Thrombospondin-4 Contributes to Spinal Sensitization and Neuropathic Pain States
- Doo-Sik Kim1,*,
- Kang-Wu Li1,*,
- Amin Boroujerdi2,
- Yanhui Peter Yu2,
- Chun-Yi Zhou2,
- Ping Deng3,
- John Park2,
- Xia Zhang1,
- Joshua Lee1,
- Michael Corpe1,
- Kelli Sharp4,
- Oswald Steward4,
- Cagla Eroglu5,
- Ben Barres6,
- Frank Zaucke7,
- Zao C. Xu3, and
- Z. David Luo1,2
- 1Departments of Anesthesiology and Perioperative Care and
- 2Pharmacology, University of California Irvine Medical Center, Irvine, California 92868,
- 3Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082,
- 4Reeve-Irvine Research Center, University of California Irvine, School of Medicine, Irvine, California 92697,
- 5Cell Biology Department, Duke University Medical Center, Durham, North Carolina 27705,
- 6Department of Neurobiology, Stanford University, Stanford, California 94305-5125, and
- 7Center for Biochemistry and Center for Molecular Medicine, Medical Faculty, University of Cologne, D-50931 Cologne, Germany
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Author contributions: D.-S.K., K.-W.L., A.B., Y.P.Y., C.-Y.Z., P.D., J.P., X.Z., K.S., O.S., Z.C.X., and Z.D.L. designed research; D.-S.K., K.-W.L., A.B., Y.P.Y., C.-Y.Z., P.D., J.P., X.Z., J.L., M.C., K.S., and Z.C.X. performed research; J.P., M.C., C.E., B.A.B., and F.Z. contributed unpublished reagents/analytic tools; D.-S.K., K.-W.L., A.B., Y.P.Y., C.-Y.Z., P.D., X.Z., J.L., K.S., Z.C.X., and Z.D.L. analyzed data; B.B., Z.C.X., and Z.D.L. wrote the paper.
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↵*D.-S.K. and K.-W.L. contributed equally to this work.
Abstract
Neuropathic pain is a common cause of pain after nerve injury, but its molecular basis is poorly understood. In a post-gene chip microarray effort to identify new target genes contributing to neuropathic pain development, we report here the characterization of a novel neuropathic pain contributor, thrombospondin-4 (TSP4), using a neuropathic pain model of spinal nerve ligation injury. TSP4 is mainly expressed in astrocytes and significantly upregulated in the injury side of dorsal spinal cord that correlates with the development of neuropathic pain states. TSP4 blockade by intrathecal antibodies, antisense oligodeoxynucleotides, or inactivation of the TSP4 gene reverses or prevents behavioral hypersensitivities. Intrathecal injection of TSP4 protein into naive rats is sufficient to enhance the frequency of EPSCs in spinal dorsal horn neurons, suggesting an increased excitatory presynaptic input, and to cause similar behavioral hypersensitivities. Together, these findings support that injury-induced spinal TSP4 may contribute to spinal presynaptic hypersensitivity and neuropathic pain states. Development of TSP4 antagonists has the therapeutic potential for target-specific neuropathic pain management.
- Received December 29, 2011.
- Revision received April 18, 2012.
- Accepted May 10, 2012.
- Copyright © 2012 the authors 0270-6474/12/328977-11$15.00/0
