P2X receptor channels in chronic pain pathways Bernier, Louis‐Philippe; Ase, Ariel R; Séguéla, Philippe
British journal of pharmacology,
June 2018, Volume:
175, Issue:
12
Journal Article
Peer reviewed
Open access
Chronic pain is a highly prevalent debilitating condition for which treatment options remain limited for many patients. Ionotropic ATP signalling through excitatory and calcium‐permeable P2X receptor ...channels is now rightfully considered as a critical player in pathological pain generation and maintenance; therefore, their selective targeting represents a therapeutic opportunity with promising yet untapped potential. Recent advances in the structural, functional and pharmacological characterization of rodent and human ATP‐gated P2X receptor channels have shed brighter light on the role of specific subtypes in the pathophysiology of chronic inflammatory, neuropathic or cancer pain. Here, we will review the contribution of P2X3, P2X4 and P2X7 receptors to chronic pain and discuss the opportunities and challenges associated with the pharmacological manipulation of their function.
Linked Articles
This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc
Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de ...novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology.
The parietal cortex is thought to be involved in visuomotor adaptation, yet it remains unclear whether it is specifically modulated by visuomotor prediction errors (i.e. PEs; mismatch between the ...predicted and actual visual consequences of the movement). One reason for this is that PEs tend to be associated with task errors, as well as changes in motor output and visual input, making them difficult to isolate. Here this issue is addressed using electroencephalography. A strategy (STR) condition, in which participants were instructed on how to counter a 45° visuomotor rotation, was compared to a condition in which participants had adapted to the rotation (POST). Both conditions were matched for task errors and movement kinematics, with the only difference being the presence of PEs in STR. Results revealed strong parietal modulations in current source density and low theta (2-4 Hz) power shortly after movement onset in STR vs. POST, followed by increased alpha/low beta (8-18 Hz) power during much of the post-movement period. Given recent evidence showing that feedforward and feedback information is respectively carried by theta and alpha/beta oscillations, the observed power modulations may reflect the bottom-up propagation of PEs and the top-down revision of predictions.
Microglia are highly motile cells that continuously monitor the brain environment and respond to damage-associated cues. While glucose is the main energy substrate used by neurons in the brain, the ...nutrients metabolized by microglia to support surveillance of the parenchyma remain unexplored. Here, we use fluorescence lifetime imaging of intracellular NAD(P)H and time-lapse two-photon imaging of microglial dynamics in vivo and in situ, to show unique aspects of the microglial metabolic signature in the brain. Microglia are metabolically flexible and can rapidly adapt to consume glutamine as an alternative metabolic fuel in the absence of glucose. During insulin-induced hypoglycemia in vivo or in aglycemia in acute brain slices, glutaminolysis supports the maintenance of microglial process motility and damage-sensing functions. This metabolic shift sustains mitochondrial metabolism and requires mTOR-dependent signaling. This remarkable plasticity allows microglia to maintain their critical surveillance and phagocytic roles, even after brain neuroenergetic homeostasis is compromised.
Canada’s National Forest Inventory (NFI) sampling program is designed to support reporting on forests at the national scale. On the other hand, continuous maps of forest attributes are required to ...support strategic analyses of regional policy and management issues. We have therefore produced maps covering 4.03 × 10
6
km
2
of inventoried forest area for the 2001 base year using standardised observations from the NFI photo plots (PP) as reference data. We used the k nearest neighbours (kNN) method with 26 geospatial data layers including MODIS spectral data and climatic and topographic variables to produce maps of 127 forest attributes at a 250 × 250 m resolution. The stand-level attributes include land cover, structure, and tree species relative abundance. In this article, we report only on total live aboveground tree biomass, with all other attributes covered in the supplementary data (
http://nrcresearchpress.com/doi/suppl/10.1139/cjfr-2013-0401
). In general, deviations in predicted pixel-level values from those in a PP validation set are greater in mountainous regions and in areas with either low biomass or sparse PP sampling. Predicted pixel-level values are overestimated at small observed values and underestimated at large ones. Accuracy measures are improved through the spatial aggregation of pixels to 1 km
2
and beyond. Overall, these new products provide unique baseline information for strategic-level analyses of forests (
https://nfi.nfis.org
).
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