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Naturally occurring psychedelics have been used for a long time as remedies or in religious ceremonies and recreational activities. Recent studies have proven the therapeutic potential of some psychedelic compounds to safely treat a wide range of diseases such as anxiety, depression, migraine, and addiction. It is hypothesized that psychedelic compounds like tryptamines can exert their effects by two possible mechanisms: binding to the transmembrane serotonin receptor and/or modifying the properties of the neuronal membrane that can alter the conformational equilibrium and desensitize receptors. The impact of three different tryptamine class compounds with a tertiary amine (dimethyltryptamine, bufotenine, and 5-MeO-DMT) in both neutral and charged forms on a model bilayer lipid membrane are studied using all-atom MD simulations. All compounds partition into the bilayer, and change membrane properties, but to different extents. We determine the tendency of compounds to partition into the membrane by free energy calculations. Neutral tryptamines partition into the bilayer almost completely. Dimethyltryptamine and 5-MeO-DMT cross the membrane spontaneously during the simulation time, but bufotenine does not, although it has the maximum effect on the structural properties of the membrane. However, protonated compounds partition partially into the bilayer and cannot pass through the middle of the membrane during the simulation time. In this way, subtle alteration of chemical structure can play a significant role in the improvement or deterioration of partitioning of these compounds into the bilayer and their passage across the membrane.
Learn More >Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.
Learn More >Rheumatoid arthritis (RA) is a chronic, systemic immune disease that causes joint affection and even disability. Activated macrophages play an important role in the pathogenesis and progression of RA by producing pro-inflammatory factors. The use of dexamethasone (DXM) is effective in relieving the intractable pain and inflammatory progression of RA. However, long-term use of DXM is strongly associated with increased rates of diabetes, osteoporosis, bone fractures, and mortality, which hinders its clinical use. In this study, the dextran sulfate-cisaconitic anhydride-dexamethasone (DXM@DS-cad-DXM) micelles were prepared to treat RA by selectively recognizing scavenger receptor (SR) on the activated macrophages. The potent targeting property of DXM@DS-cad-DXM micelles to SR was by fluorescence microscope. Additionally, the effective accumulation and powerful anti-inflammatory activity of DXM@DS-cad-DXM micelles were observed in the inflamed joints of adjuvant-induced arthritis (AIA) rats after intravenous administration. Overall, DXM@DS-cad-DXM micelles are a potentially effective nanomedicine for targeted therapy of RA.
Learn More >Low back pain (LBP) subgroup identification and management are a research priority. The clarification of subgroup differences could assist clinicians in clinical decisions contributing to a tailored treatment.
Learn More >Migraine is a common neurological disorder in developmental age, involving up to 20% of children and adolescents. Although gender differences in migraine epidemiology and clinical characteristics have been largely investigated in adulthood, this issue is considerably less known in pediatric patients. We aim at providing an overview of gender differences in pediatric migraine. The most recent literature was reviewed taking into account the epidemiological, pathophysiological, and clinical differences between boys and girls with migraine. Although many aspects need to undergo further investigation, we conclude that different aspects of childhood migraine syndrome may vary depending on the gender and age, especially with regard to pubertal development.
Learn More >Dysregulation of pain-associated genes in the dorsal root ganglion (DRG) is considered to be a molecular basis of neuropathic pain genesis. Fused in sarcoma (FUS), a DNA/RNA-binding protein, is a critical regulator of gene expression. However, whether it contributes to neuropathic pain is unknown. This study showed that peripheral nerve injury caused by the fourth lumbar (L4) spinal nerve ligation (SNL) or chronic constriction injury of the sciatic nerve produced a marked increase in the expression of FUS protein in injured DRG neurons. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5 expressing shRNA into the ipsilateral L4 DRG mitigated the SNL-induced nociceptive hypersensitivities in both male and female mice. This microinjection also alleviated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase ½ (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in the ipsilateral L4 dorsal horn. Furthermore, mimicking this increase through microinjection of AAV5 expressing full-length mRNA into unilateral L3/4 DRGs produced the elevations in the levels of p-ERK1/2 and GFAP in the dorsal horn, enhanced responses to mechanical, heat and cold stimuli, and induced the spontaneous pain on the ipsilateral side of both male and female mice in the absence of SNL. Mechanistically, the increased FUS activated the NF-κB signaling pathway by promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Our results indicate that DRG FUS contributes to neuropathic pain likely through the activation of NF-κB in primary sensory neurons.In the present study, we reported that FUS, a DNA/RNA-binding protein, is upregulated in injured DRG following peripheral nerve injury. This upregulation is responsible for nerve injury-induced translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from injured DRG neurons. Because blocking this upregulation alleviates nerve injury-induced nociceptive hypersensitivity, DRG FUS participates in neuropathic pain likely through the activation of NF-κB in primary sensory neurons. FUS may be a potential target for neuropathic pain management.
Learn More >The etiology of abdominal pain in post-infectious, diarrhea-predominant IBS (PI-IBS-D) is unknown and few treatment options exist. Catechol-O-methyltransferase (COMT), an enzyme that inactivates and degrades biologically active catecholamines, plays an important role in numerous physiologic processes, including modulation of pain perception. Our objective was to determine the mechanism(s) of how decreased colonic COMT in PI-IBS-D patients contributes to the chronic abdominal pain phenotype following enteric infections.
Learn More >Electronic devices featuring biomimetic behaviour as electronic synapses and neurons have motivated the emergence of a new era in information and humanoid robotics technologies. In the human body, a nociceptor is a unique sensory neuron receptor that is capable of detecting harmful signals, leading to the central nervous system initiating a motor response. Herein, a nickel-doped zinc oxide (NZO)/Au based memristor is fabricated for the first time and characterized for artificial nociceptor application. For this, the introduction of a nickel-doped zinc oxide (NZO) layer between P-Si and Au electrodes is used to eliminate the surface effects of the NZO layer, resulting in improved volatile threshold switching performance. Depending on the intensity, duration, and repetition rate of the external stimuli, this newly created memristor exhibits various critical nociceptive functions, including threshold, relaxation, allodynia, and hyperalgesia. The electron trapping/detrapping to/from the traps in the NZO layer is responsible for these nociceptive properties. This kind of NZO-based device produces a multifunctional nociceptor performance that is essential for applications in artificial intelligence systems, such as neural integrated devices with nanometer-sized features.
Learn More >Pruritus, which is the most frequent subjective symptom of psoriasis, may cause significant discomfort, embarrassment, and even interfere with patients normal daily activities. However, the perception of itch in various psoriasis subtypes remains unknown.
Learn More >The study was designed to evaluate the modulation of mTOR complex 1 (mTORC1) and IL-6 genes following the use of mirror therapy (MT) and pregabalin in complex regional pain syndrome type-1 patients. Two groups of 20 patients: MT group received MT and pregabalin, control therapy group received pregabalin. Neuropathic pain symptom inventory (NPSI), numeric rating scale – pain, modified motor activity log, SF-12 questionnaire for quality of life and IL-6 and mTORC1 expression were evaluated. Group MT demonstrated a statistically significant improvement in NPSI burning, NPSI allodynia and numeric rating scale pain scores, modified motor activity log and SF-12 scores. Significant downregulation of mTORC1 and IL-6 observed in both. MT is a significant adjunct to pregabalin in improving motor function, quality of life and alleviating pain in complex regional pain syndrome type 1. : CTRI/2019/01/017272 (ClinicalTrials.gov).
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