Abstract
Peripheral nerve injury induces increased expression of thrombospondin-4 (TSP4) in spinal cord and dorsal root ganglia that contributes to neuropathic pain states through unknown mechanisms. Here, we test the hypothesis that TSP4 activates its receptor, the voltage-gated calcium channel Cavα2δ1 subunit (Cavα2δ1), on sensory afferent terminals in dorsal spinal cord to promote excitatory synaptogenesis and central sensitization that contribute to neuropathic pain states. We show that there is a direct molecular interaction between TSP4 and Cavα2δ1 in the spinal cord in vivo and that TSP4/Cavα2δ1-dependent processes lead to increased behavioral sensitivities to stimuli. In dorsal spinal cord, TSP4/Cavα2δ1-dependent processes lead to increased frequency of miniature and amplitude of evoked excitatory post-synaptic currents in second-order neurons as well as increased VGlut2- and PSD95-positive puncta, indicative of increased excitatory synapses. Blockade of TSP4/Cavα2δ1-dependent processes with Cavα2δ1 ligand gabapentin or genetic Cavα2δ1 knockdown blocks TSP4 induced nociception and its pathological correlates. Conversely, TSP4 antibodies or genetic ablation blocks nociception and changes in synaptic transmission in mice overexpressing Cavα2δ1 Importantly, TSP4/Cavα2δ1-dependent processes also lead to similar behavioral and pathological changes in a neuropathic pain model of peripheral nerve injury. Thus, a TSP4/Cavα2δ1-dependent pathway activated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development.
Highlights
Vated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development
Credriven Cav␣2␦1 deletion from dorsal root ganglia (DRG) neurons in homozygous CKOAdv-Creϩ/Ϫ mice was confirmed by immunostaining data showing that 2-week Spinal Nerve Ligation (SNL) could induce DRG Cav␣2␦1 up-regulation indicated as increased Cav␣2␦1 antibody immunoreactivity in DRG neurons of control mice (WT conditional knock-out (CKO)), as we have reported previously [25], but failed to do so in homozygous CKOAdv-Creϩ/Ϫ mice (Fig. 4D)
Peripheral nerve injury induces up-regulation of TSP4 and Cav␣2␦1 in DRG/spinal cord that contributes to neuropathic pain states through mechanisms that were previously undefined [2, 24, 25, 27, 29, 31]
Summary
Vated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development. Similar to injury-induced TSP4, injury-induced Cav␣2␦1 has been shown to increase mEPSC frequency in neurons of dorsal spinal cord, which may contribute to central sensitization and neuropathic pain states (24, 25, 27, 29 –31, 33) These observations suggest the following intriguing hypothetical mechanistic model: 1) peripheral nerve injury up-regulates Cav␣2␦1 in peripheral sensory neurons and its central terminals; 2) peripheral nerve injury triggers increased synthesis and release of TSP4 in spinal cord and DRG; 3) increased TSP4 interacts directly with its receptor Cav␣2␦1 on the central terminals of sensory neurons to increase excitatory synaptogenesis and synaptic neurotransmission; 4) increased excitatory transmission in dorsal spinal cord contributes to central sensitization and neuropathic pain development. We tested critical aspects of this model and the underlying mechanisms
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