Fig. 2.

Four-way neuron-glial interactions in spinal nociceptive processing. A. Decreased GABAergic inhibition in the spinal dorsal horn induced by lipopolysaccharide (LPS) activation of microglia through TLR4, IL-1β release from microglia, suppressed astrocytic glutamate transporter activity after IL-1β-induced GLT endocytosis, and reduced glutamate-glutamine cycle-dependent GABA synthesis in presynaptic neurons [Adapted from 77,78**]. Reduced GABAergic inhibition unleashes postsynaptic excitatory neurons and contributes to pain hypersensitivity. B. Descending 5-HT-induced neuron-glial interactions and related signaling cascade that underlies pain hypersensitivity. Descending serotonin (5-HT) activates 5-HT3 receptors on spinal neurons, followed by a signaling cascade that involves release of neuronal CX3CL1, microglial IL-18, and astrocytic IL-1β and activation of their respective receptors CX3CR1 (microglia), IL18R (astrocytes) and IL-1R (neurons) [Adapted from 71]. IL-1R facilitates NMDA receptor activity that leads to neuronal hyperexcitability and behavioral hyperalgesia. Abbreviations: GABA, gamma-Aminobutyric acid; LPS, lipopolysaccharide; NMDAR, N-methyl-D-aspartate receptor; see Fig. 1 caption for other abbreviations.