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Dendritic cells (DCs) of the cDC2 lineage initiate allergic immunity and in the dermis are marked by their expression of CD301b. CD301b dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b DCs to the draining lymph node (dLN). Using a model of cutaneous allergen exposure, we show that allergens directly activated TRPV1 sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons released the neuropeptide Substance P, which stimulated proximally located CD301b DCs through the Mas-related G-protein coupled receptor member A1 (MRGPRA1). Substance P induced CD301b DC migration to the dLN where they initiated T helper-2 cell differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of an allergic immune response.
Learn More >Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria.
Learn More >Previous studies demonstrate decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy(IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. Here we prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT naïve patients with neuropathic pain.
Learn More >The present study examines the possible effect of the novel hybrid molecule JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-411-dihydro-1H-pyrido[2,3-b] [1,5] benzodiazepine) on pain-related behaviours in a persistent pain model (5% formalin test) and in the neutrophil migration events during the inflammatory process. It further introduces JM-20 in a chronic constriction injury (CCI) model to clarify the possible subjacent mechanisms with its consequent clinical relevance. A single administration of JM-20 (20 or 40 mg/kg, per os [p.o.]) decreased licking/biting exclusively in the tonic phase of the formalin test in a GABA/benzodiazepine (BZD) receptor antagonist flumazenil-sensitive manner. JM-20 reduced in vivo neutrophil migration, rolling and adhesion to the endothelium induced by intraperitoneal administration of carrageenan in mice. In addition, plasma extravasation and tumour necrosis factor alpha production in the peritoneal fluid were decreased. Treatment with JM-20 (20 mg/kg, p.o.) for 7 days after CCI reduced mechanical hypersensitivity in a NG-monomethyl-l-arginine (L-NMMA)/methylene blue/glibenclamide-sensitive manner. Histopathological signs of Wallerian degeneration (WD) of the sciatic nerve were also attenuated, as well as interleukin-1 beta release in the spinal cord. The nitrate/nitrite concentration was increased centrally and did not show differences at the peripheral nerve level. The findings of this study suggest JM-20 can decrease persistent pain. A transient activity of its BDZ portion on nociceptive pathways mediated by GABA/BZD receptors in association with its anti-inflammatory properties could be at least partially involved in this effect. JM-20 decreased CCI-induced mechanical hypersensitivity via the l-arginine/nitric oxide (NO)/cyclic GMP-sensitive ATP-sensitive potassium channel pathway. Its neuroprotective ability by preventing WD could be implicated in its anti-neuropathic mechanisms.
Learn More >Calcitonin gene-related peptide (CGRP) receptor antagonists have been shown clinically to be effective treatments for migraine. Zavegepant (BHV-3500, BMS-742413) is a high affinity antagonist of the CGRP receptor (hCGRP K = 0.023 nM) that has demonstrated efficacy in the acute treatment of migraine with intranasal delivery in a Phase 2/3 trial, despite showing low oral bioavailability in rats (F = 1.7%). Using zavegepant as a template, we sought to improve oral bioavailability through a series of azepinones which were designed in an attempt to reduce the number of rotatable bonds. These efforts led to the discovery of compound 21 which was able to mostly maintain high affinity binding (hCGRP K = 0.100 nM) and in vivo efficacy in the marmoset facial blood flow assay, while greatly improving oral bioavailability (rat F = 17%).
Learn More >In complex regional pain syndrome (CRPS), hyperalgesia encompasses uninjured sites on the ipsilateral side of the body and may also include the special senses, as auditory discomfort often is greater on the CRPS-affected side. To determine whether this hemi-lateral hyperalgesia involves the visual system, the discomfort threshold to a light-source that increased in intensity at 100 lux/second from 500 to 3,600 lux was investigated for each eye, and the nasal and temporal half of each visual field, in 33 patients with CRPS and 21 pain-free controls. Recent headache history was reviewed and, in patients with CRPS, sensitivity to mechanical and thermal stimuli was assessed in all four limbs and on each side of the forehead. In addition, the pupils were photographed in dim and bright light. The visual discomfort threshold was lower in patients than controls and was lower on the CRPS-affected than unaffected side (p < .001), indicating photophobia. Visual discomfort was unrelated to pupil diameter. Headache frequency was greater in CRPS patients than controls, and unilateral headaches were more likely to be on the CRPS-affected than contralateral side. Similarly, mechanical and thermal hyperalgesia was greater in the CRPS-affected than contralateral limb and was greater ipsilateral than contralateral to CRPS in the forehead and non-symptomatic limbs. Ipsilateral photophobia was associated with mechanical and thermal hyperalgesia in the ipsilateral forehead but not the CRPS-affected limb. Together, these findings suggest that aberrant processing of nociceptive input in the ipsilateral trigeminal-medullary region of the brainstem contributes to visual discomfort in CRPS.
Learn More >Conditioned pain modulation (CPM) protocols index magnitude of descending pain inhibition. This study evaluated whether degree of CPM, controlling for CPM expectancy confounds, was associated with analgesic and subjective responses to morphine, and whether chronic pain status or sex moderated these effects.
Learn More >In this study, patients with painful diabetic neuropathy (PDN) were trained using an experimental pain paradigm in an attempt to enroll a subset of patients who are "pain connoisseurs" and therefore more able to discriminate between active and placebo treatments.
Learn More >Head motion is a major confounding factor impairing the quality of functional magnetic resonance imaging (fMRI) data. In particular, head motion can reduce analytical efficiency, and its effects are still present even after preprocessing. To examine the validity of motion removal and to evaluate the remaining effects of motion on the quality of the preprocessed fMRI data, a new metric of group quality control (QC), dissimilarity of functional connectivity, is introduced. Here, we investigate the association between head motion, represented by mean framewise displacement, and dissimilarity of functional connectivity by applying four preprocessing methods in two independent resting-state fMRI datasets: one consisting of healthy participants (N = 167) scanned in a 3T GE-Discovery 750 with longer TR (2.5 s), and the other of chronic back pain patients (N = 143) in a 3T Siemens Magnetom Prisma scanner with shorter TR (0.555 s). We found that dissimilarity of functional connectivity uncovers the influence of participant's motion, and this relationship is independent of population, scanner, and preprocessing method. The association between motion and dissimilarity of functional connectivity, and how the removal of high-motion participants affects this association, is a new strategy for group-level QC following preprocessing.
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