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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.
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.