scholarly journals Electroacupuncture at Hua Tuo Jia Ji Acupoints Reduced Neuropathic Pain and Increased GABAA Receptors in Rat Spinal Cord

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Siao-Wei Jiang ◽  
Yi-Wen Lin ◽  
Ching-Liang Hsieh
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Transient Receptor Potential ◽  
Metabotropic Glutamate Receptor ◽  
Thermal Hyperalgesia ◽  
Control Group ◽  
Spontaneous Pain ◽  
Sprague Dawley ◽  
Hua Tuo ◽  
Study Results

Chronic constriction injury- (CCI-) induced neuropathic pain is the most similar model to hyperalgesia in clinical observation. Neuropathic pain is a neuronal dysfunction in the somatosensory system that may lead to spontaneous pain. In this study, electroacupuncture (EA) was applied at bilateral L4 and L6 of Hua Tuo Jia Ji points (EX-B2) for relieving neuropathic pain in rats. Eighteen Sprague-Dawley rats were randomly assigned to three groups: sham, 2-Hz EA, and 15-Hz EA groups. Following von Frey and cold plate tests, both the 2- and the 15-Hz EA groups had significantly lower mechanical and thermal hyperalgesia than the sham group. Western blot analysis results showed that γ-aminobutyric acid A (GABAA), adenosine A1 receptor (A1R), transient receptor potential cation channel subfamily V member 1 (TRPV1), TRPV4, and metabotropic glutamate receptor 3 (mGluR3) were similar in the dorsal root ganglion of all three groups. Furthermore, levels of GABAA receptors were higher in the spinal cord of rats in the 2- and 15-Hz EA groups compared with the sham control group. This was not observed for A1R, TRPV1, TRPV4, or mGluR3 receptors. In addition, all the aforementioned receptors were unchanged in the somatosensory cortex of the study rats, suggesting a central spinal effect. The study results provide evidence to support the clinical use of EA for specifically alleviating neuropathic pain.

scholarly journals Inhibition of miR-665 alleviates neuropathic pain by targeting SOCS1

2020 ◽  
Vol 19 (8) ◽  
pp. 1591-1597
Author(s):  
Yongqiang Lin ◽  
Mengjia Li ◽  
Gaofeng Rao ◽  
Wenfu Zhang ◽  
Xuyan Chen
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Thermal Hyperalgesia ◽  
Luciferase Assay ◽  
Cytokine Signaling ◽  
Sprague Dawley ◽  
Down Regulation ◽  
Withdrawal Threshold ◽  
Promising Therapeutic Target ◽  
Neuropathic Pain Model

Purpose: To investigate the effect of miR-665 in neuropathic pain and the possible molecular mechanism involved.Methods: A neuropathic pain model was established using chronic constriction injury (CCI) methods in Sprague Dawley (SD) rats. Mechanical and thermal hyperalgesia were measured using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), respectively. The inflammation response was determined by assessing the production of inflammation factors. The target relationship of miR-665 and suppressor of cytokine signaling 1 (SOCS1) was verified by luciferase assay.Results: In the CCI rat model, PWT and PWL decreased following treatment with miR-665 (p < 0.01). MiR-665 was elevated in the spinal cord and microglia of CCI rats at different time points (p < 0.01). Down-regulation of miR-665 increased PWT and PWL and inhibited the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in CCI rats (p < 0.01). Luciferase assay results indicate that SOCS1 was the target of miR-665 (p < 0.01). SOCS1 decreased in CCI rats (p < 0.01) after treatment with miR-665. MiR-665 negatively regulated the expression of SOCS1 (p < 0.01). Down-regulation of SOCS1 reversed the alleviating effect of decreased miR-665 on pain sensitivity and inflammationresponse (p < 0.01).Conclusion: Down-regulation of miR-665 alleviates neuropathic pain by targeting SOCS1, and hence making miR-665 a promising therapeutic target for neuropathic pain. Keywords: MiR-665, SOCS1, Neuropathic pain, CCI, Spinal cord

scholarly journals Tanshinone IIA Downregulates HMGB1 and TLR4 Expression in a Spinal Nerve Ligation Model of Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yu-Qing Ma ◽  
Yi-Rong Chen ◽  
Yu-Fang Leng ◽  
Zhi-Wei Wu
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Interleukin 1 ◽  
Thermal Hyperalgesia ◽  
Interleukin 10 ◽  
Tanshinone Iia ◽  
Group Model ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Tlr4 Mrna

