A novel rodent neck pain model of facet-mediated behavioral hypersensitivity: implications for persistent pain and whiplash injury

Clinical, epidemiological, and biomechanical studies suggest involvement of cervical facet joint injuries in neck pain. While bony motions can cause injurious tensile facet joint loading, it remains speculative whether such injuries initiate pain. There is currently a paucity of data explicitly investigating the relationship between facet mechanics and pain physiology. A rodent model of tensile facet joint injury has been developed using a customized loading device to apply 2 separate tensile deformations (low, high; n=5 each) across the C6/C7 joint, or sham (n=6) with device attachment only. Microforceps were rigidly coupled to the vertebrae for distraction and joint motions tracked in vivo. Forepaw mechanical allodynia was measured postoperatively for 7 days as an indicator of behavioral sensitivity. Joint strains for high (33.6±3.1%) were significantly elevated (p\u3c0.005) over low (11.1±2.3%). Digitization errors (0.17±0.20%) in locating bony markers were small compared to measured strains. Allodynia was significantly elevated for high over low and sham for all postoperative days. However, allodynia for low injury was not different than sham. A greater than three-fold increase in total allodynia resulted for high compared to low, corresponding to the three-fold difference in injury strain. Findings demonstrate tensile facet joint loading produces behavioral sensitivity that varies in magnitude according to injury severity. These results suggest that a facet joint tensile strain threshold may exist above which pain symptoms result. Continued investigation into the relationship between injury mechanics and nociceptive physiology will strengthen insight into painful facet injury mechanisms

Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson's Disease.

Parkinson's disease (PD) exhibits systemic effects on the human metabolism, with emerging roles for the gut microbiome. Here, we integrate longitudinal metabolome data from 30 drug-naive, de novo PD patients and 30 matched controls with constraint-based modeling of gut microbial communities derived from an independent, drug-naive PD cohort, and prospective data from the general population. Our key results are (1) longitudinal trajectory of metabolites associated with the interconversion of methionine and cysteine via cystathionine differed between PD patients and controls; (2) dopaminergic medication showed strong lipidomic signatures; (3) taurine-conjugated bile acids correlated with the severity of motor symptoms, while low levels of sulfated taurolithocholate were associated with PD incidence in the general population; and (4) computational modeling predicted changes in sulfur metabolism, driven by A. muciniphila and B. wadsworthia, which is consistent with the changed metabolome. The multi-omics integration reveals PD-specific patterns in microbial-host sulfur co-metabolism that may contribute to PD severity

7th Drug hypersensitivity meeting: part two

No abstract availabl

ATP release via anion channels

ATP serves not only as an energy source for all cell types but as an ‘extracellular messenger-for autocrine and paracrine signalling. It is released from the cell via several different purinergic signal efflux pathways. ATP and its Mg2+ and/or H+ salts exist in anionic forms at physiological pH and may exit cells via some anion channel if the pore physically permits this. In this review we survey experimental data providing evidence for and against the release of ATP through anion channels. CFTR has long been considered a probable pathway for ATP release in airway epithelium and other types of cells expressing this protein, although non-CFTR ATP currents have also been observed. Volume-sensitive outwardly rectifying (VSOR) chloride channels are found in virtually all cell types and can physically accommodate or even permeate ATP4- in certain experimental conditions. However, pharmacological studies are controversial and argue against the actual involvement of the VSOR channel in significant release of ATP. A large-conductance anion channel whose open probability exhibits a bell-shaped voltage dependence is also ubiquitously expressed and represents a putative pathway for ATP release. This channel, called a maxi-anion channel, has a wide nanoscopic pore suitable for nucleotide transport and possesses an ATP-binding site in the middle of the pore lumen to facilitate the passage of the nucleotide. The maxi-anion channel conducts ATP and displays a pharmacological profile similar to that of ATP release in response to osmotic, ischemic, hypoxic and salt stresses. The relation of some other channels and transporters to the regulated release of ATP is also discussed

Targeting histone lysine demethylases - Progress, challenges, and the future.

N-Methylation of lysine and arginine residues has emerged as a major mechanism of transcriptional regulation in eukaryotes. In humans, N(ε)-methyllysine residue demethylation is catalysed by two distinct subfamilies of demethylases (KDMs), the flavin-dependent KDM1 subfamily and the 2-oxoglutarate- (2OG) dependent JmjC subfamily, which both employ oxidative mechanisms. Modulation of histone methylation status is proposed to be important in epigenetic regulation and has substantial medicinal potential for the treatment of diseases including cancer and genetic disorders. This article provides an introduction to the enzymology of the KDMs and the therapeutic possibilities and challenges associated with targeting them, followed by a review of reported KDM inhibitors and their mechanisms of action from kinetic and structural perspectives. This article is part of a Special Issue entitled: Methylation: A Multifaceted Modification - looking at transcription and beyond