Glia
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Many studies have shown that adenosine triphosphate (ATP), as a neurotransmitter, is involved in plastic changes of synaptic transmission in central nervous system. In the present study, we tested whether extracellular ATP can induce long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn. The results showed the following: (1) ATP at a concentration of 0.3 mM induced spinal LTP of C-fiber-evoked field potentials, lasting for at least 5 h; (2) spinal application of 2',3'-O-(2,4,6-trinitrophenyl)adenosine-5-triphosphate (TNP-ATP; an antagonist of P2X(1-4) receptors), but not pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; an antagonist of P2X(1,2,3,5,7) receptors), 30 min before ATP blocked ATP-induced LTP, indicating that ATP may induce spinal LTP by activation of P2X(4) receptors; (3) at 60 min after LTP induction the level of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) was significantly elevated and at 180 min after LTP the number of P2X(4) receptors increased significantly; both p-p38 and P2X(4) receptors were exclusively co-located with the microglia marker, but not with neuronal or astrocyte marker; (4) spinal application of TNP-ATP but not PPADS prevented p38 activation; (5) spinal application of SB203580, a p38 MAPK inhibitor, prevented both spinal LTP and the upregulation of P2X(4) receptors. The results suggested that ATP may activate p38 MAPK by binding to intrinsic P2X(4) receptors in microglia, and subsequently enhance the expression of P2X(4) receptors, contributing to spinal LTP.
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The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. ⋯ The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.