Neuropharmacology
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Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia a primary damage due to the early massive increase of extracellular glutamate is followed by activation of resident immune cells, i.e microglia, and production or activation of inflammation mediators. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. ⋯ Among P2Y receptors, antagonists of P2Y12 receptors are of value because of their antiplatelet activity and possibly because of additional anti-inflammatory effects. Moreover strategies that modify adenosine or ATP concentrations at injury sites might be of value to limit damage after ischemia. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
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Neuropathic pain, a chronic pain condition following nerve damage and degeneration, involves aberrant excitability in the dorsal horn of the spinal cord. A growing body of evidence has shown that the aberrant excitability might not be a consequence merely of changes in neurons, but rather of multiple alterations in glial cells, such as microglia, the immune cells of the central nervous system. ⋯ Here, we describe recent advances in the understanding of neuron-microglia interactions by purinergic signaling in neuropathic pain following neurodegeneration. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'.
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Cannabinoid (CB) agonists suppress nausea in humans and animal models; yet, their underlying neural substrates remain largely unknown. Evidence suggests that the visceral insular cortex (VIC) plays a critical role in nausea. Given the expression of CB1 receptors and the presence of endocannabinoids in this brain region, we hypothesized that the VIC endocannabinoid system regulates nausea. ⋯ Inhibition of MAGL robustly increased 2-AG in the VIC, while FAAH inhibition had no effect on AEA. Finally, we demonstrated that inhibition of MAGL reduced VIC Fos immunoreactivity in response to LiCl treatment. Taken together, these findings provide compelling evidence that acute nausea selectively increases 2-AG in the VIC, and suggests that 2-AG signaling within the VIC regulates nausea by reducing neuronal activity in this forebrain region.
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This study analyzed and compared the effects of EGCG treatment on the expression of NTFs and NTF receptors expression in the sciatic nerve and the L3-L6 spinal cord segments at the early phase of regeneration following sciatic nerve crush injury. Analysis of BDNF, GDNF and NT3 neurotropic factors and Trk-B, Trk-C and NGFR-p75 receptors in neurons in the spinal cord of CRUSH and CRUSH + EGGC rats showed significant (p < 0.0001) decrease compared to NAÏVE and SHAM at day 1, 3, 7 and 14 after nerve injury. EGCG treatment significantly (p < 0.0001) increased the BDNF, GDN, NT3, Trk-B, Trk-C and NGFR-p75 immunostaining in the L3-L6 spinal cord compared to CRUSH animals. ⋯ EGCG treatment significantly (p < 0.0001) increased the Trk-B, Trk-C and NGFR-p75 mRNA gene expressions in the sciatic nerves compared to CRUSH group. Only at day 1, CRUSH + EGCG animals displayed significant rise in the sciatic nerves NT3 gene expression compared to CRUSH group. Our data suggest that the EGCG neuroprotective effect on the spinal cord neurons may be mediated through the modulation of NTFs and NTF receptors following nerve crush injury in a rat model.
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Benzonatate was FDA-approved in 1958 as an antitussive. Its mechanism of action is thought to be anesthesia of vagal sensory nerve fibers that mediate cough. Vagal sensory neurons highly express the Nav1.7 subtype of voltage-gated sodium channels, and inhibition of this channel inhibits the cough reflex. ⋯ We found that Na(+) currents are inhibited most potently by a benzonatate fraction containing the 9-ethoxy component. Detectable effects of benzonatate occur at concentrations as low as 0.3 μM, which has been reported in humans. We conclude that benzonatate has local anesthetic-like effects on voltage-gated sodium channels, including Nav1.7, which is a possible mechanism for cough suppression by the drug.