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 αβ-methylene ATP (αβmeATP)-triggered long-term potentiation (LTP) in the dorsal horn. Bath application of αβmeATP 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 αβmeATP acts on P2X receptors, possibly P2X3 and/or P2X2/3, 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-α (TNF-α) and interleukin (IL)-6, and antibodies to TNF-α and IL-6, as well as by double immunolabelling of activated p38 MAPK with markers of astrocytes and microglia, demonstrated that αβmeATP activated p38 MAPK in astrocytes, and that the presence of proinflammatory cytokines and p38 MAPK activation were necessary for the induction of αβmeATP-triggered LTP. These findings indicate that glial cells contribute to the αβmeATP-induced LTP, which might be part of a cellular mechanism for the induction of persistent pain.
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