Translational neuroscience
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Spinal cord injury (SCI) is an extremely serious type of physical trauma observed in clinics. Neuropathic pain resulting from SCI has a lasting and significant impact on most aspects of daily life. Thus, a better understanding of the molecular pathways responsible for the cause of neuropathic pain observed in SCI is important to develop effective therapeutic agents and treatment strategies. ⋯ Moreover, blocking mTOR and PI3K decreased the enhanced levels of substance P and calcitonin gene-related peptide (CGRP) in the dorsal horn of SCI rats. We revealed specific signaling pathways leading to SCI-evoked neuropathic pain, including the activation of PI3K, mTOR and its downstream signaling pathways. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of neuropathic pain often observed in patients with SCI.
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Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, one of the main limiting complications of OXL is neuropathic pain. In this study, the underlying mechanisms responsible for OXL evoked-neuropathic pain were examined. Using a rat model, the results demonstrated that intraperitoneal (i.p.) injection of OXL significantly increased mechanical pain and cold sensitivity as compared with control animals (P < 0.05 vs. control rats). ⋯ The data shows that TRPA1 expression was upregulated in the lumbar dorsal root ganglion (DRG) of OXL rats and blocking TRPA1 inhibited mechanical pain and heightened cold sensitivity (P < 0.05 vs. control rats). Blocking PAR2 also significantly decreased TRPA1 expression in the DRG. Findings in this study show that OXL intervention amplifies mechanical hyperalgesia and cold hypersensitivity and PAR2 plays an important role in regulating OXL-induced neuropathic pain via TRPA1 pathways.
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Computational methods have complemented experimental and clinical neurosciences and led to improvements in our understanding of the nervous systems in health and disease. In parallel, neuromodulation in form of electric and magnetic stimulation is gaining increasing acceptance in chronic and intractable diseases. ⋯ Then, we propose a strategy to employ the new theoretical concept of dynamical network biomarkers (DNB) in episodic manifestations of chronic disorders. In particular, as a first example, we introduce the use of computational models in migraine and illustrate on the basis of this example the potential of DNB as early-warning signals for neuromodulation in episodic migraine.
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Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. ⋯ In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2'-3'-didehydro-2'-3'-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.