The journal of pain : official journal of the American Pain Society
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The preprotachykinin A gene (ppt-A) codes for Substance P (SP), supports nociceptive sensitization, and modulates inflammatory responses after incision. Repeated opioid use produces paradoxical pain sensitization-termed opioid-induced hyperalgesia (OIH) -which can exacerbate pain after incision. Here the contribution of SP to peri-incisional nociceptive sensitization and nociceptive mediator production after opioid treatment was examined utilizing ppt-A knockout (-/-) mice and the neurokinin (NK1) receptor antagonist LY303870. Less mechanical allodynia was observed in ppt-A(-/-) mice compared to wild types (wt) after morphine treatment both before and after incision. Moreover, LY303870 administered with morphine reduced incisional hyperalgesia in wt mice. Incision after saline or escalating morphine treatment upregulated skin IL-1β, IL-6, G-CSF and MIP-1α levels in ppt-A(-/-) and wt mice similarly. However, chronic morphine treatment greatly exacerbated increases in skin nerve growth factor levels after incision, an effect entirely dependent upon intact SP signaling. Additionally, SP dependent upregulation of prodynorphin, NMDA1 and NK1 receptor expression in spinal cord was seen after morphine treatment and incision. A similar pattern was seen for 5-HT3 receptor expression in tissue from dorsal root ganglia. Therefore, SP may work at both central and peripheral sites to enhance nociceptive sensitization after morphine treatment and incision. ⋯ These studies show that SP signaling modulates enhanced nerve growth factor production and changes in neuronal gene expression seen after incision in mice previously exposed to morphine.
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Protein tyrosine phosphorylation has been implicated in normal and pathological functions such as cell proliferation, migration and differentiation. Recently, some studies have shown that Src family kinases (SFKs) were involved in neurological disorders and neuropathic pain states in which microglial activation plays a role. In the formalin test, we have reported that microglia undergo at least 2 distinct stages of activation on the basis of signaling events regarding p38 mitogen-activated protein kinases (MAPK). Here, we investigated the involvement of SFKs signaling in a formalin pain animal model and the association with p38 MAPK. Our results showed that SFKs were activated in the spinal microglia beginning 1 day after peripheral formalin injection lasting for 7 days. Pretreatment with SFK specific inhibitor PP2 could not inhibit formalin-induced spontaneous pain behaviors. However, PP2 inhibited formalin injury, induced persistent mechanical hyperalgesia, and reversed microglial phospho-p38 expression as well using immunohistostaining and Western blot at day 3 and 7 after injection. Our results suggested that the activation of the Src/p38MAPK signaling cascade in spinal microglia contributed to late stage persistent mechanical hyperalgesia evoked by formalin injection into the paw. ⋯ This study presents unique properties of spinal microglial activation in a pain animal model. This finding could potentially help clinicians to further understand the contributions of spinal microglia to acute and persistent pain state.
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The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. ⋯ The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.