Pain: How macrophages mediate inflammatory pain via ATP signaling
Macrophages have important roles in the induction and resolution of inflammation, but the intracellular pathways from inflammatory signals to pain response remain unclear. A recent study demonstrates that the P2X4 receptor mediates inflammatory pain by inducing formation of the potent lipid mediator prostaglandin E2.
Available from: PubMed Central
- "ATP, working through different (yet unknown) plasticity processes, eventually confers novel maladaptive activity to neurons and non-neuronal cells in the entire tissue. Together with ATP, several soluble factors and neuropeptides like nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), cytokines and prostaglandins cooperate either to directly activate nociceptors (as well as to induce secondary long-lasting chain of genomic changes) or to evoke indirect paracrine responses after non-neuronal cells activation (Shu and Mendell, 2001; Giniatullin et al., 2008; Jakobsson, 2010; Kuner, 2010; Cady et al., 2011). "
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ABSTRACT: Increasing evidence indicates the importance of extracellular adenosine triphosphate (ATP) in the modulation of neuronal function. In particular, fine control of ATP release and the selective and discrete ATP receptor operation are crucial elements of the crosstalk between neuronal and non-neuronal cells in the peripheral and central nervous systems. In peripheral neurons, ATP signaling gives an important contribution to neuronal sensitization, especially that involved in neuropathic pain. Among other subtypes, P2X3 receptors expressed on sensory neurons are sensitive even to nanomolar concentrations of extracellular ATP, and therefore are important transducers of pain stimuli. P2X3 receptor function is highly sensitive to soluble factors like neuropeptides and neurotrophins, and is controlled by transduction mechanisms, protein-protein interactions and discrete membrane compartmentalization. More recent findings have demonstrated that P2X3 receptors interact with the synaptic scaffold protein calcium/calmodulin-dependent serine protein kinase (CASK) in a state dependent fashion, indicating that CASK plays a crucial role in the modulation of P2X3 receptor stability and efficiency. Activation of P2X3 receptors within CASK/P2X3 complex has important consequences for neuronal plasticity and possibly for the release of neuromodulators and neurotransmitters. Better understanding of the interactome machinery of P2X3 receptors and their integration with other receptors and channels on neuronal surface membranes, is proposed to be essential to unveil the process of neuronal sensitization and related, abnormal pain signaling.
Available from: Ryan Patel
- "However, in response to induced peripheral inflammation, mice lacking the P2×4 receptor do not develop pain hypersensitivity and show a complete absence of inflammatory PGE2 in tissue exudates (Ulmann et al., 2010). The adverse side effects of non-steroidal anti-inflammatory drugs (NSAIDS) calls for the development of new anti-inflammatory drugs with analgesic properties, and so these findings suggest that targeting the macrophage-specific P2×4 receptor could be a useful principle in treating the early stages of osteoarthritis and other inflammatory pain diseases (Jakobsson, 2010). Interestingly, microglia also express the same surface markers as macrophages, including P2×4 receptors, ascribing multiple cellular targets to P2×4 receptor blockade for alleviating inflammatory pain (Zhuo et al., 2011). "
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ABSTRACT: This review selectively explores some areas of pain research that, until recently, have been poorly understood. We have chosen four topics that relate to clinical pain and we discuss the underlying mechanisms and related pathophysiologies contributing to these pain states. A key issue in pain medicine involves crucial events and mediators that contribute to normal and abnormal pain signaling, but remain unseen without genetic, biomarker or imaging analysis. Here we consider how the altered genetic make-up of familial pains reveals the human importance of channels discovered by preclinical research, followed by the contribution of receptors as stimulus transducers in cold sensing and cold pain. Finally we review recent data on the neuro-immune interactions in chronic pain and the potential targets for treatment in cancer-induced bone pain.
Available from: Edward D Högestätt
- "This is supported by our in vitro finding that activation of TRPA1 by AITC can up-regulate the COX-2 transcript in HEK 293 cells. Accordingly, a significant role of [Ca2+]i in regulating COX-2 expression in macrophages was recently reported49. Together these events would generate and maintain a TRPA1 and COX-dependent inflammation. "
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ABSTRACT: Transient receptor potential ankyrin 1 (TRPA1) is an ion channel involved in thermosensation and nociception. TRPA1 is activated by exogenous irritants and also by oxidants formed in inflammatory reactions. However, our understanding of its role in inflammation is limited. Here, we tested the hypothesis that TRPA1 is involved in acute inflammatory edema. The TRPA1 agonist allyl isothiocyanate (AITC) induced inflammatory edema when injected intraplantarly to mice, mimicking the classical response to carrageenan. Interestingly, the TRPA1 antagonist HC-030031 and the cyclo-oxygenase (COX) inhibitor ibuprofen inhibited not only AITC but also carrageenan-induced edema. TRPA1-deficient mice displayed attenuated responses to carrageenan and AITC. Furthermore, AITC enhanced COX-2 expression in HEK293 cells transfected with human TRPA1, a response that was reversed by HC-030031. This study demonstrates a hitherto unknown role of TRPA1 in carrageenan-induced inflammatory edema. The results also strongly suggest that TRPA1 contributes, in a COX-dependent manner, to the development of acute inflammation.
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