Nerve injury-induced pain, or neuropathic pain, is a common disorder lacking specific therapeutic agents due to the fact that underlying mechanisms are poorly understood. Peripheral nerve injury induces voltage-gated calcium channel a2d-1 subunit (Cava2d1) expression in dorsal root ganglia and spinal cord that correlates with neuropathic pain development and maintenance, and blocking such an increase results in neuropathic pain reversal. These suggest that Cava2d1 plays a critical role in spinal sensitization that underlies neuropathic pain. To further explore the mechanism underlying spinal sensitization and neuropathic pain mediated by injury-induced Cava2d1 upregulation, we plan to test the hypotheses that (1) injury-induced upregulation of the Cava2d1 interacts with injury-induced synapse inducer, thrombospondin-4 (TSP4) in dorsal root ganglia and spinal cord;(2) Both injury-induced Cava2d1 and TSP4 contribute to initiation and maintenance of neuropathic pain by (3) promoting spinal synaptogenesis. First, we will examine the spatial and temporal interactions between Cava2d1 and TSP4 in dorsal spinal cord and DRG in relation to neuropathic nociception using Western blots and immunohistochemical techniques. Second, we will compare the contribution of TSP4 to behavioral hypersensitivity observed in transgenic mice overexpressing the Cava2d1 or spinal nerve injured rats with elevated Cava2d1 expression. Finally, we will determine if co-upregulation of Cava2d1and TSP4 by nerve injury leads to enhanced synaptogenesis in the spinal dorsal horn that contributes to neuropathic pain. Completion of these studies will allow us to extend our current knowledge about the mechanisms of injury-induced Cava2d1 upregulation and its contribution to the induction and maintenance of neuropathic pain.
Chronic pain derived from nerve injury, or neuropathic pain, is a common clinical syndrome lacking specific and effective therapeutic agents due to the fact that its cellular mechanisms are poorly understood. Existing data indicate that injury-induced voltage-gated calcium channel a2d-1 subunit (Cava2d1) in dorsal root ganglia and spinal cord contributes to the development of neuropathic pain. However, mechanisms underlying injury-induced Cava2d1 in neuropathic pain are not known. We hypothesize that elevated Cava2d1 interacts with thrombospondin-4 (TSP4) post injury in promoting synapse formation, and abnormal synapse formation plays a causal role in neuropathic pain. We will test this hypothesis using genetically modified mice, nerve injury models, biochemical, electrophysiological, and behavioral pharmacology approaches. Completion of this study will provide important information for the understanding of neuropathic pain mechanisms and the development of next generation of neuropathic pain medications.
|Yu, Yanhui Peter; Gong, Nian; Kweon, Tae Dong et al. (2018) Gabapentin prevents synaptogenesis between sensory and spinal cord neurons induced by thrombospondin-4 acting on pre-synaptic Cav ?2 ?1 subunits and involving T-type Ca2+ channels. Br J Pharmacol 175:2348-2361|
|Park, John Francisco; Yu, Yanhui Peter; Gong, Nian et al. (2018) The EGF-LIKE domain of thrombospondin-4 is a key determinant in the development of pain states due to increased excitatory synaptogenesis. J Biol Chem 293:16453-16463|
|Gong, Nian; Park, John; Luo, Z David (2018) Injury-induced maladaptation and dysregulation of calcium channel ?2 ? subunit proteins and its contribution to neuropathic pain development. Br J Pharmacol 175:2231-2243|
|Park, John; Trinh, Van Nancy; Sears-Kraxberger, Ilse et al. (2016) Synaptic ultrastructure changes in trigeminocervical complex posttrigeminal nerve injury. J Comp Neurol 524:309-22|
|Pan, Bin; Guo, Yuan; Wu, Hsiang-En et al. (2016) Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury. Pain 157:2068-80|
|Park, John; Yu, Yanhui Peter; Zhou, Chun-Yi et al. (2016) Central Mechanisms Mediating Thrombospondin-4-induced Pain States. J Biol Chem 291:13335-48|
|Chang, E; Chen, X; Kim, M et al. (2015) Differential effects of voltage-gated calcium channel blockers on calcium channel alpha-2-delta-1 subunit protein-mediated nociception. Eur J Pain 19:639-48|
|Zhou, C; Luo, Z D (2015) Nerve injury-induced calcium channel alpha-2-delta-1 protein dysregulation leads to increased pre-synaptic excitatory input into deep dorsal horn neurons and neuropathic allodynia. Eur J Pain 19:1267-76|
|Li, Kang-Wu; Yu, Yanhui Peter; Zhou, Chunyi et al. (2014) Calcium channel ?2?1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis. J Biol Chem 289:7025-37|
|Zhou, C; Luo, Z D (2014) Electrophysiological characterization of spinal neuron sensitization by elevated calcium channel alpha-2-delta-1 subunit protein. Eur J Pain 18:649-58|
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