Pain: how macrophages mediate inflammatory pain via ATP signaling.

Nature Reviews Rheumatology (Impact Factor: 10.25). 12/2010; 6(12):679-81. DOI: 10.1038/nrrheum.2010.175
Source: PubMed
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    ABSTRACT: In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models. The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling. Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw. TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare.
    PLoS ONE 02/2015; 10(2):e0117770. DOI:10.1371/journal.pone.0117770 · 3.53 Impact Factor
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    ABSTRACT: Pain represents a very large social and clinical problem since the insufficient pain relief during current treatment. Plasticity of pain receptors together with sensitization of sensory neurons, and the role of soluble mediators released from non-neuronal cells render difficult to understand the spatial and temporal scale of pain development, neuronal responses and disease progression. In pathological conditions, ATP is one of the most powerful mediators that activate P2X receptors that behave as sensitive ATP-detectors, such as neuronal P2X3 receptor subtypes and P2X4 and P2X7 receptors expressed on non-neuronal cells. Dissecting the molecular mechanisms occurring in sensory neurons and in accessory cells allow design appropriate tissue- and cell- targeted approaches to treat chronic pain.
    Current Medicinal Chemistry 10/2014; 22(7). DOI:10.2174/0929867321666141011195351 · 3.72 Impact Factor
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    ABSTRACT: Background: ATP/ADP-evoked spinal astrocyte activation plays a vital role in the development of neuropathic pain. We aim to investigate the role of mammalian target of rapamycin (mTOR) pathway on the spinal astrocyte activation in the neuropathic pain development in rats. Methods: Sprague Dawley (SD) rats were subjected to chronic constriction of the sciatic nerve (CCI). Rapamycin or ADP was intrathecally injected daily to explore their effects on spinal astrocyte activation and pain development. Expression of glial fibrillary acidic protein (GFAP) and mTOR in the spinal dorsal horn was assessed by immunohistochemistry. Von Frey hairs and Hargreaves paw withdrawal test were conducted to evaluate mechanical allodynia and thermal sensitivity, respectively. Firefly luciferase ATP assay was used to assess the change of ATP level in cerebrospinal fluid (CSF) and medium of cultured astrocytes. Results: GFAP expression was enhanced in the ipsilateral spinal dorsal horn from day 3 after surgery. GFAP and mTOR expression in the rat spinal dorsal horn on post-surgical day 14 was enhanced by daily intrathecal injection of ADP, which was inhibited by rapamycin. Rapamycin decreased lower mechanical pain threshold and the thermal withdrawal latency. Intrathecal injection of ADP enhanced the ATP release, which was partially inhibited by rapamycin. Study of cultured astrocytes indicated that ATP could be released from astrocytes. Conclusion: Our data demonstrated that ADP enhanced neuropathic pain in CCI rats, which was inhibited by rapamycin. This study indicates that targeting mTOR pathway could serve as a novel therapeutic strategy in neuropathic pain management.
    Neuroscience 06/2014; 275. DOI:10.1016/j.neuroscience.2014.06.030 · 3.33 Impact Factor