title: Central Mechanisms Mediating Thrombospondin-4-induced Pain States.
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.
authors.affiliation: From the Department of Pharmacology and.
authors.forename: John
authors.initials: J
authors.lastname: Park
authors.affiliation: From the Department of Pharmacology and.
authors.forename: Yanhui Peter
authors.initials: YP
authors.lastname: Yu
authors.affiliation: From the Department of Pharmacology and.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Kang-Wu
authors.initials: KW
authors.lastname: Li
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Eric
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vo
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: Reeve-Irvine Research Center, University of California, Irvine, School of Medicine, Irvine, California 92697.
authors.forename: Kelli
authors.initials: K
authors.lastname: Sharp
authors.affiliation: Reeve-Irvine Research Center, University of California, Irvine, School of Medicine, Irvine, California 92697.
authors.forename: Oswald
authors.initials: O
authors.lastname: Steward
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Iuliia
authors.initials: I
authors.lastname: Vitko
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
authors.affiliation: Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, California 94305, and.
authors.forename: Ben
authors.initials: B
authors.lastname: Barres
authors.affiliation: Center for Biochemistry and Cologne Center for Musculoskeletal Biomechanics, Medical Faculty, University of Cologne, D50931 Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Zaucke
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.affiliation: From the Department of Pharmacology and Department of Anesthesiology and Perioperative Care, University of California, Irvine, California 92697, Reeve-Irvine Research Center, University of California, Irvine, School of Medicine, Irvine, California 92697, zluo@uci.edu.
authors.forename: Z David
authors.initials: ZD
authors.lastname: Luo
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009437:Neuralgia / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000502:physiology; D013569:Synapses / Q000502:physiology; D055366:Synaptic Potentials; D019699:Thrombospondins / Q000502:physiology*
chemical_list: C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D019699:Thrombospondins; C101864:thrombospondin 4
keywords: gene knockout; gene regulation; mouse genetics; neurobiology; neuroscience; pain; signaling