Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury

Abstract

Neuropathic pain is a major complication of spinal cord injury, and despite aggressive efforts, this type of pain is refractory to available clinical treatment. Our previous work has demonstrated a structure–function link between dendritic spine dysgenesis on nociceptive sensory neurons in the intermediate zone, laminae IV/V, and chronic pain in central nervous system and peripheral nervous system injury models of neuropathic pain. To extend these findings, we performed a follow-up structural analysis to assess whether dendritic spine remodeling occurs on superficial dorsal horn neurons located in lamina II after spinal cord injury. Lamina II neurons are responsible for relaying deep, delocalized, often thermally associated pain commonly experienced in spinal cord injury pathologies. We analyzed dendritic spine morphometry and localization in tissue obtained from adult rats exhibiting neuropathic pain one-month following spinal cord injury. Although the total density of dendritic spines on lamina II neurons did not change after spinal cord injury, we observed an inverse relationship between the densities of thin- and mushroom-shaped spines: thin-spine density decreased while mushroom-spine density increased. These structural changes were specifically noted along dendritic branches within 150 µm from the soma, suggesting a possible adverse contribution to nociceptive circuit function. Intrathecal treatment with NSC23766, a Rac1-GTPase inhibitor, significantly reduced spinal cord injury-induced changes in both thin- and mushroom-shaped dendritic spines. Overall, these observations demonstrate that dendritic spine remodeling occurs in lamina II, regulated in part by the Rac1-signaling pathway, and suggests that structural abnormalities in this spinal cord region may also contribute to abnormal nociception after spinal cord injury.

Dendritic Spine Dynamics after Peripheral Nerve Injury: An Intravital Structural Study

“…Nikon Elements AR (version 5.1, Nikon) and ImageJ software (https://imagej.nih.gov/ij/download.html) were used for image data postprocessing and analyses. To identify excitatory superficial dorsal horn neurons for analysis, we sampled neurons based on four morphologic and topographical criteria used previously (Light and Kavookjian, 1988;Yasaka et al, 2010;Cao et al, 2017) as follows: (1) neurons must be located within lamina II in the superficial dorsal horn (up to 200 mm deep); (2) YFP-labeled neurons must have clearly visible dendrites at least 100 mm in length; (3) neurons must have at least three primary dendrites extending from the cell body, although branching was not required; and (4) the cell body diameter must fall between 15-30 mm. In total, we longitudinally studied 28 dorsal horn sensory neurons in lamina II from 9 animals over time.…”

“…Our previous work showed a common structural motif of altered dendritic spine morphology strongly associated with nociceptive hyperexcitability and neuropathic pain in neurons located in the superficial and intermediate zone of the dorsal horn, laminae II or IV, respectively. Pain-associated dendritic spine morphologies include increased spine density (particularly, larger mushroom-shaped spines) and regional redistribution of spines along dendrite branches (Tan et al, 2011;Zhao et al, 2016;Cao et al, 2017). However, these previous studies relied on histologic analysis of postmortem tissue, which could only imply the dynamic dendritic spine changes associated with injuryinduced pain.…”

Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

“…Activated glia, however, have also been shown to release growth inhibition factors (e.g., NG-2, neurocan, and brevican) within a few days, thereby preventing compensatory axonal regeneration and regrowth [ 70 – 73 ]. Another study concludes that activated glia contribute to the reorganization of synaptic circuits at the spinal dorsal horn and supraspinal regions including the VPL thalamic nucleus [ 74 , 75 ]. In a recent study, Lee-Kubli et al report that SCI caused astrocytic and microglial activation in the spinal cord and satellite glial cell activation in DRGs, respectively, and suggest that SCI-induced neuronal-glial interactions may occur throughout the entire nervous system [ 76 ].…”

Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation

“…For example, CCI differentially upregulates α 1 -adrenoceptor subtypes A, B, and D and α 2 -adrenoceptor subtype A in the dorsal root ganglia (Cheng et al, 2014). Spinal nerve ligation produces upregulation of norepinephrine transporters (Rojo et al, 2012), and spinal cord impact injury can remodel the dendritic spines of lamina II neurons, which may play a role in circuit function of the dendrites and promote central sensitization (Cao et al, 2017; Tan, 2015; Mills et al, 2018).…”