Fifty-four Sprague-Dawley rats weighing 200~240 g were randomly divided into sham-operated group (sham group), vehicle-treated SNL group (model group), and Tan IIA-treated SNL group (Tan IIA group). Tan IIA was administered intraperitoneally to rats in the Tan IIA-treated group at a dose of 30 mg/kg daily for 14 days after SNL surgery. Paw withdrawal mechanical thresholds (PWTs) and paw withdrawal thermal latencies (PWLs) were measured. High-mobility group box 1 (HMGB1) and Toll-like Receptor 4 (TLR4) mRNA and protein expression in the spinal cord were measured. Tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-10 (IL-10) in the spinal cord were measured, too. Both the mechanical and heat pain thresholds were significantly decreased. After Tan IIA treatment, HMGB1, and TLR4 mRNA and protein levels, the expression of TNF-αand IF-1βwas reduced significantly. In conclusion, Tanshinone IIA reversed SNL-induced thermal hyperalgesia and mechanical allodynia and downregulated HMGB1 and TLR4 levels and inhibited the HMGB1-TLR4 pathway. Tanshinone IIA inhibited TNF-αand IL-1βexpression but not IF-10 expression in the spinal cords of SNL rats. These results indicate that Tanshinone IIA inhibited SNL-induced neuropathic pain via multiple effects, and targeting the HMGB1-TLR4 pathway could serve as the basis of new antinociceptive agents.

Motor Recovery after Chronic Spinal Cord Transection in Rats: A Proof-of-Concept Study Evaluating a Combined Strategy

2019 ◽  
Vol 18 (1) ◽  
pp. 52-62 ◽  
Author(s):  
Antonio Ibarra ◽  
Erika Mendieta-Arbesú ◽  
Paola Suarez-Meade ◽  
Elisa García-Vences ◽  
Susana Martiñón ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Treatment Strategies ◽  
Chronic Phase ◽  
Motor Recovery ◽  
Neural Regeneration ◽  
Histological Evaluation ◽  
Control Group ◽  
Proof Of Concept ◽  
Sprague Dawley ◽  
Concept Study

Background: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). Methods: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. Results: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. Conclusion: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

scholarly journals TRPV1 Blocker HCRG21 Suppresses TNF-α Production and Prevents the Development of Edema and Hypersensitivity in Carrageenan-Induced Acute Local Inflammation

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 716
Author(s):  
Oksana Sintsova ◽  
Irina Gladkikh ◽  
Anna Klimovich ◽  
Yulia Palikova ◽  
Viktor Palikov ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Thermal Hyperalgesia ◽  
Control Group ◽  
Transient Receptor Potential Vanilloid ◽  
Paw Edema ◽  
Mice Model ◽  
Edema Formation ◽  
Sensitivity Experiment ◽  
Tnf Α ◽  
Anti Inflammatory

Currently the TRPV1 (transient receptor potential vanilloid type 1) channel is considered to be one of the main targets for pro-inflammatory mediators including TNF-α. Similarly, the inhibition of TRPV1 activity in the peripheral nervous system affects pro-inflammatory mediator production and enhances analgesia in total. In this study, the analgesic and anti-inflammatory effects of HCRG21, the first peptide blocker of TRPV1, were demonstrated in a mice model of carrageenan-induced paw edema. HCRG21 in doses of 0.1 and 1 mg/kg inhibited edema formation compared to the control, demonstrated complete edema disappearance in 24 h in a dose of 1 mg/kg, and effectively reduced the productionof TNF-α in both doses examined. ELISA analysis of blood taken 24 h after carrageenan administration showed a dramatic cytokine value decrease to 25 pg/mL by HCRG21 versus 100 pg/mL in the negative control group, which was less than the TNF-α level in the intact group (40 pg/mL). The HCRG21 demonstrated potent analgesic effects on the models of mechanical and thermal hyperalgesia in carrageenan-induced paw edema. The HCRG21 relief effect was comparable to that of indomethacin taken orally in a dose of 5 mg/kg, but was superior to this nonsteroidal anti-inflammatory drug (NSAID) in duration (which lasted 24 h) in the mechanical sensitivity experiment. The results confirm the existence of a close relationship between TRPV1 activity and TNF-α production once again, and prove the superior pharmacological potential of TRPV1 blockers and the HCRG21 peptide in particular.

