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Fig. 10 | Journal of Neuroinflammation

Fig. 10

From: Morphine immunomodulation prolongs inflammatory and postoperative pain while the novel analgesic ZH853 accelerates recovery and protects against latent sensitization

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]

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