Genomics of the Effect of Spinal Cord Stimulation on an Animal Model of Neuropathic Pain

Vallejo, Ricardo; Tilley, Dana M.; Cedeño, David L.; Kelley, Courtney A.; DeMaegd, Margaret; Benyamin, Ramsin

doi:10.1111/ner.12465

Cited by 50 publications

(83 citation statements)

References 29 publications

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“…16 Because the SCS implant was relatively far from the DRG, genetic changes due to implant or the presence of an electric field in the spinal cord (L1-L2 level) may not extend far into the periphery without any injury, which seems to be a factor that conditions the effects of stimulation into the periphery. 20 The significant analgesic response, seen behaviorally, combined with the limited changes in gene expression suggests that the genes evaluated in this study are not major components of pain relief directly facilitated by SCS. Only IL-1b and IL-6 were significantly modulated, being up-regulated and down-regulated, respectively, by SCS treatment of injured animals.…”

Section: Discussionmentioning

confidence: 86%

“…Indeed, SCS does not seem to significantly affect genes in the DRG of uninjured animals, a general trend observed in a full genomics study recently published. 20 It is relevant to emphasize here that the effects of SCS on the spinal cord and DRG may differ for particular sets of genes, depending on their involvement within pathways that may be specific to the type of processes that occur in each tissue according to their specific biological role and how this is affected by injury. Nonetheless, this and previous studies confirm that peripheral nerve injury activates biological processes involving inflammation, immune response, neuroprotection, tissue remodeling, and synaptic changes that SCS is able to modulate.…”

Section: Discussionmentioning

confidence: 99%

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Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation

Tilley

Cedeño

Kelley

et al. 2017

Regional Anesthesia and Pain Medicine

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Spinal cord stimulation modulates expression of key pain-related genes in the DRG. Specifically, SCS led to reversal of IL-1b and IL-6 expression induced by injury. Interleukin 6 expression was still significantly larger than in sham animals, which may correlate to residual sensitivity following continuous SCS treatment. In addition, expression of GABAbr1 and Na/K ATPase was down-regulated to within control levels following SCS and correlates with applied current.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation

Tilley

Cedeño

Kelley

et al. 2017

Regional Anesthesia and Pain Medicine

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“…Recently, our group reported increased gene expression for Tlr2 and Cxcl16 , markers of astrocytic activation, and Cd68 , a marker of microglial activation, after continuous SCS in an animal model of neuropathic pain (Vallejo et al. ). Similarly, Sato et al.…”

Section: Introductionmentioning

confidence: 98%

“…Activation of microglia is a critical process in the evolution of the acute inflammatory pain state into the chronic pain state (Vallejo et al 2010;Tsuda, 2018), and activation of astrocytes potentiate and perpetuate the process (Milligan & Watkins, 2009;Vallejo et al 2010). Recently, our group reported increased gene expression for Tlr2 and Cxcl16, markers of astrocytic activation, and Cd68, a marker of microglial activation, after continuous SCS in an animal model of neuropathic pain (Vallejo et al 2016). Similarly, Sato et al (2014) observed a reduction of mechanical hyperalgesia and microglia and astrocyte activity after 6 h of SCS.…”

Section: Introductionmentioning

confidence: 99%

Glia to neuron ratio in the posterior aspect of the human spinal cord at thoracic segments relevant to spinal cord stimulation

