Abstract
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.
Highlights
Postsynaptic N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) at spinal synapses are required for postsynaptic long-term potentiation and chronic pain
These results indicate that a loss of PreNMDARs was linked to a failure of activity-dependent preLTP at synapses between nociceptors and spinal-periaqueductal gray (PAG) projection neurons
Ca2+ influx via PreNMDARs leads to activation of small-conductance Ca2+-activated K+ (SK) channels, which results in presynaptic depression of C-fiber synapses in the spinal cord
Summary
Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. Previous studies have demonstrated that peripheral inflammation or injury leads to repetitive firing of nociceptive afferents and increased glutamate release from presynaptic spinal nociceptor terminals[11,12] Would this presynaptic activity alone be enough to trigger LTP (pre-LTP)? Emerging anatomical and physiological reports have documented the key significance of presynaptic NMDARs (PreNMDARs) in shaping synapse-specific effects on neurotransmitter release and plasticity, i.e. LTP or LTD in cortical synapses[14,15,22,23,25] Despite these longstanding insights and advances, whether and how PreNMDARs in spinal nociceptor terminals contribute to spinal presynaptic plasticity and further to pain hypersensitivity remains to be thoroughly examined. We identify PreNMDARs in spinal nociceptor terminals as key constituents of activitydependent secondary pain hypersensitivity associated with tissue injury
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