Exercise-induced analgesia (EIA) refers to the elevation of pain thresholds and reduction in sensitivity to noxious stimuli achieved through exercise training. As a non-pharmacological treatment strategy, exercise therapy has demonstrated positive effects on both acute and chronic pain. Increasing evidence indicates that modulation of glial cell activity is an important mechanism underlying analgesia. Spinal glial cells contribute to the development and maintenance of pathological pain by promoting pain signal transmission through inflammatory responses and synaptic remodeling. Exercise can differentially regulate microglia and astrocyte activity, inhibiting multiple inflammatory signaling pathways, such as P2X4/P2X7 purinergic receptors, brain-derived neurotrophic factor (BDNF)/phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR), interleukin (IL)-6/Janus kinase (JAK) 2/signal transducer and activator of transcription 3 (STAT3), p38-mitogen-activated protein kinases (MAPK), and Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB), thereby reducing the release of pro-inflammatory cytokines, decreasing inflammatory and nociceptive hypersensitivity, and alleviating pathological pain. This review also summarized the effects of different exercise intensities, durations, and frequencies on glial cell responses in order to provide a theoretical foundation for optimizing exercise-based interventions for pathological pain conditions.
Humans ; Microglia/metabolism* ; Astrocytes/metabolism* ; Exercise/physiology* ; Signal Transduction ; Analgesia/methods* ; Spinal Cord/cytology* ; Exercise Therapy ; Pain Management/methods* ; Animals ; Brain-Derived Neurotrophic Factor/metabolism*

Spinal cord injury (SCI), which is much in the public eye, is still a refractory disease compromising the well-being of both patients and society. In spite of there being many methods dealing with the lesion, there is still a deficiency in comprehensive strategies covering all facets of this damage. Further, we should also mention the structure called the corticospinal tract (CST) which plays a crucial role in the motor responses of organisms, and it will be the focal point of our attention. In this review, we discuss a variety of strategies targeting different dimensions following SCI and some treatments that are especially efficacious to the CST are emphasized. Over recent decades, researchers have developed many effective tactics involving five approaches: (1) tackle more extensive regions; (2) provide a regenerative microenvironment; (3) provide a glial microenvironment; (4) transplantation; and (5) other auxiliary methods, for instance, rehabilitation training and electrical stimulation. We review the basic knowledge on this disease and correlative treatments. In addition, some well-formulated perspectives and hypotheses have been delineated. We emphasize that such a multifaceted problem needs combinatorial approaches, and we analyze some discrepancies in past studies. Finally, for the future, we present numerous brand-new latent tactics which have great promise for curbing SCI.
Animals ; Astrocytes/cytology* ; Axons/physiology* ; Cell Transplantation ; Disease Models, Animal ; Electric Stimulation ; Humans ; Microglia/cytology* ; Motor Neurons/cytology* ; Nerve Regeneration ; Neuroglia/cytology* ; Neuronal Plasticity ; Neurons/cytology* ; Oligodendroglia/cytology* ; Pyramidal Tracts/pathology* ; Recovery of Function ; Regenerative Medicine/methods* ; Spinal Cord Injuries/therapy*

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism

Chronic spinal cord compression is the common clinical prognosis with various outcomes, but the affecting factors and mechanisms still remain unexplored. The structure and function of neurovascular unit manifest great significance in the central nervous system diseases. This paper discusses matrix metalloproteinase (MMP) impact on the stability of the neural vascular unit, by directly decomposing extracellular matrix, inducing the glial cell migration, activating angiogenesis, regulating function of blood spinal cord barrier, and put forward the MMP may be the key points in regulation of spinal cord neurovascular unit structure and function change to affect the outcome of chronic oppressive cervical spinal cord.
Cell Movement ; Humans ; Matrix Metalloproteinases ; physiology ; Nerve Compression Syndromes ; diagnosis ; enzymology ; Neurons ; cytology ; Prognosis ; Spinal Cord Injuries ; diagnosis ; enzymology

OBJECTIVETo explore the effect of electro-acupuncture to improve the bladder function after acute spinal cord injury in rats and its possible mechanism.

