Caveolin-1 in Spinal Cord Modulates Type-2 Diabetic Neuropathic Pain Through the Rac1/NOX2/NR2B Signaling Pathway

Abstract The mechanisms underlying type-2 diabetic neuropathic pain (DNP) are unclear. This study investigates the coupling of postsynaptic density-95 (PSD-95) to N-methyl-D-aspartate receptor subunit 2B (GluN2B), and the subsequent phosphorylation of GluN2B (Tyr1472-GluN2B) in the spinal cord in a rat model of type-2 DNP. Expression levels of PSD-95, Tyr1472-GluN2B, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its phosphorylated counterpart (Thr286-CaMKII), and α-amino-3-hydroxy-5-methyl-4-soxazole propionic acid receptor subtype 1 (GluR1) and its phosphorylated counterpart (Ser831-GluR1) were significantly increased versus controls in the spinal cord of type-2 DNP rats whereas the expression of total spinal GluN2B did not change. The intrathecal injection of Ro25-6981 (a specific antagonist of GluN2B) or Tat-NR2B9c (a mimetic peptide disrupting the interaction between PSD-95 and GluN2B) induced an antihyperalgesic effect and blocked the increased expression of Tyr1472-GluN2B, CaMKII, GluR1, Thr286-CaMKII, and Ser831-GluR1 in the spinal cords; the increase in spinal cord PSD-95 was not affected. These findings indicate that the PSD-95-GluN2B interaction may increase phosphorylation of GluN2B, and subsequently induce the expression of phosphorylation of CaMKII and GluR1 in the spinal cord of type-2 DNP rats. Targeting the interaction of PSD-95 with GluN2B may provide a new therapeutic strategy for type-2 DNP.

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Effects of curcumin on TTX-R sodium currents of dorsal root ganglion neurons in type 2 diabetic rats with diabetic neuropathic pain

Neuroscience Letters ◽

10.1016/j.neulet.2015.08.011 ◽

2015 ◽

Vol 605 ◽

pp. 59-64 ◽

Cited By ~ 7

Author(s):

Bo Meng ◽

Lu-lu Shen ◽

Xiao-ting Shi ◽

Yong-sheng Gong ◽

Xiao-fang Fan ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Diabetic Rats ◽

Dorsal Root Ganglion Neurons ◽

Sodium Currents ◽

Diabetic Neuropathic Pain ◽

Ganglion Neurons ◽

Type 2 Diabetic

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Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10

Neurobiology of Disease ◽

10.1016/j.nbd.2013.05.003 ◽

2013 ◽

Vol 58 ◽

pp. 169-178 ◽

Cited By ~ 26

Author(s):

Yan Ping Zhang ◽

Chun Yu Song ◽

Yue Yuan ◽

Ariel Eber ◽

Yiliam Rodriguez ◽

...

Keyword(s):

Neuropathic Pain ◽

Mouse Model ◽

Coenzyme Q10 ◽

Diabetic Mouse ◽

Therapeutic Effects ◽

Diabetic Neuropathic Pain ◽

Type 2 Diabetic

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Tetrahydropalmatinee alleviates diabetic neuropathic pain by inhibiting the inflammation via p38-MAPK signaling pathway in microglia

10.21203/rs.3.rs-601230/v1 ◽

2021 ◽

Author(s):

Lianzhi Cheng ◽

Junlong Ma ◽

Aijuan Jiang ◽

Kai Cheng ◽

Fanjing Wang ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Signaling Pathway ◽

P38 Mapk ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Inflammatory Factors ◽

