Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity

Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. While pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors Tgr5 and the Mas-gene-related GPCRs Mrgpra3 and Mrgprc11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intracolonic administration of individual TGR5, MRGPRA3, or MRGPRC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Coadministration of these agonists as an "itch cocktail" augmented hypersensitivity to colorectal distension and changed mouse behavior. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed TGR5, as well as the human ortholog MRGPRX1, and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders. - 2019 American Society for Clinical Investigation. All rights reserved.Work was supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (1083480 to SMB and DPP), an NHMRC R.D. Wright Biomedical Research Fellow (APP1126378 to SMB), and an Australian Research Council (ARC) Discovery Early Career Research Award (DE130100223 to AMH). NWB was supported by grants from the NIH (NS102722; DE026806; DK118971) and the US Department of Defence (W81XWH1810431).Scopu

Angular distribution of coherent bremsstrahlung

The angular distribution of the linearly polarised photon beam produced by coherent bremsstrahlung from an aligned diamond radiator has been measured at the MAMI A2 tagged photon facility. The measurements were made with a prototype position sensitive photon detector which utilises the pair production process and a double sided silicon strip detector. This polarised photon beam is used for nuclear and hadronic experiments and in their analysis the polarisation is obtained from a calculation, which matches the experimental intensity spectrum. As the polarisation is related to the photon beam angular distribution, the present measurements can be used to test this calculation. The overall agreement is found to be good although there are some regions where significant discrepancies exist

Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity

Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. Whilst pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors Tgr5 and the Mas-gene-related G protein-coupled receptors, Mrgpra3 and Mrgpra11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intra-colonic administration of individual TGR5, MRGPRA3, or MRGPRC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Co-administration of these agonists as an 'itch cocktail' augmented hypersensitivity to colorectal distension and changed mouse behaviour. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed TGR5 as well as the human ortholog MRGPRX1 and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders.Joel Castro, Andrea M. Harrington, TinaMarie Lieu, Sonia Garcia-Caraballo, Jessica Maddern, Gudrun Schober, Tracey O, Donnell, Luke Grundy, Amanda L. Lumsden, Paul Miller, Andre Ghetti, Martin S. Steinhoff, Daniel P. Poole, Xinzhong Dong, Lin Chang, Nigel W. Bunnett, Stuart M. Brierle

A focussing disc DIRC for PANDA

The PANDA experiment at the FAIR upgrade to GSI, Darmstadt, aims to study modern hadronic physics with unprecedented precision. Excellent particle identification of both charged and neutral particles is necessary to achieve the physics aims of PANDA. Two DIRC detectors are foreseen for charged particle identification, one in a barrel configuration for the central region, and the second in a disc configuration for the forward endcap. The design of the forward disc DIRC centres around the novel application of passive chromatic dispersion correction elements, allied with focussing optics, to achieve excellent resolution of Chernekov angle. A system of comprehensive prototype development will show the feasibility of the system. Key to the success of the prototype is fully understanding the production, transport and detection of the Cherenkov photons within the detector. Photon yield and its dependence on the polar angle of the detector have been measured. Observed photon yield is also the basis for subsequent studies into the benefit of chromatic dispersion correction elements, focussing and overall detector performance