is true that triptans have been the first successful mechanism-driven treatment in the field, recently, new targets involved in migraine pathogenesis have emerged and new drug classes have been studied for migraine attack therapy. Areas covered: Pharmacodynamics and pharmacokinetics of the new acute treatments of migraine (i.e. ditans, gepants, and glutamate receptor antagonists), considering also marketed drugs in new formulations and administration routes. Expert Opinion: Research on the administration routes of marketed drugs was performed in order to improve, in accordance with basic pharmacokinetics parameters, the speed of action of these medications. Similar to the triptans, the new acute treatments are migraine-specific medications, acting on the trigeminovascular system, albeit with different mechanisms. Although available data do not conclusively indicate the superiority of a class over the others, the pharmacodynamics explains the peculiar tolerability and safety profile of different drug classes emerging from clinical trials. Further studies are needed to investigate the possibility of combining different drug classes to optimize the clinical response and the potential role of the novel drugs in medication-overuse headache.
Learn More >The effect of implicit theories of pain on pain and disability in people with chronic low back pain.
Implicit theories of pain represent a socio-cognitive mechanism linked to important coping, emotional, and expressive reactions to chronic pain. Evidence suggests that chronic low back pain (CLBP) patients who hold an incremental theory of pain (i.e. view pain as a malleable) use more active coping strategies, display less pain behavior, and report lower levels of depression than those with an entity theory of pain (i.e. view pain as a fixed). However, a link between implicit theories of pain and symptoms of pain and disability in people with CLBP has not been established.
Learn More >To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH).
Learn More >Medication overuse headache (MOH) is the most prevalent chronic headache disorder with a prevalence between 1-2% worldwide. The disease has been acknowledged for almost 30 years, yet experts still disagree on how best to treat MOH. By performing a search in PubMed on the terms "medication overuse headache", "analgesics abuse headache", "rebound headache", "drug induced headache", and "headache AND drug misuse" limited to human studies published in English between January 1 2004 and November 1 2017, we aimed to evaluate current literature concerning predictors of treatment outcome, inpatient and outpatient treatment programs, initial versus latent administration of prophylactic medications, and to review the effect of prophylactic medications. Selection criteria were prospective, comparative or controlled trials on treatment of MOH in persons of at least 18 years of age. Several studies evaluated risk factors to predict the outcome of MOH treatment, but many studies were underpowered. Psychiatric comorbidity, high dependence score and overuse of barbiturates, benzodiazepines and opioids predicted a poorer outcome of withdrawal therapy. Patients with these risk factors benefit from inpatient treatment, whereas patients without risk factors benefit equally from in and outpatient treatment. Some medications for migraine prophylactics have shown better effect on MOH compared with placebo, but not when combined with withdrawal. We conclude that detoxification programs are of great importance in MOH treatment. Latent administration of prophylactic medications reduces the number of patients needing prophylactic medication. Individualizing treatment according to the predictors of outcome may improve treatment outcome and thus reduce work-related and treatment-related costs. This article is protected by copyright. All rights reserved.
Learn More >Previous studies reported an increased risk of ischemic stroke in younger migraineurs. We aimed to investigate the association between age and cerebrovascular reactivity (CVR) to vasodilatory stimuli in cerebral arteries in patients with migraine and normal controls.
Learn More >To develop an evidence-based guideline for the non-pharmacological management of persistent headaches associated with neck pain (i.e., tension-type or cervicogenic).
Learn More >Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment to relieve pain. Contralateral TENS (i.e., TENS administered to the contralateral side of a painful body part) is beneficial when TENS cannot be directly applied to pain site, such as in cases of trauma. Although TENS produces segmental analgesia in an ipsilateral limb, it has been unclear whether TENS produces higher analgesic effects in the contralateral segmental area. The aim of present study was to investigate the analgesic effects of TENS in contralateral segmental or extra-segmental areas on physiological and subjective pain outcomes, using a nociceptive flexion reflex (NFR) method.
Learn More >The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients is primarily driven by hormone-dependent and inflammatory processes – the latter being frequently associated with severe, acute and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and anti-nociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful SAR investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific and selective hEP4-R antagonist with excellent DMPK properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patients` quality of life.
Learn More >Acupuncture therapy is effective for relieving postoperative pain. Our previous study showed that electroacupuncture (EA) at Futu (LI18) and Hegu (LI4)-Neiguan (PC6) could alleviate incisional neck pain, which was related with its effect in upregulating γ-aminobutyric acid (GABA) expression in cervical (C3-6) dorsal root ganglions (DRGs); but whether its receptor subsets GABAα2R and GABAR1 in C3-6 DRGs are involved in EA analgesia or not, it remains unknown.
Learn More >Generalized pain hypersensitivity is frequently observed in chronic pain conditions. Currently, identification is based on expert clinical opinion, and in very few cases combined with quantitative sensory testing. The objectives of this study were to develop and evaluate a short self-report measure of generalized pain hypersensitivity: a generalized pain questionnaire (GPQ).
Learn More >Oxycodone is one of the options for the management of CLBP in patients with an inadequate response to other analgesics. However, oxycodone is not yet approved for noncancer pain in Japan. Here, we assessed the efficacy and long-term safety of S-8117, a controlled-release oxycodone formulation, for the management of Japanese CLBP patients.
Learn More >Peripheral neuropathy is a commonly encountered disorder in clinical practice. In light of an aging population and the diabetes and obesity pandemic, the prevalence of peripheral neuropathy is increasing, posing a significant public health concern. This article provides a diagnostic framework for neuropathies and summarizes treatment options.
Learn More >To compare the impacts of trigeminal neuralgia (TN) and painful posttraumatic trigeminal neuropathy (PPTTN) on psychologic function and health-related quality of life (HRQoL) using a comprehensive quantitative assessment.
Learn More >It is presently unclear whether extended-release naltrexone hydrochloride treatment induces pain or aggravates existing pain among individuals with opioid use disorders. We assessed changes in pain among individuals receiving treatment with either extended-release naltrexone hydrochloride or buprenorphine-naloxone hydrochloride.
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