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Botulinum neurotoxin type A, an FDA-approved prophylactic drug for chronic migraine, is thought to achieve its therapeutic effect through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with myelinated nociceptors and potentially the vasculature and immune cells. Prior investigations to determine botulinum neurotoxin type A effects on meningeal nociceptors were carried out in male rats and tested with stimuli that act outside the blood brain barrier. Here, we sought to explore the effects of extracranial injections of botulinum neurotoxin type A on activation of meningeal nociceptors by cortical spreading depression, an event which occurs inside the blood brain barrier, in female rats.
Learn More >Heightened pain sensitivity, the amount of pain experienced in response to a noxious event, is a known risk factor for development of chronic pain. We have previously reported that pain-free, sensorimotor Peak Alpha Frequency (PAF) is a reliable biomarker of pain sensitivity for thermal, prolonged pains lasting tens of minutes. To test whether PAF can provide information about pain sensitivity occurring over clinically relevant timescales (i.e., weeks), EEG was recorded before and while participants experienced a long-lasting pain model, repeated intramuscular injection of nerve growth factor (NGF), that produces progressively developing muscle pain for up to 21 days. We demonstrate that pain-free, sensorimotor PAF is negatively correlated with NGF pain sensitivity; increasingly slower PAF is associated with increasingly greater pain sensitivity. Furthermore, PAF remained stable following NGF injection indicating that the presence of NGF pain for multiple weeks is not sufficient to induce the PAF slowing reported in chronic pain. In total, our results demonstrate that slower pain-free, sensorimotor PAF is associated with heightened sensitivity to a long-lasting musculoskeletal pain and also suggest that the apparent slowing of PAF in chronic pain may reflect pre-disease pain sensitivity.
Learn More >Membrane metallo-endopeptidase (MME), also known as neprilysin (NEP), has been of interest for its role in neurodegeneration and pain due to its ability to degrade β-amyloid and substance-P, respectively. In addition to its role in the central nervous system, MME has been reported to be expressed in the peripheral system, specifically in the inner and outer border of myelinating fibers, in the Schmidt-Lantermann cleft and in the paranodes. Recently, mutations of this gene have been associated with Charcot-Marie-Tooth Type 2 (CMT2). Peripheral nerve morphometry in mice lacking MME previously showed minor abnormalities in aged animals in comparison to CMT2 patients. We found that MME expression was dysregulated after nerve injury in a Neuregulin-1 dependent fashion. We therefore explored the hypothesis that MME may have a role in remyelination. In the naïve state in adulthood we did not find any impairment in myelination in MME KO mice. After nerve injury the morphological outcome in MME KO mice was indistinguishable from WT littermates in terms of axon regeneration and remyelination. We did not find any difference in functional motor recovery. There was a significant difference in sensory function, with MME KO mice starting to recover response to mechanical stimuli earlier than WT. The epidermal reinnnervation, however, was unchanged and this altered sensitivity may relate to its known function in cleaving the peptide substance-P, known to sensitise nociceptors. In conclusion, although MME expression is dysregulated after nerve injury in a NRG1-dependent manner this gene is dispensable for axon regeneration and remyelination after injury.
Learn More >Migraine is among the most common and most disabling disorders worldwide, yet its underlying pathophysiology is among the most poorly understood. New information continues to emerge on mechanisms within the central and peripheral nervous systems that may contribute to migraine attacks. Additionally, new therapeutics have recently become available and along with much needed relief for many patients, these drugs provide insight into the disorder based on their mechanism of action. This review will cover new findings within the last several years that add to the understanding of migraine pathophysiology, including those related to the vasculature, calcitonin gene-related peptide (CGRP), and mechanisms within the cortex and meninges that may contribute to attacks. Discussion will also cover recent findings on novel therapeutic targets, several of which continue to show promise in new preclinical studies, including acid-sensing ion channels (ASICs) and the delta-opioid receptor (DOR).
Learn More >A recent study with Ca-sensitive-dyes in neurons in whole DRGs (Table 5) found that much lower percentages of nociceptors were polymodal-nociceptors (PMNs) (Emery , 2016), than the 50-80% values in many electrophysiological fiber studies. This conflict highlighted the lack of knowledge about percentages of nociceptor-subtypes in the DRG. This was analysed from intracellularly-recorded neurons in rat lumbar DRGs stimulated from outside the skin. Polymodal nociceptors (PMNs) were 11% of all neurons and 19% of all nociceptors. Most PMNs had C-fibers (CPMNs). Percentages of C-nociceptors that were CPMNs varied with receptive field (RF) depths, whether superficial (∼80%), dermal (25%), deep (0%) or cutaneous (superficial + dermal) (40%). This explains CPMN percentages 40-90%, being highest, in electrophysiological studies using cutaneous nerves, and lowest in studies that also include deep RFs, including ours, and the recent Ca-imaging studies in whole DRGs. Despite having been originally described in 1967 (Burgess and Perl), both Aβ-nociceptors and Aβ-moderate pressure receptors (MPRs) remain overlooked. Most A-fiber nociceptors in rodents have Aβ-fibers. Of rat lumbar Aβ-nociceptors with superficial RFs, 50% were MPRs with variable medium-low trkA-expression. Despite having conduction velocities at the two extremes for nociceptors, both CPMNs and MPRs have relatively low thresholds, superficial/epidermal RFs and low trkA-expression. For abbreviations used see Table 5.
Learn More >While older adults with cancer are more likely to develop chemotherapy-induced peripheral neuropathy (CIPN), the study aimed to determine if patient-reported and objective measures of CIPN differ by age among cancer survivors.
Learn More >Pain is the main complication of sickle cell disease (SCD). Individuals with SCD experience acute pain episodes and chronic daily pain, both of which are managed with opioids. Opioids have deleterious side effects and use-associated stigma that make them less than ideal for SCD pain management. After recognizing the neuropathic qualities of SCD pain, clinically-approved therapies for neuropathic pain, including gabapentin, now present unique non-opioid based therapies for SCD pain management. These experiments explored the efficacy of gabapentin in relieving evoked and spontaneous chronic pain, and hypoxia/reoxygenation (H/R)-induced acute pain in mouse models of SCD. When administered following H/R, a single dose of gabapentin alleviated mechanical hypersensitivity in SCD mice by decreasing peripheral fibre activity. Gabapentin treatment also alleviated spontaneous ongoing pain in SCD mice. Longitudinal daily administration of gabapentin failed to alleviate H/R-induced pain or chronic evoked mechanical, cold or deep tissue hypersensitivity in SCD mice. Consistent with this observation, voltage-gated calcium channel (VGCC) α δ subunit expression was similar in sciatic nerve, dorsal root ganglia and lumbar spinal cord tissue from SCD and control mice. Based on these data, gabapentin may be an effective opioid alternative for the treatment of chronic spontaneous and acute H/R pain in SCD.
Learn More >To describe the development of a virtual reality (VR) treatment for phantom limb pain (PLP) and phantom sensations and provide feasibility data from testing the treatment in a population of veterans.
Learn More >To investigate the association between the presence of self-reported neck pain in patients with migraine and clinical features, upper cervical mobility, and neck muscle performance.
Learn More >The clinical characteristics of cluster headache (CH) are based mainly on retrospective attack descriptions of "usual" attacks, but whether these reports are reliable is uncertain. We aimed to compare retrospective and prospective attack descriptions and describe the within- and between patient variability of attacks.
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