Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI)

Vierck, Chuck

doi:10.1016/j.jpain.2019.08.007

Cited by 29 publications

(32 citation statements)

References 205 publications

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“…Like many forms of chronic pain, SCI-induced pain is often refractory to treatment by available pain medications, including opioids (Bryce, 2018). While alterations within the damaged spinal cord as well as the brain contribute to chronic SCI pain (Kramer et al, 2017;Vierck, 2020), our group and others have shown that electrical activity generated in peripheral terminals and cell bodies of sensory neurons located in DRGs persistently increases after SCI (Carlton et al, 2009;Bedi et al, 2010;Ritter et al, 2015;Odem et al, 2018). Mechanisms of hyperactivity in nociceptors are logical targets for ameliorating chronic SCI pain because Nav1.8 expression (characteristic of most nociceptors and important for their action potential [AP] generation) was found to be necessary for chronic SCI pain in rats as measured by reflexive and operant behavioral tests (Yang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury

et al. 2020

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Chronic pain caused by spinal cord injury (SCI) is notoriously resistant to treatment, particularly by opioids. After SCI, DRG neurons show hyperactivity and chronic depolarization of resting membrane potential (RMP) that is maintained by cAMP signaling through PKA and EPAC. Importantly, SCI also reduces the negative regulation by Gai of adenylyl cyclase and its production of cAMP, independent of alterations in G protein-coupled receptors and/or G proteins. Opioid reduction of pain depends on coupling of opioid receptors to Gai/o family members. Combining high-content imaging and cluster analysis, we show that in male rats SCI decreases opioid responsiveness in vitro within a specific subset of small-diameter nociceptors that bind isolectin B4. This SCI effect is mimicked in nociceptors from naive animals by a modest 5 min depolarization of RMP (15 mM K 1 ; 245 mV), reducing inhibition of cAMP signaling by l-opioid receptor agonists DAMGO and morphine. Disinhibition and activation of C-Raf by depolarization-dependent phosphorylation are central to these effects. Expression of an activated C-Raf reduces sensitivity of adenylyl cyclase to opioids in nonexcitable HEK293 cells, whereas inhibition of C-Raf or treatment with the hyperpolarizing drug retigabine restores opioid responsiveness and blocks spontaneous activity of nociceptors after SCI. Inhibition of ERK downstream of C-Raf also blocks SCI-induced hyperexcitability and depolarization, without direct effects on opioid responsiveness. Thus, depolarization-dependent C-Raf and downstream ERK activity maintain a depolarized RMP and nociceptor hyperactivity after SCI, providing a self-reinforcing mechanism to persistently promote nociceptor hyperexcitability and limit the therapeutic effectiveness of opioids.

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Section: Introductionmentioning

confidence: 99%

Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury

et al. 2020

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“…The injury occurs in two stages, a primary insult from trauma, ischemia, or toxins and a secondary injury characterized by inflammatory cascade, accumulation of toxic neurotransmitters, and production of nerve regeneration inhibitory factors. The tissue damage interrupts of ascending and descending nerve fibers, demyelinates propriospinal and other long tracts, followed by gliosis and scarring with impaired function below the injury site 2 , 3 . SCI prevention, regenerative therapies, and rehabilitation offer limited solutions in today’s medical practice.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of sh-miR-199a-5p-Modified Olfactory Ensheathing Cells Promotes the Functional Recovery in Rats with Contusive Spinal Cord Injury

Gao

Zhao

et al. 2020

Cell Transplant

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MicroRNAs (miRNAs) function as gene expression switches, and participate in diverse pathophysiological processes of spinal cord injury (SCI). Olfactory ensheathing cells (OECs) can alleviate pathological injury and facilitate functional recovery after SCI. However, the mechanisms by which OECs restore function are not well understood. This study aims to determine whether silencing miR-199a-5p would enhance the beneficial effects of the OECs. In this study, we measured miR-199a-5p levels in rat spinal cords with and without injury, with and without OEC transplants. Then, we transfected OECs with the sh-miR-199a-5p lentiviral vector to reduce miR-199a-5p expression and determined the effects of these OECs in SCI rats by Basso–Beattie–Bresnahan (BBB) locomotor scores, diffusion tensor imaging (DTI), and histological methods. We used western blotting to measure protein levels of Slit1, Robo2, and srGAP2. Finally, we used the dual-luciferase reporter assay to assess the relationship between miR-199-5p and Slit1, Robo2, and srGAP2 expression. We found that SCI significantly increased miR-199a-5p levels ( P < 0.05), and OEC transplants significantly reduced miR-199a-5p expression ( P < 0.05). Knockdown of miR-199a-5p in OECs had a better therapeutic effect on SCI rats, indicated by higher BBB scores and fractional anisotropy values on DTI, as well as histological findings. Reducing miR-199a-5p levels in transplanted OECs markedly increased spinal cord protein levels of Slit1, Robo2, and srGAP2. Our results demonstrated that transplantation of sh-miR-199a-5p-modified OECs promoted functional recovery in SCI rats, suggesting that miR-199a-5p knockdown was more beneficial to the therapeutic effects of OEC transplants. These findings provided new insights into miRNAs-mediated therapeutic mechanisms of OECs, which helps us to develop therapeutic strategies based on miRNAs and optimize cell therapy for SCI.

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“…The lack of correlation between segmental level and pain could be explained by overactivity in neurones located just above the SCI. Vierck ( 14 ) suggests that BLSCIN pain is caused by a combination of different neural mechanisms. He suggests that the main mechanism is damage to pathways from the dorsal horn to reticular nuclei in the brainstem.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of spasticity and below-level neuropathic pain related to spinal cord injury level and damage to the lower spinal segments

Skoog¹,

Jakobsson²

2020

J Rehabil Med-CC

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Objective: To evaluate spasticity and below-level spinal cord injury neuropathic pain after spinal cord injury in patients with, or without, damage to the lumbar spinal cord and roots. Design/patients: Chart review of 269 patients with spinal cord injury from segments C1 to T11. Methods: Patients were interviewed concerning leg spasticity and below-level spinal cord injury neuropathic pain in the lower trunk and legs. Damage to the lumbar spinal cord and roots was inferred where there was radiological evidence of a vertebral fracture, spinal stenosis or the narrowing of spinal foramina of a vertebra from thoracic 11 to lumbar 5, or; magnetic resonance imaging showing evidence of damage to the lumbar spinal cord and roots. Results: Among 161 patients without damage to the lumbar spinal cord and roots, 87% of those with cervical spinal cord injury experienced spasticity, compared with 85% with thoracic spinal cord injury. The corresponding figures for patients in whom damage to the lumbar spinal cord and roots was present were 57% and 52%, respectively. Belowlevel spinal cord injury neuropathic pain was not associated with damage to the lumbar spinal cord and roots. In those patients with no damage to the lumbar spinal cord and roots, regression showed that neither outcome was significantly associated with the level of spinal cord injury. Conclusion: The lack of segmental dependency for spinal cord injury and spasticity suggests mechanisms restricted mainly to the lumbar spinal cord. For below-level spinal cord injury neuropathic pain, additional mechanisms, other than lesions of the spino-thalamic tract, must be considered.

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Mechanisms of Below-Level Pain Following Spinal Cord Injury (SCI)

Cited by 29 publications

References 205 publications

Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury

Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury

Transplantation of sh-miR-199a-5p-Modified Olfactory Ensheathing Cells Promotes the Functional Recovery in Rats with Contusive Spinal Cord Injury

Prevalence of spasticity and below-level neuropathic pain related to spinal cord injury level and damage to the lower spinal segments

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