Dendritic Spine Dysgenesis in Neuropathic Pain

Tan, Andrew M.

doi:10.1016/bs.pmbts.2014.12.001

Cited by 25 publications

(21 citation statements)

References 142 publications

(164 reference statements)

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“…In our published studies, we have identified a common structural motif of dendritic spine morphology strongly associated with post‐injury hyperexcitability disorders, for example, spasticity (Bandaru et al, ; Guo et al, ; Tan et al, ; Tan & Waxman, ; Zhao et al, ). As shown in our current retrospective study, we observed two features of abnormal dendritic spine remodeling in ipsilateral ventral horn motor neurons: I) increased spine density, particularly mushroom‐shaped dendritic spines, and II) a greater distribution of spines in regions closer to the cell body.…”

Section: Discussionmentioning

confidence: 99%

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

et al. 2019

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Burn injuries and associated complications present a major public health challenge. Many burn patients develop clinically intractable complications, including pain and other sensory disorders. Recent evidence has shown that dendritic spine neuropathology in spinal cord sensory and motor neurons accompanies central nervous system (CNS) or peripheral nervous system (PNS) trauma and disease. However, no research has investigated similar dendritic spine neuropathologies following a cutaneous thermal burn injury. In this retrospective investigation, we analyzed dendritic spine morphology and localization in alpha‐motor neurons innervating a burn‐injured area of the body (hind paw). To identify a molecular regulator of these dendritic spine changes, we further profiled motor neuron dendritic spines in adult mice treated with romidepsin, a clinically approved Pak1‐inhibitor, or vehicle control at two postburn time points: Day 6 immediately after treatment, or Day 10 following drug withdrawal. In control treated mice, we observed an overall increase in dendritic spine density, including structurally mature spines with mushroom‐shaped morphology. Pak1‐inhibitor treatment reduced injury‐induced changes to similar levels observed in animals without burn injury. The effectiveness of the Pak1‐inhibitor was durable, since normalized dendritic spine profiles remained as long as 4 days despite drug withdrawal. This study is the first report of evidence demonstrating that a second‐degree burn injury significantly affects motor neuron structure within the spinal cord. Furthermore, our results support the opportunity to study dendritic spine dysgenesis as a novel avenue to clarify the complexities of neurological disease following traumatic injury.

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Section: Discussionmentioning

confidence: 99%

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

et al. 2019

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“…These pain-associated spine profiles appear to be conserved across several injury and disease models of neuropathic pain, including peripheral nerve injury, diabetes mellitus, severe cutaneous burn injury, and SCI. 37 , 38 Importantly, in all of these pain models, it was demonstrated that disruption of Rac1 is necessary and sufficient for both the reduction in dendritic spine dysgenesis and neuropathic pain. Rac1 activity has a significant role in regulating the actin filament cytoskeleton in dendritic spines and concomitantly promotes the clustering of AMPA receptors in the post-synaptic spine membrane.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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“…We have previously documented in several studies that dendritic spine dysgenesis in the nociceptive neurons in the dorsal horn accompanies central sensitization and neuropathic pain. 12 , 13 In experimental burn injury, dendritic spines change to a dysgenic state in a Rac1-dependent manner. Inhibition of Rac1 suppresses dendritic spine dysgenesis and attenuates neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

“…15 – 17 Thus, in this study, we sought alternative druggable targets and identified Pak1 as a potentially useful therapeutic target for addressing pain. 11 , 13 Pak1 is a Rac1 effector kinase that links Rac1 signaling to cytoskeletal reorganization underlying dendritic spine plasticity. Although Pak1 has been implicated in a spectrum of neurological diseases and disorders, 18 – 21 this kinase has not been studied in mechanisms underlying neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury

et al. 2018

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Painful burn injuries are among the most debilitating form of trauma, globally ranking in the top 15 leading causes of chronic disease burden. Despite its prevalence, however, chronic pain after burn injury is under-studied. We previously demonstrated the contribution of the Rac1-signaling pathway in several models of neuropathic pain, including burn injury. However, Rac1 belongs to a class of GTPases with low therapeutic utility due to their complex intracellular dynamics. To further understand the mechanistic underpinnings of burn-induced neuropathic pain, we performed a longitudinal study to address the hypothesis that inhibition of the downstream effector of Rac1, Pak1, will improve pain outcome following a second-degree burn injury. Substantial evidence has identified Pak1 as promising a clinical target in cognitive dysfunction and is required for dendritic spine dysgenesis associated with many neurological diseases. In our burn injury model, mice exhibited significant tactile allodynia and heat hyperalgesia and dendritic spine dysgenesis in the dorsal horn. Activity-dependent expression of c-fos also increased in dorsal horn neurons, an indicator of elevated central nociceptive activity. To inhibit Pak1, we repurposed an FDA-approved inhibitor, romidepsin. Treatment with romidepsin decreased dendritic spine dysgenesis, reduced c-fos expression, and rescued pain thresholds. Drug discontinuation resulted in a relapse of cellular correlates of pain and in lower pain thresholds in behavioral tests. Taken together, our findings identify Pak1 signaling as a potential molecular target for therapeutic intervention in traumatic burn-induced neuropathic pain.

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Dendritic Spine Dysgenesis in Neuropathic Pain

Cited by 25 publications

References 142 publications

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

Spinal cord motor neuron plasticity accompanies second‐degree burn injury and chronic pain

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

Therapeutic potential of Pak1 inhibition for pain associated with cutaneous burn injury

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