Pharmacology & therapeutics
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Modern neuroscience advanced our understanding of putative migraine mechanisms, which led to improved therapeutics. Indeed, mechanism-based acute migraine therapy gained steam in the early 1990s after the introduction of the triptans (5-HT1B,D agonists). ⋯ To date, migraine prophylactic drugs are advanced based on expanded indications for already approved pharmaceuticals (e.g., topiramate, valproate, propranolol, and timolol). An improved understanding of the predisposition to an attack, genomic discoveries, valid and reliable biomarkers and surrogates, and predictive preclinical models likely will unravel the neuronal substrates for central hyperexcitability and nociceptive dysmodulation, hopefully leading us to better mechanism-based targets for prevention, and ultimately yielding drugs with optimal therapeutic ratios or indices.
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The release of noradrenaline from nerve terminals is modulated by a variety of presynaptic receptors. These receptors belong to one of the following three receptor superfamilies: transmitter-gated ion channels, G protein-coupled receptors (GPCR), and membrane receptors with intracellular enzymatic activities. For representatives of each of these three superfamilies, receptor activation has been reported to cause either an enhancement or a reduction of noradrenaline release. ⋯ This review gives a short overview of the presynaptic receptors on noradrenergic nerve terminals and summarizes the events involved in vesicle exocytosis in order to finally delineate the most important signaling cascades that mediate the modulation via presynaptic receptors. In addition, the interactions between the various presynaptic receptors are described and the underlying molecular mechanisms are elucidated. Together, these presynaptic signaling mechanisms form a sophisticated network that precisely adapts the amount of noradrenaline being released to a given situation.