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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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6-Cyano-7-nitroquinoxaline-2,3-dione
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Analysis of Variance
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Animals
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Antibodies / therapeutic use
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Disease Models, Animal
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Excitatory Amino Acid Antagonists / pharmacology
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Green Fluorescent Proteins / genetics
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Humans
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Hyperalgesia / metabolism
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Hyperalgesia / pathology
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In Vitro Techniques
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Inhibitory Postsynaptic Potentials / drug effects
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Inhibitory Postsynaptic Potentials / genetics
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Injections, Spinal
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Male
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Mice
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Mice, Transgenic
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Motor Activity / drug effects
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Neuralgia / drug therapy
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Neuralgia / etiology
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Neuralgia / metabolism*
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Oligodeoxyribonucleotides, Antisense / administration & dosage
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Pain Measurement
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Pain Threshold / drug effects
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Pain Threshold / physiology*
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Rats
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Rats, Sprague-Dawley
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Sodium Channel Blockers / pharmacology
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Spinal Cord / drug effects
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Spinal Cord / metabolism*
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Spinal Cord / pathology
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Spinal Cord / physiopathology
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Spinal Nerves / injuries
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Tetrodotoxin / pharmacology
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Thrombospondins / deficiency
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Thrombospondins / genetics
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Thrombospondins / metabolism*
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Up-Regulation / drug effects
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Up-Regulation / physiology*
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Valine / analogs & derivatives
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Valine / pharmacology
Substances
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Antibodies
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Excitatory Amino Acid Antagonists
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Oligodeoxyribonucleotides, Antisense
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Sodium Channel Blockers
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Thrombospondins
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enhanced green fluorescent protein
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thrombospondin 4
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Green Fluorescent Proteins
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Tetrodotoxin
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6-Cyano-7-nitroquinoxaline-2,3-dione
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2-amino-5-phosphopentanoic acid
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Valine