Long-term potentiation of neuronal excitation by neuron-glia interactions in the rat spinal dorsal horn

By imaging neuronal excitation in rat spinal cord slices with a voltage-sensitive dye, we examined the role of glial cells in the P2X receptor agonist alpha beta-methylene ATP (alpha beta meATP)-triggered long-term potentiation (LTP) in the dorsal horn. Bath application of alpha beta meATP potentiated neuronal excitation in the superficial dorsal horn. The potentiation was inhibited in the presence of the P2X receptor antagonists TNP-ATP, PPADS and A-317491, and was not induced in slices taken from rats neonatally treated with capsaicin. These results suggest that alpha beta meATP acts on P2X receptors, possibly P2X(3) and/or P2X(2/3), in capsaicin-sensitive primary afferent terminals. Furthermore, the potentiation was inhibited by treatment with the glial metabolism inhibitor monofluoroacetic acid. Results obtained with the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, and antibodies to TNF-alpha and IL-6, as well as by double immunolabelling of activated p38 MAPK with markers of astrocytes and microglia, demonstrated that alpha beta meATP activated p38 MAPK in astrocytes, and that the presence of proinflammatory cytokines and p38 MAPK activation were necessary for the induction of alpha beta meATP-triggered LTP. These findings indicate that glial cells contribute to the alpha beta meATP-induced LTP, which might be part of a cellular mechanism for the induction of persistent pain.