Complete spinal cord injury (SCI) transforms how brain derived neurotrophic factor (BDNF) affects nociceptive sensitization

Huang, Ya-Ching; Lee, Kuan H.; Grau, James W.

doi:10.1016/j.expneurol.2016.11.001

Cited by 34 publications

(45 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, our prior work has related the development of maladaptive plasticity to alterations in nociceptive processing within the dorsal horn (Garraway et al, 2014), which may be less affected by spinal shock. Finally, recent evidence suggests that injury can engage compensatory processes within the dorsal horn that foster neural excitation soon after injury, a modification that may enable nociceptive-induced over-excitation (Huang et al, 2016, 2017, 2018). Further work is needed to detail how these processes interact.…”

Section: Discussionmentioning

confidence: 99%

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury

Turtle

Henwood

Strain

et al. 2019

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

In humans, spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that can engage pain (nociceptive) fibers. Prior work has shown that this nociceptive input can expand the area of tissue damage (secondary injury), undermine behavioral recovery, and enhance the development of chronic pain. Here, it is shown that nociceptive input given a day after a lower thoracic contusion injury in rats enhances the infiltration of red blood cells at the site of injury, producing an area of hemorrhage that expands secondary injury. Peripheral nociceptive fibers were engaged 24 h after injury by means of electrical stimulation (shock) applied at an intensity that engages unmyelinated pain (C) fibers or through the application of the irritant capsaicin. Convergent western immunoblot and cyanmethemoglobin colorimetric assays showed that both forms of stimulation increased the concentration of hemoglobin at the site of injury, with a robust effect observed 3–24 h after stimulation. Histopathology confirmed that shock treatment increased the area of hemorrhage and the infiltration of red blood cells. SCI can lead to hemorrhage by engaging the sulfonylurea receptor 1 (SUR1) transient receptor potential melastatin 4 (TRPM4) channel complex in neurovascular endothelial cells, which leads to cell death and capillary fragmentation. Histopathology confirmed that areas of hemorrhage showed capillary fragmentation. Co-immunoprecipitation of the SUR1-TRPM4 complex showed that it was up-regulated by noxious stimulation. Shock-induced hemorrhage was associated with an acute disruption in locomotor performance. These results imply that noxious stimulation impairs long-term recovery because it amplifies the breakdown of the blood spinal cord barrier (BSCB) and the infiltration of red blood cells, which expands the area of secondary injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury

Turtle

Henwood

Strain

et al. 2019

Experimental Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In uninjured rats, BDNF reduced membrane-bound KCC2 and the inhibitory effect of the GABA A agonist muscimol. After spinal cord injury, BDNF increased KCC2 expression, which might help restore GABAergic inhibition (Huang et al 2017). …”

Section: Dorsal Horn and Nociceptionmentioning

confidence: 99%

Substance P and pain chronicity

2018

View full text Add to dashboard Cite

Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265–301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249–303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6–10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249–4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390–394, 1998). Compounds that inhibit SP’s action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298–308, 2005; Trenkwaldner et al. Sleep Med 31:78–85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.

show abstract

“…For instance, BDNF normally downregulates KCC2, producing an increase in central sensitization. In contrast, following transection injury, BDNF causes an increase in membrane bound KCC2, thereby restoring the inhibitory action of GABAergic neurons, leveling the excitatory/inhibitory balance and decreasing central sensitization (Huang et al, 2017 ). The variability in pathological states of neural circuitry as well as the unique mechanisms of unique modes of neuromodulation are important considerations for not only the interpretation of current literature, but also a challenge to the design of future, mechanistic studies.…”

Section: Exogenous Vs Endogenous Modulation Of Neural Activitymentioning

confidence: 99%

Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

Hogan

Hamilton

Horner

2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Neural stimulation modulates the depolarization of neurons, thereby triggering activity-associated mechanisms of neuronal plasticity. Activity-associated mechanisms in turn play a major role in post-mitotic structure and function of adult neurons. Our understanding of the interactions between neuronal behavior, patterns of neural activity, and the surrounding environment is evolving at a rapid pace. Brain derived neurotrophic factor is a critical mediator of activity-associated plasticity, while multiple immediate early genes mediate plasticity of neurons following bouts of neural activity. New research has uncovered genetic mechanisms that govern the expression of DNA following changes in neural activity patterns, including RNAPII pause-release and activity-associated double stranded breaks. Discovery of novel mechanisms governing activity-associated plasticity of neurons hints at a layered and complex molecular control of neuronal response to depolarization. Importantly, patterns of depolarization in neurons are shown to be important mediators of genetic expression patterns and molecular responses. More research is needed to fully uncover the molecular response of different types of neurons-to-activity patterns; however, known responses might be leveraged to facilitate recovery after neural damage. Physical rehabilitation through passive or active exercise modulates neurotrophic factor expression in the brain and spinal cord and can initiate cortical plasticity commensurate with functional recovery. Rehabilitation likely relies on activity-associated mechanisms; however, it may be limited in its application. Electrical and magnetic stimulation direct specific activity patterns not accessible through passive or active exercise and work synergistically to improve standing, walking, and forelimb use after injury. Here, we review emerging concepts in the molecular mechanisms of activity-derived plasticity in order to highlight opportunities that could add value to therapeutic protocols for promoting recovery of function after trauma, disease, or age-related functional decline.

show abstract

Complete spinal cord injury (SCI) transforms how brain derived neurotrophic factor (BDNF) affects nociceptive sensitization

Cited by 34 publications

References 83 publications

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury

Substance P and pain chronicity

Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review

Contact Info

Product

Resources

About