Figure 5.

A schematic diagram illustrating our hypothesized model of soluble tumor necrosis factor (solTNF)-induced morphine tolerance development in the periaqueductal gray (PAG). Based on the major conclusions of our own data and the data of others, we hypothesize that chronic morphine binds to ventrolateral (vlPAG) Toll-like receptor 4 (TLR4) and leads to cleavage of transmembrane TNF (tmTNF) to solTNF by TNF-converting enzyme (TACE) to increase proinflammatory gene expression (TLR4, interleukin-1β (IL-1β)) and decrease astrocytic glutamate transporter mRNA (glutamate type I transporter (GLT-1) and glutamate aspartate transporter (GLAST)) in the vlPAG. These changes effectively increase the availability of glutamate in the synapse, thereby decreasing the ability of morphine to hyperpolarize GABAergic neurons. These changes associated with morphine tolerance prevent morphine from initiating signaling through the descending analgesic circuit. A full color version of this figure is available at the Neuropsychopharmacology journal online.