Cerebrospinal Fluid Levels of Vascular Endothelial Growth Factor Correlate With Reported Pain and Are Reduced by Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome

McCarthy, Kevin F.; Connor, Thomas J.; McCrory, Connail

doi:10.1111/j.1525-1403.2012.00527.x

Cited by 53 publications

(59 citation statements)

References 17 publications

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“…Contrary to the results of the blood analysis in our study, other preclinical and human studies investigating the correlation between neuroinflammation and back pain measured cytokine concentrations in cerebrospinal fluid (CSF), a biofluid compartment closer to the neural interface. In particular, the methodologies used to determine TNF‐α values vary, and while some studies demonstrate enhanced plasma levels by LPS‐induction, our ELISA protocol failed to sufficiently assess TNF‐α . Furthermore, while elevation of IL‐1β has been reported in FBSS patients with predominant neuropathic leg pain, this was not the case in our VAS B dominant FBSS subgroup.…”

Section: Discussionmentioning

confidence: 80%

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain

Kinfe

Muhammad

Link

et al. 2017

Neuromodulation: Technology at the Neural Interface

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Section: Discussionmentioning

confidence: 80%

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain

Kinfe

Muhammad

Link

et al. 2017

Neuromodulation: Technology at the Neural Interface

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“…Patients with chronic pain also display increased CCL2 and CCL3 levels in the cerebrospinal fluid or plasma [44, 45]. Chemokine-mediated neuron-glia interactions are bidirectional.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys

Kiguchi

Ding

Peters

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Neuroinflammation is a pathological condition that underlies diabetes and affects sensory processing. Given the high prevalence of pain in diabetic patients and crosstalk between chemokines and opioids, it is pivotal to know whether neuroinflammation-associated mediators are dysregulated in the central nervous system of diabetic primates. Therefore, the aim of this study was to investigate whether mRNA expression levels of glial markers, chemokines, and opioid receptors are altered in the spinal cord and thalamus of naturally occurring type 2 diabetic monkeys (n=7) compared with age-matched non-diabetic monkeys (n=6). By using RT-qPCR, we found that mRNA expression levels of both GFAP and IBA1 were up-regulated in the spinal dorsal horn (SDH) of diabetic monkeys compared with non-diabetic monkeys. Among all chemokines, expression levels of three chemokine ligand-receptor systems, i.e., CCL2-CCR2, CCL3-CCR1/5, and CCL4-CCR5, were up-regulated in the SDH of diabetic monkeys. Moreover, in the SDH, seven additional chemokine receptors, i.e., CCR4, CCR6, CCR8, CCR10, CXCR3, CXCR5, and CXCR6, were also up-regulated in diabetic monkeys. In contrast, expression levels of MOP, KOP, and DOP, but not NOP receptors, were down-regulated in the SDH of diabetic monkeys, and the thalamus had fewer changes in the glial markers, chemokines and opioids. These findings indicate that neuroinflammation, manifested as glial activation and simultaneous up-regulation of multiple chemokine ligands and receptors, seems to be permanent in type 2 diabetic monkeys. As chemokines and opioids are important pain modulators, this first-in-primate study provides a translational bridge for determining the functional efficacy of spinal drugs targeting their signaling cascades.

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“…These results suggest that spinal cord VEGFR2 activation by different VEGF isoforms could contribute to nociceptive processing. Despite evidence from clinical studies that demonstrate an involvement of VEGF receptors in pain (Langenberg et al, 2011, McCarthy and McCrory, 2013), and experimental evidence showing that spinal VEGF levels are associated with pain (Nesic et al, 2010), there are few published findings on the effects of VEGF-A in spinal nociceptive processing. As spinal VEGF-A splicing and isoform expression, and therefore by inference VEGFR2 activation, were altered in PSNI we determined the effect of VEGFR antagonism on central nociceptive processing.…”

Section: Resultsmentioning

confidence: 99%

“…Observed differences in VEGF-A effects could be attributable to different concentrations used, the source of VEGF-A 165 a, the degree of injury, or different endogenous isoform complement (Bates et al, 2002a). Clinically, elevated levels of VEGF-A in the spinal cord of neuropathic pain patients correlate with reported pain (McCarthy and McCrory, 2013). VEGF-A and VEGF-A receptor 2 are present in both peripheral and central nervous systems including spinal cord (Bates et al, 2002b, Beazley-Long et al, 2013, Sondell et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

Hulse

Drake

Bates

et al. 2016

Neurobiology of Disease

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Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord.Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons. Serine arginine protein kinase 1 (SRPK1) is the principal route of SRSF1 activation. Spinal SRPK1 inhibition attenuated SRSF1 activity, abolished neuropathic pain behaviors and suppressed central sensitization. SRSF1 was principally expressed in large diameter myelinated (NF200-rich) dorsal root ganglia sensory neurons and their excitatory central terminals (vGLUT1 + ve) within the dorsal horn of the lumbar spinal cord.Expression of pro-nociceptive VEGF-Axxxa within the spinal cord was increased after nerve injury, and this was prevented by SRPK1 inhibition. Additionally, expression of anti-nociceptive VEGF-Axxxb isoforms was elevated, and this was associated with reduced neuropathic pain behaviors. Inhibition of VEGF receptor-2 signaling in the spinal cord attenuated behavioral nociceptive responses to mechanical, heat and formalin stimuli, indicating that spinal VEGF receptor-2 activation has potent pro-nociceptive actions. Furthermore, intrathecal VEGF-A165a resulted in mechanical and heat hyperalgesia, whereas the sister inhibitory isoform VEGF-A165b resulted in anti-nociception. These results support a role for myelinated fiber pathways, and alternative pre-mRNA splicing of factors such as VEGF-A in the spinal processing of neuropathic pain. They also indicate that targeting pre-mRNA splicing at the spinal level could lead to a novel target for analgesic development.

show abstract

Cerebrospinal Fluid Levels of Vascular Endothelial Growth Factor Correlate With Reported Pain and Are Reduced by Spinal Cord Stimulation in Patients With Failed Back Surgery Syndrome

Cited by 53 publications

References 17 publications

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain

Altered expression of glial markers, chemokines, and opioid receptors in the spinal cord of type 2 diabetic monkeys

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

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