Development of spinal neuronal hyperexcitability and structural plasticity after cervical facet injury: Implications for modulating persistent pain

Chronic neck pain is a prevalent and costly condition that commonly develops after whiplash injuries. The cervical facet joint and its capsular ligament are frequently identified as a source of pain in patients, particularly those with whiplash-associated disorders. Spinal neuronal hyperexcitability is a common feature of persistent pain that can be induced by enhanced excitatory signaling in the dorsal horn. Spinal dorsal horn neurons develop hyperexcitability after painful facet joint injury, but the neurophysiological mechanisms that lead to spinal hyperexcitability and persistent pain after facet joint loading remain unclear. This thesis uses a rat model of painful facet joint injury to define the peripheral and spinal signals that promote dorsal horn neuronal hyperexcitability. In particular, the development of spinal hyperexcitability is evaluated by characterizing neuronal activity at multiple times within the first day after painful facet joint injury. To evaluate the role of injury-induced joint afferent activity in the potentiation of excitatory signaling and spinal neuronal excitability, afferent activity is blocked at various times after painful facet joint injury. Excitatory synaptogenesis and the mechanisms inducing synaptogenesis are evaluated to determine whether structural plasticity in the spinal cord contributes to facet-mediated pain. Spinal cord stimulation (SCS) is an effective clinical therapy that attenuates chronic pain by modulating spinal hyperexcitability, but the mechanisms and effectiveness of SCS for persistent neuropathic or joint-mediated pain remain unclear. This thesis evaluates the use of a novel mode of SCS, burst SCS, in rat models of cervical radiculopathy and painful facet joint injury. The role of GABA signaling in the inhibitory effects of burst SCS on dorsal horn neurons is assessed by applying GABA receptor antagonists to the spinal cord during the application of burst SCS. Studies in this thesis demonstrate that afferent discharge induced by injurious loading of the facet joint initiates excitatory synaptic and structural changes in the spinal cord that promote neuronal hyperexcitability, but SCS can attenuate persistent pain by reducing spinal hyperexcitability. This thesis provides a foundation for future investigations into the mechanisms underlying the transduction of mechanical joint injury to centrallymediated pain and the development of effective therapies for chronic pain. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Bioengineering First Advisor Beth A. Winkelstein This dissertation is available at ScholarlyCommons: http://repository.upenn. edu/edissertations/1246 Subject Categories Biomedical | Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: http://repository.upenn. edu/edissertations/1246 DEVELOPMENT OF SPINAL NEURONAL HYPEREXCITABILITY AND STRUCTURAL PLASTICITY AFTER CERVICAL FACET INJURY: IMPLICATIONS FOR MODULATING PERSISTENT PAIN Nathan D. Crosby A DISSERTATION in Bioengineering Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2014 Supervisor of Dissertation ________________________________________ Beth A. Winkelstein, Professor of Bioengineering Graduate Group Chairperson ________________________________________ Jason A. Burdick, Professor of Bioengineering Dissertation Committee David F. Meaney, Professor and Chair of Bioengineering Gordon Barr, Associate Professor of Psychology in Anesthesiology and Critical Care Wenqin Luo, Assistant Professor of Neuroscience Iyad Obeid, Associate Professor of Electrical and Computer Engineering, Temple Univ.