et al. 2019

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Spinal cord stimulation (SCS) applied between T8 and T11 segments has been shown to be effective for the treatment of chronic pain of the lower back and limbs. However, the mechanism of the analgesic effect at these medullary levels remains unclear. Numerous studies relate glial cells with development and maintenance of chronic neuropathic pain. Glial cells are electrically excitable, which makes them a potential therapeutic target using SCS. The aim of this study is to report glia to neuron ratio in thoracic segments relevant to SCS, as well as to characterize the glia cell population at these levels. Dissections from gray and white matter of posterior spinal cord segments (T8, T9, intersection T9/T10, T10 and T11) were obtained from 11 human cadavers for histological analyses. Neuronal bodies and glial cells (microglia, astrocytes and oligodendrocytes) were immunostained, microphotographed and counted using image analysis software. Statistical analyses were carried out to establish significant differences of neuronal and glial populations among the selected segments, between the glial cells in a segment, and glial cells in white and gray matter. Results show that glia to neuron ratio in the posterior gray matter of the human spinal cord within the T8–T11 vertebral region is in the range 11 : 1 to 13 : 1, although not significantly different among vertebral segments. Glia cells are more abundant in gray matter than in white matter, whereas astrocytes and oligodendrocytes are more abundant than microglia (40 : 40 : 20). Interestingly, the population of oligodendrocytes in the T9/T10 intersection is significantly larger than in any other segment. In conclusion, glial cells are the predominant bodies in the posterior gray and white matter of the T8–T11 segments of the human spinal cord. Given the crucial role of glial cells in the development and maintenance of neuropathic pain, and their electrophysiological characteristics, anatomical determination of the ratio of different cell populations in spinal segments commonly exposed to SCS is fundamental to understand fully the biological effects observed with this therapy.

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“…It can result in successful pain relief in patients with chronic pain arising from various disorders, including painful diabetic polyneuropathy (PDPN) . Besides symptomatic treatment, there are numerous indications that continuous neuromodulation of the spinal cord results in physiological changes . These physiological changes are key players in understanding the working mechanism behind SCS and identifying targets for improvement.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Spinal Cord Stimulation Alleviates Mechanical Hypersensitivity and Increases Peripheral Cutaneous Blood Perfusion in Experimental Painful Diabetic Polyneuropathy

Beek

Hermes

Honig

et al. 2018

Neuromodulation: Technology at the Neural Interface

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ObjectivesThis study utilizes a model of long‐term spinal cord stimulation (SCS) in experimental painful diabetic polyneuropathy (PDPN) to investigate the behavioral response during and after four weeks of SCS (12 hours/day). Second, we investigated the effect of long‐term SCS on peripheral cutaneous blood perfusion in experimental PDPN.MethodsMechanical sensitivity was assessed in streptozotocin induced diabetic rats (n = 50) with von Frey analysis. Hypersensitive rats (n = 24) were implanted with an internal SCS battery, coupled to an SCS electrode covering spinal levels L2–L5. The effects of four weeks of daily conventional SCS for 12 hours (n = 12) or Sham SCS (n = 12) were evaluated with von Frey assessment, and laser Doppler imaging (LDI).ResultsAverage paw withdrawal thresholds (PWT) increased during long‐term SCS in the SCS group, in contrast to a decrease in the Sham group (Sham vs. SCS; p = 0.029). Twenty‐four hours after long‐term SCS average PWT remained higher in the SCS group. Furthermore, the SCS group showed a higher cutaneous blood perfusion during long‐term SCS compared to the Sham group (Sham vs. SCS; p = 0.048). Forty‐eight hours after long‐term SCS, no differences in skin perfusion were observed.DiscussionWe demonstrated that long‐term SCS results in decreased baseline mechanical hypersensitivity and results in increased peripheral blood perfusion during stimulation in a rat model of PDPN. Together, these findings indicate that long‐term SCS results in modulation of the physiological circuitry related to the nociceptive system in addition to symptomatic treatment of painful symptoms.

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Genomics of the Effect of Spinal Cord Stimulation on an Animal Model of Neuropathic Pain

Cited by 50 publications

References 29 publications

Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation

Changes in Dorsal Root Ganglion Gene Expression in Response to Spinal Cord Stimulation

Glia to neuron ratio in the posterior aspect of the human spinal cord at thoracic segments relevant to spinal cord stimulation

Long-Term Spinal Cord Stimulation Alleviates Mechanical Hypersensitivity and Increases Peripheral Cutaneous Blood Perfusion in Experimental Painful Diabetic Polyneuropathy

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