scholarly journals Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization

2021 ◽  
Vol 17 ◽  
pp. 174480692199652
Author(s):  
Feng Zhou ◽  
Xian Wang ◽  
Baoyu Han ◽  
Xiaohui Tang ◽  
Ru Liu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Thermal Hyperalgesia ◽  
Short Chain Fatty Acids ◽  
Antibiotic Administration ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Inflammatory Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

scholarly journals EGCG Prevents the Loss of Pontine Noradrenergic Neurons Induced by Diabetes: A Role in Diabetic Neuropathic Pain

2012 ◽  
Vol 18 (S5) ◽  
pp. 5-6 ◽  
Author(s):  
Carla Morgado ◽  
João Silva ◽  
André Miranda ◽  
Patrícia Pereira-Terra ◽  
Diogo Raposo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Diabetic Rats ◽  
Pain Modulation ◽  
Diabetic Patients ◽  
Spontaneous Pain ◽  
Noradrenergic Neurons ◽  
Diabetic Neuropathic Pain ◽  
Descending Pain Modulation ◽  
Pain Responses

Diabetes is a major health problem with an alarming increasing prevalence, and is the most frequent cause of neuropathy worldwide. Neuropathy affects 50–60% of diabetic patients, being a major life-quality impairment for a quarter of these patients. Diabetic neuropathic pain (DNP) is characterized by spontaneous pain, mechanical hyperalgesia and tactile allodynia and is accompanied by functional and neurochemical changes at the peripheral nerves, spinal cord and supraspinal pain control areas. Regarding the effects of diabetic neuropathy in the central somatossensory system, it was shown that streptozotocin (STZ)-diabetic rats present spontaneous hyperactivity and hyperexcitability of spinal nociceptive neurons, which may be subserving the exacerbated pain responses. The spinal functional changes and pain may be due to increased peripheral input(2), changes in spinal nociceptive modulatory mechanisms and altered supraspinal descending pain modulation. Noradrenergic descending pain modulation seems to be impaired since STZ-diabetic rats present decreased numbers of noradrenergic neurons at the A5 and A7 pontine cell groups, along with lower levels of noradrenaline at the spinal cord and higher behavioral responses to pain. This is consistent with the strong noradrenergic projection from A5 and A7 neurons to the spinal dorsal horn and the modulation of nociceptive transmission by local release of noradrenaline. The mechanisms underlying the decrease in noradrenergic neurons in the brainstem during diabetes remain unclear. Our recent findings that diabetes induces oxidative stress damage in neurons from those areas, lead us to hypothesize that it may contribute to their loss. Thereafter, with the present study we aimed to evaluate the effects of Epigallocathechin Gallate (EGCG), a potent antioxidant present in green tea, on spinal noradrenaline levels, on A5 and A7 noradrenergic neurons and on behavioral pain responses of STZ-diabetic rats.

Calcineurin Regulates Synaptic Plasticity and Nociceptive Transmissionat the Spinal Cord Level

2021 ◽  
pp. 107385842110468
Author(s):  
Yuying Huang ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Protein Phosphatase ◽  
Transient Receptor Potential ◽  
Calcineurin Inhibitors ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Negative Feedback Regulation ◽  
Spinal Cord Level ◽  
Calcineurin Activity

Calcineurin, the predominant Ca2+/calmodulin-dependent serine/threonine protein phosphatase (also known as protein phosphatase 2B), is highly expressed in immune T cells and the nervous system, including the dorsal root ganglion and spinal cord. It controls synaptic transmission and plasticity by maintaining the appropriate phosphorylation status of many ion channels present at presynaptic and postsynaptic sites. As such, normal calcineurin activity in neurons and synapses is mainly involved in negative feedback regulation in response to increased neuronal activity and intracellular Ca2+ levels. Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) are widely used as immunosuppressants in tissue and organ transplantation recipients and for treating autoimmune diseases but can cause severe pain in some patients. Furthermore, diminished calcineurin activity at the spinal cord level may play a major role in the transition from acute to chronic neuropathic pain after nerve injury. Restoring calcineurin activity at the spinal cord level produces long-lasting pain relief in animal models of neuropathic pain. In this article, we provide an overview of recent studies on the critical roles of calcineurin in regulating glutamate NMDA and AMPA receptors, voltage-gated Ca2+ channels, potassium channels, and transient receptor potential channels expressed in the spinal dorsal horn and primary sensory neurons.

