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To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy.
Learn More >Migraine is a common disorder most typically presenting as headache and often associated with vertigo and motion sickness. It is a genetically complex condition with multiple genes ultimately contributing to the predisposition and development of this episodic neurological disorder. We identified a large American family of 29 individuals of which 17 members suffered from at least one of these disorders, migraine, vertigo, or motion sickness. Many of these individuals suffered from several simultaneously. We hypothesized that vertigo and motion sickness may involve genes that are independent to those directly contributing to migraine susceptibility.
Learn More >Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women.
Learn More >Transcutaneous electrical nerve stimulation (TENS) is commonly used for pain control. However, the effects of TENS on osteoarthritis (OA) pain and potential underlying mechanisms remain unclear.
Learn More >Interleukin-33 (IL-33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL-33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL-33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2 substantially reduced scratching behaviors in 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water-induced dry skin in mice. Intrathecal administration of the neutralizing anti-ST2 or anti-IL-33 antibody remarkably decreased the scratching response in DNFB-induced ACD mice. Expression of spinal IL-33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL-33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2 . Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL-33 pretreatment exacerbated gastrin-releasing peptide (GRP)-evoked scratching behaviors. This increased gastrin-releasing peptide receptor (GRPR) expression was abolished by St2 . Tnf-α upregulation was suppressed by St2 . Our results indicate that the spinal IL-33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2-STAT3 cascade activation, promoting TNF-α release to regulate the GRP/GRPR signaling-related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.
Learn More >Migraine is a debilitating condition, however, the pharmacological effects on central nervous system networks following successful therapy is poorly understood. Defining this neurocircuitry is critical to our understanding of the disorder and for the development of anti-migraine drugs. Using an established inflammatory soup (IS) model of migraine-like pathophysiology (N=12) compared to sham synthetic interstitial fluid (SIF) migraine induction (N=12), our aim was to evaluate changes in network-level functional connectivity following sumatriptan-naproxen infusion in awake, conscious, rodents (Sprague-Dawley rats). Sumatriptan-naproxen infusion fMRI data was analyzed using an independent competent analysis approach. Whole brain analysis yielded significant between-group (IS vs. SIF) alterations in functional connectivity across the cerebellar, default mode, basal ganglia, autonomic, and salience networks. These results demonstrate the large-scale anti-migraine effects of sumatriptan-naproxen co-administration following dural sensitization.
Learn More >The spinal gray matter region around the central canal, lamina X, is critically involved in somatosensory processing and visceral nociception. Although several classes of primary afferent fibers terminate or decussate in this area, little is known about organization and functional significance of the afferent supply of lamina X neurons. Using the hemisected ex vivo spinal cord preparation, we show that virtually all lamina X neurons receive primary afferent inputs, which are predominantly mediated by the high-threshold Aδ- fibers and C-fibers. In two-thirds of the neurons tested, the inputs were monosynaptic, implying a direct targeting of the population of lamina X neurons by the primary nociceptors. Beside the excitatory inputs, 48% of the neurons also received polysynaptic inhibitory inputs. A complex pattern of interactions between the excitatory and inhibitory components determined the output properties of the neurons, one-third of which fired spikes in response to the nociceptive dorsal root stimulation. In this respect, the spinal gray matter region around the central canal is similar to the superficial dorsal horn, the major spinal nociceptive processing area. We conclude that lamina X neurons integrate direct and indirect inputs from several types of thin primary afferent fibers and play an important role in nociception.
Learn More >To identify the factors associated with the excess risk of pain observed among older women compared with men.
Learn More >High-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has a good level of evidence of efficacy as a method for providing analgesic effects in patients with chronic pain. However, there is still no consensus regarding the parameters of stimulation to use and the detailed protocol to apply for therapeutic practice. In this article, we review the main technical points to address, and we propose a practical algorithm of how to use rTMS for chronic pain treatment in daily clinical practice.
Learn More >Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218 L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7d), physical restraint (3d), and forced swimming (3d). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.
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