METHODSSixty healthy adult male SD rats of SPF grade, with body weight of 220 to 250 g, one week after feeding adaptation, were randomly divided into sham operation group, model group, electro-acupuncture group, electro-acupuncture control group with 15 rats in each group. Sham operation group underwent no stimulation, and the moderate damage model of spinal cord injury were made in other three groups according to modified Allens method. The model group were not treated, electro-acupuncture group were treated with electro-acupuncture on Zhibianxue and Shuidaoxue, and electro-acupuncture control group were treated with electro-acupuncture on 0.5 inch next to Zhibianxue and Shuidaoxue. The frequency of 2/100 Hz, current of 1 mA, stimulation time of 15 min, once a day, left and right alternately stimulate every time, for a total of 7 times. The changes of residual urine volume and urine output in rats at the 1st and the 7th days after operation were observed. And 7 d later, the rats were sacrificed and the injured spinal cord were taken out to observe the apoptosis, and to detect the changes of Bcl-2, Bax, Bad content.

RESULTSAfter modeling,the rats of three groups showed different bladder dysfunction. In electro-acupuncture group and electro-acupuncture control group, the residual urine volume of the 7th day after operation was significant lower than the 1st day after operation (P < 0.001), and there was statistically significant difference on the 7th day after operation between two groups (P < 0.001). Compared with model group, the urine output of electro-acupuncture group and electro-acupuncture control group was significantly increased on the 7th day after operation, and there was sig- nificant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.001). Electro-acupuncture can inhibit apoptosis of spinal cord neurons by TUNEL detection. Postoperative at 7 d, the rate of nerve cell apoptosis in electro -acupuncture group and electro-acupuncture control group was significant increased than model group (P < 0.01, P < 0.05), and there was significant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.005). Compared with model group, the positive expression rate of Bax, Bad decreased (P < 0.01, P < 0.05), and Bcl-2 increased (P < 0.01) in electro-acupuncture group and electro-acupuncture control group,there was significant difference between electro-acupuncture group and electro-acupuncture control group (P < 0.01).

CONCLUSIONElectro-acupuncture can obviously promote the repair of acute spinal cord injury,its mechanism may be through increasing Bcl-2, inhibiting the expression of Bax, Bad, which inhibits the apoptosis of spinal cord neurons.

Animals ; Apoptosis ; Electroacupuncture ; Immunohistochemistry ; In Situ Nick-End Labeling ; Male ; Neurons ; cytology ; physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Injuries ; pathology ; physiopathology ; therapy ; Urinary Bladder ; physiopathology

Spinal microglia and astrocytes play an important role in mediating behavioral hypersensitive state following peripheral nerve injury. However, little is known about the expression patterns of activated microglia and astrocytes in the spinal dorsal horn. The aim of the present study was to investigate the spatial distribution of microglial and astrocytic activation in cervical, thoracic, lumbar and sacral segments of spinal dorsal horn following chronic constriction injury (CCI) of sciatic nerve. The hind paw withdrawal threshold (PWT) of wild type (WT), CX3CR1(YFP) and GFAP(YFP) transgenic mice to mechanical stimulation was determined by von Frey test. Immunofluorescence staining was used to examine the spatial distribution of microglial and astrocytic activation in the spinal dorsal horn. Following CCI, all the WT, CX3CR1(YFP) and GFAP(YFP) mice developed robust allodynia in the ipsilateral paw on day 3 after CCI, and the allodynia was observed to last for 14 days. In comparison with sham groups, the PWTs of CCI group animals were significantly decreased (P < 0.01, n = 6). On day 14 after CCI, CX3CR1(YFP)-GFP immunofluorescence intensity was significantly increased in the ipsilateral lumbar spinal dorsal horn of the CX3CR1(YFP) mice (P < 0.01, n = 6), but no detectable changes were observed in other spinal segments. Increased GFAP(YFP)-GFP immunofluorescence intensity was observed in the ipsilateral thoracic, lumbar and sacral spinal segments of the GFAP(YFP) mice on day 14 after CCI. Iba-1 and GFAP immunofluorescence staining in WT mice showed the same result of microglia and astrocyte activation on day 14 after CCI. CX3CR1(YFP)-GFP and GFAP(YFP)-GFP immunofluorescence signal was colocalized with microglial marker Iba-1 and astrocytic marker GFAP, respectively. Interestingly, on day 3 after CCI, Iba-1-immunoreactivity was significantly increased in the ipsilateral thoracic, lumbar and sacral spinal segments of WT mice, whereas the significant upregulation of GFAP-immunoreactivity restrictedly occurred in the ipsilateral lumbar spinal segment. These results suggest that microglial and astrocytic activation may be involved in the development and maintenance of secondary allodynia in mice with neuropathic pain.
Animals ; Astrocytes ; physiology ; Disease Models, Animal ; Hyperalgesia ; Mice ; Mice, Transgenic ; Microglia ; physiology ; Neuralgia ; Peripheral Nerve Injuries ; Sciatic Nerve ; injuries ; Spinal Cord Dorsal Horn ; cytology ; Up-Regulation

