Activation of KCNQ Channels Suppresses Spontaneous Activity in Dorsal Root Ganglion Neurons and Reduces Chronic Pain after Spinal Cord Injury

Unraveling the cellular and molecular mechanisms of spinal cord injury is fundamental for our possibility to develop successful therapeutic approaches. These approaches need to address the issues of the emergence of a non-permissive environment for axonal growth in the spinal cord, in combination with a failure of injured neurons to mount an effective regeneration program. Experimental in vivo models are of critical importance for exploring the potential clinical relevance of mechanistic findings and therapeutic innovations. However, the highly complex organization of the spinal cord, comprising multiple types of neurons, which form local neural networks, as well as short and long-ranging ascending or descending pathways, complicates detailed dissection of mechanistic processes, as well as identification/verification of therapeutic targets. Inducing different types of dorsal root injury at specific proximo-distal locations provide opportunities to distinguish key components underlying spinal cord regeneration failure. Crushing or cutting the dorsal root allows detailed analysis of the regeneration program of the sensory neurons, as well as of the glial response at the dorsal root-spinal cord interface without direct trauma to the spinal cord. At the same time, a lesion at this interface creates a localized injury of the spinal cord itself, but with an initial neuronal injury affecting only the axons of dorsal root ganglion neurons, and still a glial cell response closely resembling the one seen after direct spinal cord injury. In this review, we provide examples of previous research on dorsal root injury models and how these models can help future exploration of mechanisms and potential therapies for spinal cord injury repair.

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Axotomy- and Autotomy-Induced Changes in the Excitability of Rat Dorsal Root Ganglion Neurons

Journal of Neurophysiology ◽

10.1152/jn.2001.85.2.630 ◽

2001 ◽

Vol 85 (2) ◽

pp. 630-643 ◽

Cited By ~ 113

Author(s):

Fuad A. Abdulla ◽

Peter A. Smith

Keyword(s):

Sciatic Nerve ◽

Dorsal Root Ganglion ◽

Spontaneous Activity ◽

Dorsal Root ◽

Sensory Nerves ◽

Dorsal Root Ganglion Neurons ◽

Small Cells ◽

Resting Membrane Potential ◽

Ganglion Neurons ◽

Induced Changes

The spontaneous, ectopic activity in sensory nerves that is induced by peripheral nerve injury is thought to contribute to the generation of “neuropathic” pain in humans. To examine the cellular mechanisms that underlie this activity, neurons in rat L4–L5 dorsal root ganglion (DRG) were first grouped as “large,” “medium,” or “small” on the basis of their size (input capacitance) and action potential (AP) shape. A fourth group of cells that exhibited a pronounced afterdepolarization (ADP) were defined as AD-cells. Whole cell recording was used to compare the properties of control neurons with those dissociated from rats in which the sciatic nerve had been sectioned (“axotomy” group) and with neurons from rats that exhibited self-mutilatory behavior in response to sciatic nerve section (“autotomy” group). Increases in excitability in all types of DRG neuron were seen within 2–7 wk of axotomy. Resting membrane potential (RMP) and the amplitude and duration of the afterhyperpolarization (AHP) that followed the AP were unaffected. Effects of axotomy were greatest in the small, putative nociceptive cells and least in the large cells. Moderate changes were seen in the medium and AD-cells. Compared to control neurons, axotomized neurons exhibited a higher frequency of evoked AP discharge in response to 500-ms depolarizing current injections; i.e., “gain” was increased and accommodation was decreased. The minimum current required to discharge an AP (rheobase) was reduced. There were significant increases in spike width in small cells and significant increases in spike height in small, medium, and AD-cells. The electrophysiological changes promoted by axotomy were intensified in animals that exhibited autotomy; spike height, and spike width were significantly greater than control for all cell types. Under our experimental conditions, spontaneous activity was never encountered in neurons dissociated from animals that exhibited autotomy. Thus changes in the electrical properties of cell bodies alone may not entirely account for injury-induced spontaneous activity in sensory nerves. The onset of autotomy coincided with alterations in the excitability of large, putative nonnociceptive, neurons. Thus large cells from the autotomy group were muchmore excitable than those from the axotomy group, whereas small cells from the autotomy group were only slightly more excitable. This is consistent with the hypothesis that the onset of autotomy is associated with changes in the properties of myelinated fibers. Changes in Ca2+ and K+ channel conductances that contribute to axotomy- and autotomy-induced changes in excitability are addressed in the accompanying paper.

