Fig. 10

Schematic of postulated mechanisms of microglial activation by morphine but not by ZH853. Proposed mechanisms by which morphine activates glia or enhances trauma-induced activation include (1) induction of neuronal CGRP that activates microglial CGRP receptors [45], (2) binding at toll-like receptors (TLRs) alone or in concert with damage- or pathogen-associated molecular patterns (DAMPs, PAMPS) [46], and (3) activation of purinergic P2X receptors including by upregulation through MOR [47] (but see [48]). Each of these mechanisms causes phosphorylation of the mitogen-activated protein kinase (MAPK) p38 to increase transcription and translation of cytokines, including interleukin-1β (IL-1β [49], example shown), P2X7R activation also induces NOD-like receptor family, pyrin domain containing 3 (NLRP3) to become a complex (inflammasome) [50] that contains and releases active caspase-1 which cleaves pro-IL-1β into the active cytokine IL-1β [51]. IL-1β activates IL-1 receptors on astrocytes and neurons, further increasing inflammation. Ultimately, this proinflammatory pathway causes dorsal horn plasticity that leads to central sensitization and increased pain [52]