The aim of the present study is to observe the receptor kinetics property of long-term potentiation (LTP) of excitatory postsynaptic potential (EPSP) in spinal cord motoneurons (MNs) by descending activation. The intracellular recording techniques were conducted in spinal cord MNs of neonatal rats aged 8-14 days. The changes of EPSP induced by ipsilateral ventrolateral funiculus (iVLF) stimulation (iVLF-EPSPs) were observed, and receptor kinetics of iVLF-EPSPs were analyzed. The results showed that, the amplitude, area under curve and maximum left slope of EPSP were positively correlated with stimulus intensity (P < 0.05 or P < 0.01), while the apparent receptor kinetic parameters apparent dissociation rate constant (K(2)), apparent equilibrium dissociation constant (K(T)) of EPSP were negatively correlated with stimulus intensity (P < 0.01 or P < 0.05). The iVLF-EPSPs were persistently increased after tetanic stimulation (100 Hz, 50 pulses/train, duration 0.4-1.0 ms, 6 trains, main interval 10 s, 10-100 V) in 5 of 11 tested MNs. The amplitude of iVLF-EPSPs was potentiated to more than 120% of baseline and lasted at least 30 min, which could be referred to as iVLF-LTP. Meanwhile, the area under curve and maximum left slope of EPSPs were also increased to more than 120% of baseline. During iVLF-LTP, apparent receptor kinetics analyses of iVLF-EPSPs indicated that K(2) and KT were decreased significantly to less than 80% of the baseline within 10 min and gradually and partially recovered in 3 MNs. These results of receptor kinetics analyses of iVLF-EPSPs suggest a possible enhancement in affinity of postsynaptic receptors in the early stage of iVLF-LTP in some MNs.
Animals ; Excitatory Postsynaptic Potentials ; Kinetics ; Long-Term Potentiation ; Motor Neurons ; physiology ; Rats ; Spinal Cord ; cytology ; Synaptic Transmission

OBJECTIVETo study the protective effects of sacral nerve root electrostimulation on intestinal mechanical barrier in rats with spinal cord injury (SCI).

METHODSFifty six Wistar rats were divided into normal group, SCI control group and SCI group with sacral nerve root electrostimulation (8 rats in each subgroup at 24, 48, 72 h after spinal cord injury). The following experiments were performed respectively in rats from the 3 groups: bacteria culture from intestinal mesentery lymph nodes, liver, spleen, intestinal morphology observation and detection the protein expression level of ZO-1.

RESULTSThe intestinal mucosa appeared different degree of damage in SCI control group; cell-cell connections between intestinal epithelial cells were destroyed; Endotoxin levels in blood and the number of bacterial translocation increased obviously. Sacral nerve stimulation was found toimprove the intestinal mucosal, reduce the endotoxin content in the blood to normal level and the decrease the incidences of bacterial translocation of the gut origin. The expression of tight junction protein ZO-1 of rat intestinal tissue had no statistical differences among the 3 groups. On the other hand, the distribution of tight junction protein ZO-1 appeared different degrees of scattered and irregular in the control group while that in the experimental group appeared different degree of improvement as determined by the immunohistochemistry of rat intestinal tissue.