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(385) Targeting KCNQ channels to prevent spinal cord injury-induced chronic pain

Journal of Pain ◽

10.1016/j.jpain.2015.01.304 ◽

2015 ◽

Vol 16 (4) ◽

pp. S72

Author(s):

Q. Yang ◽

Z. Wu ◽

J. Hadden ◽

J. Du ◽

S. Carlton ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Chronic Pain ◽

Kcnq Channels ◽

Cord Injury

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Systematic Administration of B Vitamins Alleviates Diabetic Pain and Inhibits Associated Expression of P2X3 and TRPV1 in Dorsal Root Ganglion Neurons and Proinflammatory Cytokines in Spinal Cord in Rats

Pain Research and Management ◽

10.1155/2020/3740162 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Duan-Duan He ◽

Yu Gao ◽

Shan Wang ◽

Zhong Xie ◽

Xue-Jun Song

Keyword(s):

Spinal Cord ◽

Blood Glucose ◽

Dorsal Root Ganglion ◽

Proinflammatory Cytokines ◽

Dorsal Root ◽

B Vitamins ◽

Dorsal Root Ganglion Neurons ◽

Drg Neurons ◽

B Vitamin ◽

Ganglion Neurons

Background. Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats. Methods. DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation. Results. There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% (n = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1β, tumor necrosis factor-α, and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment. Conclusions. B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic.

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Axotomy of tributaries of the pelvic and pudendal nerves induces changes in the neurochemistry of mouse dorsal root ganglion neurons and the spinal cord

Brain Structure and Function ◽

10.1007/s00429-015-1019-6 ◽

2015 ◽

Vol 221 (4) ◽

pp. 1985-2004 ◽

Cited By ~ 5

Author(s):

Carly J. McCarthy ◽

Eugenia Tomasella ◽

Mariana Malet ◽

Kim B. Seroogy ◽

Tomas Hökfelt ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Mouse Dorsal Root Ganglion ◽

Ganglion Neurons

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Localization, morphology, and immunohistochemistry of spinal cord and dorsal root ganglion neurons that innervate the gastrocnemius and superficial digital flexor muscles in cattle

American Journal of Veterinary Research ◽

10.2460/ajvr.2005.66.710 ◽

2005 ◽

Vol 66 (4) ◽

pp. 710-720 ◽

Cited By ~ 4

Author(s):

Roberto Chiocchetti ◽

Annamaria Grandis ◽

Cristiano Bombardi ◽

Paolo Clavenzani ◽

Alessandro Spadari ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Flexor Muscles ◽

Ganglion Neurons

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The causal role of magnesium deficiency in the neuroinflammation, pain hypersensitivity and memory/emotional deficits in ovariectomized and aging mice

10.21203/rs.3.rs-379976/v1 ◽

2021 ◽

Author(s):

Xian-guo Liu ◽

Jun Zhang ◽

Chun-lin Mai ◽

Ying Xiong ◽

Zhen-Jia Lin ◽

...

Keyword(s):

Chronic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Dorsal Root ◽

Dorsal Root Ganglion Neurons ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Emotional Deficits ◽

Ganglion Neurons ◽

Neuronal Disorders

Abstract Background: Postmenopausal women often suffer from chronic pain, memory decline and mood depression. The mechanisms underlying the neuronal disorders are not fully understood and effective treatment is still lacking.Methods: Oral administration of magnesium-L-threonate was tested to treat the neuronal disorders in ovariectomized and aging mice. The pain hypersensitivity, memory function and depression were measured with a set of behavioral tests. Western blots and immunochemistry were used to assess molecular changes.Results: Chronic oral administration of magnesium-L-threonate substantially prevented or reversed the chronic pain, and memory/emotional deficits in both ovariectomized and aging female mice. We found that phospho-p65, an active form of nuclear factor-kappaB, tumor necrosis factor-alpha and interleukin-1beta were significantly upregulated in the neurons of dorsal root ganglion, spinal dorsal horn and hippocampus in ovariectomized and aging mice. The microglia and astrocytes were activated in spinal dorsal horn and hippocampus. The peptidergic C-fibers in dorsal horn were increased, which are associated with potentiation of C-fiber-mediated synaptic transmission in the model mice. In parallel with neuroinflammation and synaptic potentiation, free Mg2+ levels in plasma, cerebrospinal fluid and dorsal root ganglion neurons were significantly reduced. Oral magnesium-L-threonate normalized the neuroinflammation, synaptic potentiation and Mg2+ deficiency, but did not affect the estrogen decline in ovariectomized and aging mice. Furthermore, in cultured dorsal root ganglion neurons estrogen elevated intracellular Mg2+, and depressed the upregulation of phospho-p65, tumor necrosis factor-alpha and interleukin-1beta exclusively in the presence of extracellular Mg2+.Conclusions: Estrogen decline in menopause causes neuroinflammation by reducing intracellular Mg2+ in neurons, leading to chronic pain, memory/emotional deficits. Thus, supplement Mg2+ by oral magnesium-L-threonate may be a novel approach for treating menopause-related neuronal disorders.

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