Mol Pain
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Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia—spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo–in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. ⋯ These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain.
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We recently demonstrated that brain natriuretic peptide is expressed in the dorsal root ganglia, and that brain natriuretic peptide is required for normal detection of pruritogens. We further showed that the receptor for brain natriuretic peptide, natriuretic peptide receptor A, is present in the spinal cord, and elimination of these neurons profoundly attenuates scratching to itch-inducing compounds. However, the potential modulatory roles of brain natriuretic peptide in nociception, inflammation, and neuropathic mechanisms underlying the sensation of pain have not been investigated in detail. ⋯ These results demonstrate that brain natriuretic peptide is not essential for pain-related behaviors.
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The aim of this study was to predict key genes and their relationships for anxiety and nociceptive sensitivity related to Comt1 genetype. ⋯ Ego network analysis was a useful and comprehensive method for biomarkers screening. Several modules such as module 3 and module 36 were important subnetworks. Potential genes in these modules including ADCYs, GNAI1, DRD2, PNOC, CCR2, DRD2, and LPAR1 might be important genes in the research of anxiety and nociceptive sensitivity.
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Background Neuropathic pain is a major pathology of the central nervous system associated with neuroinflammation. Ryk (receptor-like tyrosine kinase) receptors act as repulsive axon-guidance molecules during development of central nervous system and neural injury. Increasing evidence suggests the potential involvement of Wnt/Ryk (wingless and Int) signaling in the pathogenesis of neuropathic pain. ⋯ Further, it also blocked Ca2+-dependent signals including CaMKII and PKCγ, subsequent release of CCL2 (CCR-like protein) in the dorsal horn. An in vitro study showed that inactivating Ryk receptors with anti-Ryk antibodies or lentiviral Ryk shRNA led to the inactivation of Wnt1 for excitatory synaptic transmission in spinal slices and subsequent decrease in CCL2 expression in the dorsal root ganglia neurons. Conclusion These studies demonstrate the existence of critical crosstalk between astrocytes and unmyelinated fibers, which indicate the presynaptic mechanism of Ryk in cytokine transmission of neuropathic pain and the therapeutic potential for Wnt/Ryk signaling pathway in the treatment of neuropathic pain.
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Objective Cancer-induced bone pain is a common clinical problem in breast cancer patients with bone metastasis. However, the mechanisms driving cancer-induced bone pain are poorly known. Recent studies show that a novel protease, asparaginyl endopeptidase (AEP) plays crucial roles in breast cancer metastasis and progression. ⋯ Targeted suppression of AEP with specific small compounds significantly reduced the bone pain while purified recombinant AEP proteins increased bone pain. Conclusions AEP aggravate the development of breast cancer bone metastasis and bone pain by increasing the expression of neurotrophin receptors. AEP might be an effective target for treatment of breast cancerinduced bone pain.