CONCLUSIONsacral nerve root electrostimulation can rehabilitate the peristalsis of denervated colon, promote defeacation and decrease bacterial amount, protection of the intestinal mechanical barrier between intestinal epithelial cells and tight junction, reducing the endotoxin content in the blood and suppressing bacterial translocation from the gut.

Animals ; Bacterial Translocation ; Electric Stimulation Therapy ; Endotoxins ; blood ; Epithelial Cells ; cytology ; Intestinal Mucosa ; physiology ; Peristalsis ; Rats ; Rats, Wistar ; Spinal Cord ; Spinal Cord Injuries ; physiopathology ; Zonula Occludens-1 Protein ; metabolism

The aim of the paper is to study the effect of spontaneous firing of injured dorsal root ganglion (DRG) neuron in chronic compression of DRG (CCD) model on excitability of wide dynamic range (WDR) neuron in rat spinal dorsal horn. In vivo intracellular recording was done in DRG neurons and in vivo extracellular recording was done in spinal WDR neurons. After CCD, incidence of spontaneous discharge and firing frequency enhanced to 59.46% and (4.30 ± 0.69) Hz respectively from 22.81% and (0.60 ± 0.08) Hz in normal control group (P < 0.05). Local administration of 50 nmol/L tetrodotoxin (TTX) on DRG neuron in CCD rats decreased the spontaneous activities of WDR neurons from (191.97 ± 45.20)/min to (92.50 ± 30.32)/min (P < 0.05). On the other side, local administration of 100 mmol/L KCl on DRG neuron evoked spontaneous firing in a reversible way (n = 5) in silent WDR neurons of normal rats. There was 36.36% (12/33) WDR neuron showing after-discharge in response to innocuous mechanical stimuli on cutaneous receptive field in CCD rats, while after-discharge was not seen in control rats. Local administration of TTX on DRG with a concentration of 50 nmol/L attenuated innocuous electric stimuli-evoked after-discharge of WDR neurons in CCD rats in a reversible manner, and the frequency was decreased from (263 ± 56.5) Hz to (117 ± 30) Hz (P < 0.05). The study suggests that the excitability of WDR neurons is influenced by spontaneous firings of DRG neurons after CCD.
Action Potentials ; Animals ; Ganglia, Spinal ; physiology ; Neurons ; physiology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Dorsal Horn ; cytology

BACKGROUNDThe Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of spinal cord injury, we developed a cellular model of Raf/ERK up-regulation by overexpressing c-Raf in cultured spinal cord neurons (SCNs) and dorsal root ganglions (DRGs).

METHODSDRGs and SCNs were prepared from C57BL/6J mouse pups. DRGs or SCNs were infected with Ad-Raf-1 or Ad-Null adenovirus alone. Cell adhesion assay and cell migration assay were investigated, DiI labeling was employed to examine the effect of the up-regulation of Ras/Raf/ERK1/2 signaling on the dendritic formation of spinal neurons. We used the TO-PRO-3 staining to examine the apoptotic effect of c-Raf on DRGs or SCNs. The effect on the synapse formation of neurons was measured by using immunofluorescence.

RESULTSWe found that Raf/ERK up-regulation stimulates the migration of both SCNs and DRGs, and impairs the formation of excitatory synapses in SCNs. In addition, we found that Raf/ERK up-regulation inhibits the development of mature dendritic spines in SCNs. Investigating the possible mechanisms through which Raf/ERK up-regulation affects the excitatory synapse formation and dendritic spine development, we discovered that Raf/ERK up-regulation suppresses the development and maturation of SCNs.

CONCLUSIONThe up-regulation of the Raf/ERK signaling pathway may contribute to the pathogenesis of spinal cord injury through both its impairment of the SCN development and causing neural circuit imbalances.

Animals ; Cell Movement ; physiology ; Dendritic Spines ; metabolism ; physiology ; Female ; Ganglia, Spinal ; cytology ; MAP Kinase Signaling System ; physiology ; Mice ; Neurogenesis ; genetics ; physiology ; Neurons ; cytology ; Pregnancy ; Signal Transduction ; genetics ; physiology ; Spinal Cord ; cytology ; Synapses ; metabolism ; physiology ; Up-Regulation ; raf Kinases ; genetics ; metabolism ; ras Proteins ; genetics ; metabolism