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Psilocybin is being studied for use in treatment-resistant depression.

Persistent mechanical pain hypersensitivity associated with peripheral inflammation, surgery, trauma, and nerve injury impairs patients' quality of life and daily activity. However, the molecular mechanism and treatment are not yet fully understood. Herein, we show that chemical ablation of isolectin B4-binding (IB4) afferents by IB4-saporin injection into sciatic nerves completely and selectively inhibited inflammation- and tissue injury-induced mechanical pain hypersensitivity while thermal and mechanical pain hypersensitivities were normal following nerve injury. To determine the molecular mechanism involving the specific types of mechanical pain hypersensitivity, we compared gene expression profiles between IB4 neuron-ablated and control dorsal root ganglion (DRG) neurons. We identified Tmem45b as one of 12 candidate genes that were specific to somatosensory ganglia and down-regulated by IB4 neuronal ablation. Indeed, Tmem45b was expressed predominantly in IB4 DRG neurons, where it was selectively localized in the Golgi apparatus of DRG neurons but not detectable in the peripheral and central branches of DRG axons. Tmem45b expression was barely detected in the spinal cord and brain. Although Tmem45b-knockout mice showed normal responses to noxious heat and noxious mechanical stimuli under normal conditions, mechanical pain hypersensitivity was selectively impaired after inflammation and tissue incision, reproducing the pain phenotype of IB4 sensory neuron-ablated mice. Furthermore, acute knockdown by intrathecal injection of Tmem45b small interfering RNA, either before or after inflammation induction, successfully reduced mechanical pain hypersensitivity. Thus, our study demonstrates that Tmem45b is essential for inflammation- and tissue injury-induced mechanical pain hypersensitivity and highlights Tmem45b as a therapeutic target for future treatment.

There is a critical need to diagnose and treat headache disorders in primary care settings. This is especially true for those who face systemic barriers to healthcare access due to racism or poverty. In order to target those at higher risk of disability associated with neurologic disease in our healthcare system, we embedded a specialized headache and neurology clinic within the Brigham and Women's Hospital Southern Jamaica Plain Community Health Center in Boston, MA. The goal was to create a sustainable, integrated clinic consistent with the CHC's racial justice mission, with an emphasis on equitable care, awareness of structural barriers to care, improved communication with primary care and inclusion of trainees as important members of a healthcare team. In its' first year, the clinic had over 400 patient visits, with a near-perfect rate of completion of consults. In addition to improved access to tertiary care headache services, successes have included improving continuity of care, cultivating a model of shared care with primary care practitioners and stimulating interest in headache medicine among staff and trainees. Challenges have included the use of staff time to complete prior authorizations, and the need to find or develop Spanish-language and culturally appropriate patient educational resources. By providing care within the patient's medical home, the headache specialist gains a deeper appreciation of a patient's social determinants of health and can readily access resources to navigate barriers. The personal and professional fulfillment that headache specialists may experience while doing this important work could help protect against burnout. Sustainability depends on ensuring equitable provider reimbursement; departmental and institutional support is essential. We believe this clinic can serve as a model for specialists throughout the United States who wish to improve the delivery of care to patient populations who face access barriers.

Stigma is increasingly recognized as an important social feature of living with migraine.

To establish a new rat model of craniofacial myalgia, and to clarify which central nervous system pathways are activated in the model.

Perioperative neurocognitive disorders (PND) is a common complication that occurs among elderly patients in the perioperative course. Current clinical evidence has shown that isoflurane exposure could cause cognitive decline but the exact molecular mechanisms remain unclear. As both NMDARs-dependent synaptic plasticity and histone acetylation play vital roles in processing learning and memory, we postulated that these alternations might occur in the isoflurane-associated PND. Here, we found that isoflurane impaired fear memory in aged mice, decreased GluN2B-containing NMDA receptors phosphorylation and trafficking, as well as the expression of EphB2, a key regulator of synaptic localization of NMDA receptors. We also identified that isoflurane could increase the expression of HDAC2, which was significantly enriched at the ephb2 gene promoter and regulated the transcription of ephb2. Furthermore, we showed that Suberoylanilide hydroxamic acid (SAHA), a non-selective HDAC inhibitor or knocking-down HDAC2 rescued the cognitive dysfunction in isoflurane-treated aged mice via increasing acetylation of H3Ac, expression of EphB2 and promoting NMDA receptor trafficking. Collectively, our study highlighted the crucial role of histone posttranslational modifications for EphB2-GluN2B signals in isoflurane-associated PND and modulating HDAC2 might be a new therapeutic strategy for isoflurane-associated PND.

Exchange proteins directly activated by cAMP (EPAC) are guanine nucleotide exchange factors for the small GTPases, Rap1 and Rap2. They regulate several physiological functions and mitigation of their activity has been suggested as a possible treatment for multiple diseases such as cardiomyopathy, diabetes, chronic pain, and cancer. Several EPAC-specific modulators have been developed, however studies that quantify their structure-activity relationships are still lacking. Here we propose a quantitative structure-activity relationship (QSAR) model for a series of EPAC-specific compounds. The model demonstrated high reproducibility and predictivity and the predictive ability of the model was tested against a series of compounds that were unknown to the model. The compound with the highest predicted affinity was validated experimentally through fluorescence-based competition assays and NMR experiments revealed its mode of binding and mechanism of action as a partial agonist. The proposed QSAR model can, therefore, serve as an effective screening tool to identify promising EPAC-selective drug leads with enhanced potency.

As an important member of ion channels family, the voltage-gated sodium channel (VGSC/Na) is associated with a variety of diseases, including epilepsy, migraine, ataxia, etc., and has always been a hot target for drug design and discovery. Many subtype-selective modulators targeting VGSCs have been reported, and some of them have been approved for clinical applications. However, the drug design resources related to VGSCs are insufficient, especially the lack of accurate and extensive compound data toward VGSCs. To fulfill this demand, we develop the Voltage-gated Sodium Channels Database (VGSC-DB). VGSC-DB is the first open-source database for VGSCs, which provides open access to 6055 data records, including 3396 compounds from 173 references toward nine subtypes of Nas (Na1.1 ~ Na1.9). A total of 28 items of information is included in each data record, including the chemical structure, biological activity (IC/EC), target, binding site, organism, chemical and physical properties, etc. VGSC-DB collects the data from small-molecule compounds, toxins and various derivatives. Users can search the information of compounds by text or structure, and the advanced search function is also supported to realize batch query. VGSC-DB is freely accessible at http://cadd.zju.edu.cn/vgsc/ , and all the data can be downloaded in XLSX/SDF file formats.

Acute burn pain is difficult to manage, and poorly managed pain can lead to deleterious consequences such as post-traumatic stress disorder, prolonged recovery, chronic pain and long-term dependence on opioids. Understanding the role of nursing in promoting self-efficacy and minimizing opioid use is valuable. It is unknown whether strategic efforts aimed at enhancing patient self-efficacy will improve pain managment and lessen opioid requirements in the adult burn population.

Features of multisystem inflammatory syndrome in children (MIS-C) overlap with other syndromes, making the diagnosis difficult for clinicians. We aimed to compare clinical differences between patients with and without clinical MIS-C diagnosis and develop a diagnostic prediction model to assist clinicians in identification of patients with MIS-C within the first 24 hours of hospital presentation.