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Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.
Learn More >The term vestibular migraine designates recurrent vertigo that is caused by migraine. Vestibular migraine presents with episodes of spontaneous or positional vertigo lasting seconds to days that are accompanied by migraine symptoms. Because headache is often absent during acute attacks, other migraine features have to be identified by thorough history taking. In contrast, vestibular testing serves mainly for the exclusion of other diagnoses. Treatment still lacks solid evidence. It is targeted at the underlying migraine and comprises explanation and reassurance, lifestyle modifications, and drugs.
Learn More >In September 2017, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved the joint Clinical Practice Guideline (CPG) for Diagnosis and Management of Low Back Pain. This CPG was intended to provide healthcare providers a framework by which to evaluate, treat, and manage patients with low back pain (LBP).
Learn More >Neuronal hyperactivity in the spinal dorsal horn can amplify nociceptive input in diabetic neuropathic pain. The glutamate N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDA receptors and AMPA receptors, respectively) are involved in spinal nociceptive transmission. However, it is unclear whether painful diabetic neuropathy is associated with changes in the activity of synaptic NMDA receptors and AMPA receptors in spinal dorsal horn neurons. AMPA receptors lacking GluA2 are Ca2+ permeable (CP-AMPA receptors), and their currents display characteristic inward rectification. In this study, we showed that evoked excitatory postsynaptic currents (EPSCs) exhibited inward rectification in spinal dorsal neurons in diabetic rats induced by streptozotocin. Interestingly, presynaptic and postsynaptic NMDA receptor activity in the spinal dorsal horn was similar in diabetic and control rats. In the dorsal spinal cord, the membrane GluA2 protein level was significantly less in diabetic than in control rats, whereas the cytosolic GluA2 level was greater in diabetic than in control rats. In contrast, the GluA1 subunit levels in the plasma membrane and cytosol did not differ between the two groups. Blocking CP-AMPA receptors significantly reduced the amplitude of EPSCs of dorsal horn neurons in diabetic but not in control rats. Furthermore, blocking spinal CP-AMPA receptors reduced pain hypersensitivity in diabetic rats but had no effect on nociception in control rats. Our study suggests that diabetic neuropathy augments CP-AMPA receptor activity in the spinal dorsal horn by causing intracellular retention of GluA2 and impairing GluA2 membrane trafficking. Increased prevalence of spinal CP-AMPA receptors sustains diabetic neuropathic pain. SIGNIFICANCE STATEMENT: This study demonstrates that the prevalence of synaptic calcium permeable-AMPA receptors is increased in the spinal dorsal horn, which mediates pain hypersensitivity in diabetic neuropathy. Thus, calcium permeable-AMPA receptors play an important role in glutamatergic synaptic plasticity in the spinal cord in painful diabetic neuropathy. This new knowledge improves our understanding of the mechanisms involved in central sensitization associated with diabetic neuropathic pain and suggest that calcium permeable-AMPA receptors are an alternative therapeutic target for treating this chronic pain condition.
Learn More >Evidence suggests there to be an association between chronic pain and disruption of the body schema. We tested the hypothesis in fibromyalgia syndrome.
Learn More >Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN and TN can exist without a neurovascular contact. A common observation during microvascular decompression (MVD) surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology (PEA) to analyse the levels of 92 protein biomarkers related to inflammation in lumbar CSF from patients with TN (n=27) before and after MVD compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the CSF from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins appeared to be of specific interest for TN; TRAIL and TNF-β. Thus, inflammatory activity might be one important mechanism in TN.
Learn More >Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain (CPP). Here we investigated the effects of linaclotide, an FDA approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium transplantation into the intestinal mesentery, rats developed endometrial lesions as well as vaginal hyperalgesia to distension and decreased mechanical hindpaw withdrawal thresholds. Daily oral administration of linaclotide, a peripherally restricted guanylate cyclase-C (GC-C) agonist peptide acting locally within the gastrointestinal tract increased pain thresholds to vaginal distension and mechanical hindpaw withdrawal thresholds relative to vehicle treatment. Furthermore, using a cross-over design, administering linaclotide to rats previously administered vehicle resulted in increased hindpaw withdrawal thresholds, whilst replacing linaclotide with vehicle treatment decreased hindpaw withdrawal thresholds. Retrograde tracing of sensory afferent nerves from the ileum, colon and vagina revealed that central terminals of these afferents lie in close apposition to one another within the dorsal horn of the spinal cord. We also identified dichotomizing dual-labelled ileal/colon innervating afferents as well as colon/vaginal dual-labelled neurons and a rare population of triple traced ileal/colon/vaginal neurons within thoracolumbar DRG. These observations provide potential sources of cross-organ interaction at the level of the DRG and spinal cord. GC-C expression is absent in the vagina and endometrial cysts suggesting that the actions of linaclotide are via shared nerve pathways between these organs. In summary, linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but concurrent treatment of comorbid CPP syndromes.
Learn More >The cost of US health care continues to increase, with treatments related to low back and neck pain and other musculoskeletal disorders accounting for the third highest amount of various disease categories. Interventional techniques for managing pain apart from conservative modalities and surgical interventions, have generally been thought to be growing rapidly. However, a recent analysis of utilization of interventional techniques from 2000 to 2016 has shown a modest decline from 2009 to 2016, compared to 2000 to 2009.
Learn More >It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.
Learn More >Protein kinase Mζ (PKMζ), a typical brain-specific PKC isoform, has been shown to be critical in the maintenance of long-term potentiation and memory storage. Zeta inhibitory peptide (ZIP), a peptide with selective inhibition of PKMζ, has been used in relieving experimental neuropathic pain and disrupting memory. The aim of this study was to investigate the effects of intra-amygdalar infusion of ZIP on neuropathic pain induced by chronic constriction injury (CCI), and inflammatory pain induced by complete Freund's adjuvant (CFA) in adult rats.
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