Figure 10.

Schematic illustration of neuron–glia and glia–glia interactions in the spinal cord dorsal horn in bone cancer pain. Bone cancer-induced hyperexcitability of primary sensory neurons (peripheral sensitization) causes excessive release of neurotransmitters or neuromodulators from central afferent terminals to activate adjacent glia and postsynaptic neurons in the spinal dorsal horn. P2X7R is upregulated in microglia and activated by ATP, which is produced by activated astrocytes, as well as by primary afferent terminals and spinal cord neurons. Upon activation, microglia synthesize and release IL-18 via phosphorylation of p38 MAPK, leading to enhanced excitatory synaptic transmission and neuronal hyperactivity in the dorsal horn (central sensitization). As a result of this IL-18-mediated neuromodulation in the spinal cord pain circuit, pain sensitivity is enhanced. Solid lines indicate the pathways and mechanisms demonstrated in this study. Dashed lines indicate other possible pathways and mechanisms.