Antiallodynic Effect of Intrathecal Korean Red Ginseng in Cisplatin-Induced Neuropathic Pain Rats

Pharmacology ◽  
2019 ◽  
Vol 105 (3-4) ◽  
pp. 173-180 ◽  
Author(s):  
Yeo Ok Kim ◽  
Ji A Song ◽  
Woong Mo Kim ◽  
Myung Ha Yoon
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Mrna Expression ◽  
Therapeutic Potential ◽  
Red Ginseng ◽  
Sprague Dawley ◽  
Korean Red Ginseng ◽  
Receptor Mrna ◽  
Antiallodynic Effect

Background: Chemotherapy-induced neuropathic pain (CINP) is a serious side effect of chemotherapy. Korean Red Ginseng (KRG) is a popular herbal medicine in Asian countries. We examined the therapeutic potential of intrathecally administered KRG for CINP and clarified the mechanisms of action with regard to 5-hydroxytryptamine (5-HT)7 receptor at the spinal level. Methods: CINP was evoked by intraperitoneal injection of cisplatin in male Sprague-Dawley rats. After examining the effects of intrathecally administered KRG on CINP, 5-HT receptor antagonist (dihydroergocristine [DHE]) was pretreated to determine the involvement of 5-HT receptor. In addition, intrathecal 5-HT7 receptor antagonist (SB269970) was administered to define the role of 5-HT7 receptor on the effect of KRG. 5-HT7 receptor mRNA expression levels and 5-HT concentrations were examined in the spinal cord. Results: Intrathecally administered KRG produced a limited, but a dose-dependent, antiallodynic effect. Intrathecally administered DHE antagonized the antiallodynia caused by KRG. Furthermore, intrathecal SB269970 also reversed the effect of KRG. No changes in 5-HT7 receptor mRNA expression were seen in the dorsal horn of the spinal cord after cisplatin injection. After injecting cisplatin, 5-HT levels were decreased in the spinal cord, whereas those of 5-HT were increased by intrathecal KRG. Conclusions: Intrathecally administered KRG decreased CINP. In addition, spinal 5-HT7 receptors contributed to the antiallodynic effect of KRG.

Comprehensive analysis of neurobehavior associated with histomorphological alterations in a chronic constrictive nerve injury model through use of the CatWalk XT system

2014 ◽  
Vol 120 (1) ◽  
pp. 250-262 ◽  
Author(s):  
Chien-Yi Chiang ◽  
Meei-Ling Sheu ◽  
Fu-Chou Cheng ◽  
Chun-Jung Chen ◽  
Hong-Lin Su ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
S100 Protein ◽  
Thermal Hyperalgesia ◽  
Nerve Damage ◽  
Dorsal Spinal Cord ◽  
Sensory Evoked ◽  
Dorsal Spinal

Object Neuropathic pain is debilitating, and when chronic, it significantly affects the patient physically, psychologically, and socially. The neurobehavior of animals used as a model for chronic constriction injury seems analogous to the neurobehavior of humans with neuropathic pain. However, no data depicting the severity of histomorphological alterations of the nervous system associated with graded changes in neurobehavior are available. To determine the severity of histomorphological alteration related to neurobehavior, the authors created a model of chronic constrictive injury of varying intensity in rats and used the CatWalk XT system to evaluate neurobehavior. Methods A total of 60 Sprague-Dawley rats, weighing 250–300 g each, were randomly assigned to 1 of 5 groups that would receive sham surgery or 1, 2, 3, or 4 ligatures of 3-0 chromic gut loosely ligated around the left sciatic nerve. Neurobehavior was assessed by CatWalk XT, thermal hyperalgesia, and mechanic allodynia before injury and periodically after injury. The nerve tissue from skin to dorsal spinal cord was obtained for histomorphological analysis 1 week after injury, and brain evoked potentials were analyzed 4 weeks after injury. Results. Significant differences in expression of nerve growth factor existed in skin, and the differences were associated with the intensity of nerve injury. After injury, expression of cluster of differentiation 68 and tumor necrosis factor–α was increased, and expression of S100 protein in the middle of the injured nerve was decreased. Increased expression of synaptophysin in the dorsal root ganglion and dorsal spinal cord correlated with the intensity of injury. The amplitude of sensory evoked potential increased with greater severity of nerve damage. Mechanical allodynia and thermal hyperalgesia did not differ significantly among treatment groups at various time points. CatWalk XT gait analysis indicated significant differences for print areas, maximum contact maximum intensity, stand phase, swing phase, single stance, and regular index, with sham and/or intragroup comparisons. Conclusions. Histomorphological and electrophysiological alterations were associated with severity of nerve damage. Subtle neurobehavioral differences were detected by the CatWalk XT system but not by mechanical allodynia or thermal hyperalgesia. Thus, the CatWalk XT system should be a useful tool for monitoring changes in neuropathic pain, especially subtle alterations.

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