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Non-invasive vagus nerve stimulation (nVNS; gammaCore®) has the potential to prevent migraine days in patients with migraine on the basis of mechanistic rationale and pilot clinical data.
Learn More >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.
Learn More >Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care.
Learn More >Proteasome inhibitors (PIs), especially bortezomib (BTZ), have come to the forefront over the last years because of their unprecedented efficacy mainly against multiple myeloma (MM). Unfortunately, peripheral neuropathy (PN) secondary to treatment of MM with PIs has emerged as a clinically relevant complication, which negatively impacts the quality of life of MM survivors. Bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, which develops in 30% to 60% of patients during treatment. Typically, BIPN is a length-dependent sensory axonopathy characterized by numbness, tingling, and severe neuropathic pain in stocking and glove distribution. BIPN mechanisms have not yet been fully elucidated. Experimental studies suggest that aggresome formation, endoplasmic reticulum stress, myotoxicity, microtubule stabilization, inflammatory response, and DNA damage could contribute to this neurotoxicity. A new generation of structurally distinct PIs has been developed, being increasingly used in clinical settings. Carfilzomib exhibits a much lower neurotoxicity profile, with a significantly lower incidence of PN compared to BTZ. Pre-existing PN increases the risk of developing BIPN. Besides, BIPN is related to dose, schedule and mode of administration and modifications of these factors have lowered the incidence of PN. However, to date there is no cure for PIs-induced PN (PIIPN), and a careful neurological monitoring and dose adjustment is a key strategy for preserving quality of life. This review critically looks at the pathogenesis, incidence, risk factors, both clinical and pharmacogenetics, clinical phenotype and management of PIIPN. We also make recommendations for further elucidating the whole clinical spectrum of PIIPN.
Learn More >Collapsin response mediator proteins (CRMPs) are a family of ubiquitously expressed, homologous phosphoproteins best known for coordinating cytoskeletal formation and regulating cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. These functions are tightly regulated by post-translational modifications including phosphorylation, SUMOylation, oxidation, and O-GlcNAcylation. While CRMP2's physiological functions rely mostly on its non-phosphorylated state, dysregulation of CRMP2 phosphorylation and SUMOylation has been reported to be involved in the pathophysiology of multiple diseases including cancer, chronic pain, spinal cord injury, neurofibromatosis type 1, and others. Here, we provide a consolidated update on what is known about CRMP2 signaling and function, first focusing on axonal growth and neuronal polarity, then illustrating the link between dysregulated CRMP2 post-translational modifications and diseases. We additionally discuss the roles of CRMP2 in non-neuronal cells, both in the CNS and regions of the periphery. Finally, we offer thoughts on the therapeutic implications of modulating CRMP2 function in a variety of diseases.
Learn More >Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose.
Learn More >Chronic pain is an unmet clinical problem with vast individual, societal and economic impact. Pathologic activity of the peripheral somatosensory afferents is one of the major drivers of chronic pain. This overexcitable state of somatosensory neurons is, in part, produced by the dysregulation of genes controlling neuronal excitability. Despite intense research, a unifying theory behind neuropathic remodelling is lacking. Here we show that transcriptional suppressor, repressor element 1-silencing transcription factor (REST, NRSF), is necessary and sufficient for the development of hyperalgesic state following chronic nerve injury or inflammation. Viral overexpression of REST in mouse DRG induced prominent mechanical and thermal hyperalgesia in vivo. Sensory neuron specific, inducible Rest knock-out prevented the development of such hyperalgesic state in three different chronic pain models. Genetic deletion of Rest reverted injury-induced hyperalgesia. Moreover, viral overexpression of REST in the same neurons in which its gene has been genetically deleted restored neuropathic hyperalgesia. Finally, sensory neuron specific Rest knockout prevented injury-induced downregulation of REST target genes in DRG neurons. This work identified REST as a major regulator of peripheral somatosensory neuron remodelling leading to chronic pain. The findings might help to develop a novel therapeutic approaches to combat chronic pain.This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Learn More >Neuropathy is a common, morbid complication of the metabolic syndrome, prediabetes, and diabetes. Recent studies have indicated a potential role for the immune system in the development of neuropathy. In particular, toll-like receptors (TLR) 2 and 4 have been linked to metabolic dysfunction, and blocking TLR4 is proposed as a treatment for neuropathic pain. In the current study, we investigated the role of the immune system, particularly TLRs 2 and 4, in the pathogenesis and progression of neuropathy. Sural or sciatic nerve gene expression arrays from humans and murine neuropathy models of prediabetes and diabetes were first analyzed to identify differentially expressed TLR2- and TLR4-associated genes within the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. We observed that genes associated with TLRs 2 and 4, particularly lipopolysaccharide binding protein (LPB) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), were dysregulated across species and across multiple murine models of prediabetic and diabetic neuropathy. To further understand the role of these pathways in vivo, TLR 2 and 4 global knockout mice placed on a 60% high fat diet (HFD-TLR2/4) were compared with wild type (WT) mice on a high fat diet (HFD-WT) and WT controls on a standard diet (CON). Mice then underwent metabolic, neuropathic, and immunological phenotyping at two time points to assess the impact of TLR signaling on neuropathy and immunity during metabolic dysfunction over time. We found that HFD-TLR2/4 and HFD-WT mice weighed more than CON mice but did not have increased fasting blood glucose levels. Despite normal blood glucose levels, HFD-TLR2/4 mice eventually developed neuropathy at the later time point (28 wks of age) but were somewhat protected from neuropathy at the early time point (16 wks of age) as measured by shorter hind paw withdraw latencies. This is in contrast to HFD-WT mice which developed neuropathy within 11 wks of being placed on a high fat diet and were neuropathic by all measures at both the early and late time points. Finally, we immunophenotyped all three mouse groups at the later time point and found differences in the number of peripheral blood Ly6C-myeloid cells as well as F4/80+ expression. These results indicate that TLR signaling influences early development of neuropathy in sensory neurons, potentially via immune modulation and recruitment.
Learn More >Migraine mechanisms are *These authors contributed equally to this work. only partly known. Some studies have previously described genes differentially expressed between blood from migraineurs and controls. The objective of this study was to describe gene expression in subtypes of migraine outside of attack and in healthy controls.
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