Biophysical and pharmacological characterisation of recombinant and native rat P2X7 receptors

P2X7 receptors exhibit a mainly non-neuronal localisation on immune and glial cells and primarily function as non-selective cation channels. After prolonged or repeated exposure to agonist, functional and cellular changes occur: the formation of a large diameter pore, cell lysis and the release of mature, biologically active interleukin-1β (IL-1β) a potent inflammatory cytokine. It is this repertoire of functions, along with its localisation that underlies the hypothesis for its involvement in pain processing. The biophysics and pharmacology of rat P2X7 receptors were investigated using stable cell lines. Increases in the current amplitude were shown to be dependent upon the agonist concentration and current deactivation was agonist application number and voltage dependent. These results increased our understanding of the receptor, but have also had implications for the design of protocols to investigate antagonist potency and efficacy. GSK31418A was identified as a potent, reversible and voltage-independent antagonist of rat and human P2X7 receptors. GSK314181A was >10000 fold selective over P2X4 receptors and >1000 fold selective over P2X2/3 receptors. GSK314181A produced a significant reversal of FCA-induced hypersensitivity when profiled in vivo, providing further validation of the role of P2X7 receptors in inflammatory pain. Although the influence of glia cells on neuronal activity in the CNS is now well documented, the role of peripheral glia, Schwann cells and satellite cells of sensory ganglia, is less well established. Non-neuronal cells in DRG cultures were shown to express P2X7 receptors by pharmacological, biophysical and immunofluorescence techniques. Native P2X7 receptors expressed on these cells were shown to have many of the properties of recombinant P2X7 receptors, in regards to the response to agonist activation and pharmacology. Finally, I have shown that Lamotrigine is an effective inhibitor of recombinant rat and human P2X7 receptors and native P2X7 receptors expressed in DRG. The potent inhibition of human P2X7 by Lamotrigine was replicated with the chemical analogue and neuroprotective agent Sipatrigine. However, little effect was recorded for a P2X7 antagonist in two models of epileptiform activity studies

Surveillance of zoonotic infectious disease transmitted by small companion animals

The One Health paradigm for global health recognizes that most new human infectious diseases will emerge from animal reservoirs. Little consideration has been given to the known and potential zoonotic infectious diseases of small companion animals. Cats and dogs closely share the domestic environment with humans and have the potential to act as sources and sentinels of a wide spectrum of zoonotic infections. This report highlights the lack of a coordinated global surveillance scheme that monitors disease in these species and makes a case for the necessity of developing a strategy to implement such surveillance