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Spinal Astrocytic Thrombospondin-4 Induced by Excitatory Neuronal Signaling Mediates Pain After Facet Capsule Injury

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Abstract

Thrombospondin-4 (TSP4) is a synaptogenic molecule that is upregulated in the spinal cord after painful facet joint injury and may contribute to spinal hyperexcitability. However, the mechanisms leading to increased spinal TSP4 are unclear. Because primary afferent activity is critical in the development of spinal hyperexcitability after facet joint injury, this study evaluated the role of afferent firing in the increase of spinal TSP4 and excitatory synapses. Intra-articular bupivacaine was administered immediately or 4 days after painful facet joint injury in male Holtzman rats, and TSP4 and excitatory synapses were quantified in the spinal cord at day 7. Immediate, but not delayed bupivacaine treatment, prevents the injury-induced increase in TSP4 and excitatory synapses in the dorsal horn (p < 0.0001). Preliminary in vitro experiments suggest that the excitatory signaling molecules ATP and glutamate may stimulate astrocytic TSP4 expression (p ≤ 0.04). Collectively, these results suggest that afferent activity early after facet joint injury is critical for the induction of spinal TSP4. This study advances the understanding of the timing and role of afferent activity in TSP4 expression after injury, which is critical for the therapeutic targeting of TSP4 to treat persistent pain conditions.

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Acknowledgments

This work was supported by grants from the National Institutes of Health (#AR056288), the Catharine Sharpe Foundation, and a fellowship from the Ashton Foundation. The authors would also like to thank Frank Zaucke for providing the anti-TSP4 antibody.

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Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd St, Philadelphia, PA, 19104-6321, USA

    Nathan D. Crosby & Beth A. Winkelstein

  2. Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Beth A. Winkelstein

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  1. Nathan D. Crosby
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Correspondence to Beth A. Winkelstein.

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Associate Editor Michael S. Detamore oversaw the review of this article.

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Crosby, N.D., Winkelstein, B.A. Spinal Astrocytic Thrombospondin-4 Induced by Excitatory Neuronal Signaling Mediates Pain After Facet Capsule Injury. Ann Biomed Eng 44, 3215–3224 (2016). https://doi.org/10.1007/s10439-016-1639-x

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