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Migraine is a ubiquitous neurologic disease that afflicts people of all ages. Its molecular pathogenesis involves peptides that promote intracranial vasodilation and modulate nociceptive transmission upon release from sensory afferents of cells in the trigeminal ganglion and parasympathetic efferents of cells in the sphenopalatine ganglion. Experimental data have confirmed that intravenous infusion of these vasoactive peptides induce migraine attacks in people with migraine, but it remains a point of scientific contention whether their site of action lies outside or within the central nervous system. In this context, it has been hypothesized that transient dysfunction of brain barriers before or during migraine attacks might facilitate the passage of migraine-inducing peptides into the central nervous system. Here, we review evidence suggestive of brain barrier dysfunction in migraine pathogenesis and conclude with lessons learned in order to provide directions for future research efforts.
Learn More >As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin-induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain including statistically significantly decreased histone H3.1 lysine 27 mono-methylation (H3.1K27me1, 54.8% of control) and lysine 56 tri-methylation (7.5% of control), as well as a trend suggesting increased histone 3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1-10 μM of NCDM-64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose-dependently elevated its levels with a greater than a 2-fold increase observed at 10 μM compared to vehicle-treated control cells. Moreover, pre-treatment of mice with NCDM-64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel non-opioid therapeutics for the effective management of chronic pain. This article is protected by copyright. All rights reserved.
Learn More >Capsaicin, the compound in hot chili peppers responsible for their pungency and an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), has long been known to promote the desensitization of nociceptors at high concentrations. This has led to the utilization and implementation of topical capsaicin cream as an analgesic to treat acute and chronic pain. Critically, the application of capsaicin cream is limited due to capsaicin's high pungency, which is experienced prior to analgesia. To combat this issue, novel capsaicin analogues were developed to provide analgesia with reduced pungency. Analogues reported in this paper add to and show some differences from previous structure-activity relationship (SAR) studies of capsaicin-like molecules against TRPV1, including the necessity of phenol in the aromatic "A-region", the secondary amide in the "B-region", and modifications in the hydrophobic "C-region". This provided a new framework for small-molecule design using capsaicin as the starting point. In this study, we describe the synthesis of capsaicin analogues, their activity in Ca assays, and initial pungency and feasibility studies of capsaicin analogues YB-11 and YB-16 as analgesics. Our results demonstrate that male and female mice treated with YB capsaicin analogues showed diminished pain-associated behavior in the spontaneous formalin assay as well as reduced thermal sensitivity in the hotplate assay.
Learn More >Sedation for pain medicine procedures provides a unique challenge for proceduralists. Many patients dealing with pain are on chronic opioids and require higher doses of sedation for adequate procedural comfort. Chronic pain patients have various comorbidities including depression, neuropsychiatric disorders, peripheral vascular disease, and renal impairment, among others [1]. These confounding variables make the overall treatment of their pain condition much more challenging.
Learn More >Non-invasive vagus nerve stimulation (nVNS) is effective in several types of headache disorders. We sought to unravel the mechanism of how nVNS exhibits this efficacy. This study used a randomized, single-blind, sham-controlled, crossover-design, and comprised three projects with three independent cohorts of healthy participants. Project I (n=15) was explorative. Six quantitative sensory test (QST) parameters, including mechanical pain threshold (MPT), were measured over the left V1 dermatome and forearm, and compared before and after unilateral nVNS. Projects II (n=20) and III (n=21) were online pre-registered . QST parameters were compared over the left (Project II) or bilateral V1 and V3 dermatomes (Project III), respectively, in addition to the left forearm as a control. A secondary analysis of heart rate variability (HRV) using a historical control group was used to control for systemic effects of nVNS. Verum-nVNS induced trigeminal-specific modulation of pain threshold (i.e., MPT) over the left V1 in Project I, left V1 and V3 in Project II, and bilateral V1 and V3 in Project III. Data pooled from Project II and III demonstrated greater increase of MPT in the V1 vs. V3 dermatome. There were no differences associated with sham-nVNS in any projects. HRV parameters did not change after nVNS. Our results provide functional evidence of a long hypothesized functional trigemino-vagal system in humans and may explain why nVNS is effective in some headache but not in somatic pain disorders. Since unilateral nVNS modulated the trigeminal thresholds bilaterally, this effect is probably indirect through a central top-down mechanism.
Learn More >The diagnostic criteria of new daily persistent headache (NDPH) have been revised since 2013. The current review focused on the progress of NDPH research over the last few years.
Learn More >Recent sham-controlled studies suggest placebo effects contribute to acute pain relief following mindfulness interventions. However, the specific effects of mindfulness processes and their interaction with placebo effects remain unclear. This study aimed to characterize the role of mindfulness and placebo processes underlying mindfulness-based pain attenuation. Both treatment (focused-attention mindfulness vs sham) and instruction ("told mindfulness" vs "told sham") were manipulated in a balanced placebo design. Changes in acute heat pain were evaluated in 153 healthy adults randomized to receive 6 x 20 minutes of one of the four treatment by instruction interventions or no treatment. Participants receiving any intervention demonstrated improved pain outcomes (unpleasantness, intensity and tolerance) relative to no treatment. The instruction manipulation increased expectation for pain relief in those told mindfulness relative to told sham, but there were no main effects or interactions of treatment or instruction on pain outcomes. However, irrespective of actual intervention received, the belief of receiving mindfulness predicted increased pain threshold and tolerance, with expectancy fully mediating the effect on pain tolerance. These findings suggest a lack of specific effects of mindfulness and instruction on acute pain. Nonetheless, participants' expectancies and beliefs about the treatment they received did predict pain relief. Together with the overall improvement following any intervention, these findings suggest that expectancy and belief may play a stronger role in attenuating acute pain in novices following brief mindfulness interventions than the actual mindfulness-specific processes or instructions delivered.
Learn More >The basal ganglia modulate somatosensory pain pathways but it is unclear whether a common circuit exists to mitigate hyperalgesia in pain states induced by peripheral nociceptive stimuli. As a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNr) may be a candidate for this role. To test this possibility, we optogenetically modulated SNr GABAergic neurons and examined pain thresholds in freely behaving male mice in inflammatory and neuropathic pain states as well as comorbid depression in chronic pain. We observed that stimulation of either SNr GABAergic neurons or their projections to the subthalamic nucleus (STN) significantly alleviated nociceptive responses in all pain states on the contralateral side and comorbid depression in chronic pain, and that this analgesic effect was eliminated when SNr-STN GABAergic projection was blocked. However, SNr modulation did not affect baseline pain thresholds. We also found that SNr-STN GABAergic projection was attenuated in pain states, resulting in disinhibition of STN neurons. Thus, impairment of the SNr-STN GABAergic circuit may be a common pathophysiology for the maintenance of hyperalgesia in both inflammatory and neuropathic pain states and the comorbid depression in chronic pain; compensating this circuit has potential to effectively treat related pain conditions.
Learn More >Juvenile fibromyalgia (JFM) is a prevalent chronic pain condition affecting children and adolescents worldwide during a critical period of brain development. To date, no published studies have addressed the pathophysiology of JFM. Here we characterize gray matter volume (GMV) alterations in JFM patients for the first time and investigate their functional and clinical relevance.
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