An Emerging New Paradigm in Opioid Withdrawal: A Critical Role for Glia-Neuron Signaling in the Periaqueductal Gray

Figure 1

Possible cellular/molecular mechanisms of glia-to-neuron interaction in the PAG in morphine withdrawal. Morphine binds to MD-2 and induces TLR4 oligomerization on the glial cell network to induce synthesis of TNFα through possible TRAF6 and NF-κB pathways, and so forth. Glial TNFα binds the TNFRI on the neurons to induce the phosphorylation of ERK, further the phosphorylation of CREB. TNFRI signal may induce phosphorylation (P) of NMDA receptor to increase Ca²⁺ influx. This increase in intracellular Ca²⁺ leads to several downstream effects including activation of CaM, adenylyl cyclase, cAMP, and further activation of PKA and changes of gene expression (CREB and Fos). GPCR may be activated to induce adenylyl cyclase and PKA activation and to increase gene transcription (CREB and Fos). GPCR: G-protein coupled receptor; glu: glutamate; CaM: calmodulin; NMDA-R: N-methyl-D-aspartate receptor.