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From receptors to pain: The therapeutic targets for neuropathic pain Yong Ho Kim Neuropathic mechanical allodynia, induced by normally innocuous lowthreshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Neuropathic pain and allodynia may arise from sensitization of central circuits. We reported mechanisms of spinal TRPV1-depedent central sensitization resulting from presynaptic facilitation of primary afferent terminals and long-term depression (LTD) of GABAergic interneurons as a consequence of TRPV1 activation in the spinal cord. In the first part, I will show that functional coupling of mGluR5-TRPV1 via diacylglycerol (DAG) generated by mGluR5 activation on the central presynaptic terminals of nociceptive neurons may be an important mechanism underlying central sensitization under pathological pain conditions. In the second part, I will present that activation of spinal TRPV1 induces long-term depression (LTD) in GABAergic substantia gelatinosa (SG) neurons and produces mechanical allodynia by reducing inhibitory inputs to projection neurons. Chronic mechanical pain following nerve injury was reversed by a spinally applied TRPV1 antagonist. Taken together, spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of CNS-specific TRPV1 antagonists for treating neuropathic pain. 1 In the third part, I will discuss that a new drug delivery method for alleviating neuropathic pain. Activation of TLR5 results in neuronal entry of the membrane-impermeable lidocaine derivative QX-314, leading to TLR5dependent blockade of sodium currents, predominantly in A-fiber neurons of DRGs. Co-application of flagellin and QX-314 (flagellin/QX-314) dosedependently suppresses mechanical allodynia, but this blockade is abrogated in Tlr5-deficient mice. Thus, these findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment. 2