Fig. 1

Stabilization of spines by direct physical contact with PAP in pathological pain. Schematic shows the direct and physical contacts between astrocytes and neuronal synapse. ① When repetitive nociceptive stimuli are transmitted in the spinal cord, the voltage-gated Ca²⁺ channel (VGCC) mediates Ca²⁺ influx in response to membrane depolarization and the intracellular Ca²⁺ triggers glutamate release from synaptic vesicles. ② Cell adhesion molecules (CAMs) such as neurexin-neuroligin or ephrin-Eph mediate direct physical contacts between PAPs and synaptic regions. ③ Gliotransmitters are released from PAPs and strengthen the synaptic transmission. Among them, the released ATP from astrocytes activates purinergic receptors such as P2X (ligand-gated nonselective cation channel) and P2Y (ligand-gated G protein coupled receptor) located in pre- and postsynaptic regions. ④ Increased glutamate in the synaptic cleft activates postsynaptic receptors such as AMPA and NMDA receptors, resulting in increased excitatory postsynaptic currents (EPSCs) and enhanced the synaptic transmission. ⑤ Finally, the body can recognize the pain in the chronic manner. However, it remains unclear whether astrocytic CAMs are really involved in chronic pain