Specific Marker ◽

Diabetic Neuropathic Pain ◽

Tnf Α

Abstract Object: Exploring the effect of Tetrahydropalmatine (THP) on diabetic neuropathic pain (DNP) and its possible mechanism. Methods: The type 2 diabetic (T2DM) rat models were prepared by high-fat and high-sugar feeding combined with a single small-dose intraperitoneal injection of streptozotocin (STZ). When the mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) of T2DM model rats decreased to less than 85% which were judged as DNP-bearing rats. After treatment with or without THP, the protein expression of hypertonic glycerol reactive kinase (p38), phosphorylated hypertonic glycerol-responsive kinase (p-p38) and OX42 (a specific marker of microglia) were detected by Western Blot and and the mRNA content of p38 and OX42 were detected by qRT-PCR. The expression of pro-inflammatory factors IL-1β, IL-6, TNF-α, as well as chemotactic factors and their receptors including CXCL1, CXCR2, CCL2 and CCR2 in spinal tissues were detected by ELISA. Serum FINS and GSP content were also detected by ELISA. Double-label immunofluorescence were used to observe the expression of OX42 and p-p38 in the spinal dorsal horn. Results: Results showed that THP inhibited microglial activation of spinal in DNP rats. And after THP intervention, the MWT and TWL of DNP rats decreased, the expression of p38, p-p38 and OX42 in the spinal cord tissues of rats was significantly reduced while the mRNA of p38 and OX42 also reduced. The expression of IL-1β, IL-6, TNF-α, CXCL1, CXCR2, CCL2 and CCR2 in the spinal cord tissues of rats was significantly reduced (P < 0.01). At the same time, THP significantly proved FINS, but did not affect FBG and GSP in DNP rats. Conclusions: THP significantly alleviates pain symptoms in DNP rats, and this effect may be achieved by inhibiting the inflammatory response caused by the activation of microglia mediated by the p38-MAPK signaling pathway.

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Activation of GABAB Receptor Suppresses Diabetic Neuropathic Pain through Toll-Like Receptor 4 Signaling Pathway in the Spinal Dorsal Horn

Mediators of Inflammation ◽

10.1155/2018/6016272 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Peng Liu ◽

Hong-Bin Yuan ◽

Shuang Zhao ◽

Fei-Fei Liu ◽

Yu-Qing Jiang ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Signaling Pathway ◽

Gabab Receptor ◽

Intrathecal Injection ◽

Spinal Cord Tissue ◽

Gamma Aminobutyric Acid ◽

Toll Like Receptor ◽

Diabetic Neuropathic Pain ◽

Toll Like Receptor 4

Diabetic neuropathic pain (DNP) is a prevalent complication in diabetes patients. Neuronal inflammation and activation of Toll-like receptor 4 (TLR4) are involved in the occurrence of DNP. However, the underlying mechanisms remain unclear. Downregulation of gamma-aminobutyric acid B (GABAB) receptor contributes to the DNP. GABAB receptor interacts with NF-κB, a downstream signaling factor of TLR4, in a neuropathic pain induced by chemotherapy. In this study, we determined the role of TLR4/Myd88/NF-κB signaling pathways coupled to GABAB receptors in the generation of DNP. Intrathecal injection of baclofen (GABAB receptor agonist), LPS-RS ultrapure (TLR4 antagonist), MIP (MyD88 antagonist), or SN50 (NF-κB inhibitor) significantly increased paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWTL) in DNP rats, while intrathecal injection of saclofen (GABAB receptor blocker) decreased PWT and PWTL in DNP rats. The expression of TLR4, Myd88, NF-κBp65, and their downstream components IL-1 and TNF-α was significantly higher in the spinal cord tissue in DNP rats compared to control rats. Following inhibition of TLR4, Myd88, and NF-κB, the expression of IL-1 and TNF-α decreased. Activation of GABAB receptors downregulated the expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. Blockade of GABAB receptors significantly upregulated expression of TLR4, Myd88, NF-κBp65, IL-1, and TNF-α. These data suggest that activation of the TLR4/Myd88/NF-κB signaling pathway is involved in the occurrence of DNP in rats. Activation of GABAB receptor in the spinal cord may suppress the TLR4/Myd88/NF-κB signaling pathway and alleviate the DNP.

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Effects of electroacupuncture at 2 and 100 Hz on rat type 2 diabetic neuropathic pain and hyperalgesia-related protein expression in the dorsal root ganglion

Journal of Zhejiang University SCIENCE B ◽

10.1631/jzus.b1600247 ◽

2017 ◽

Vol 18 (3) ◽

pp. 239-248 ◽

Cited By ~ 7

Author(s):

Xiao-fen He ◽

Jun-jun Wei ◽

Sheng-yun Shou ◽

Jian-qiao Fang ◽

Yong-liang Jiang

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Protein Expression ◽

Dorsal Root ◽

Related Protein ◽

Diabetic Neuropathic Pain ◽

Type 2 Diabetic

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Licorice extract ameliorates hyperglycemia through reshaping gut microbiota structure and inhibiting TLR4/NF-κB signaling pathway in type 2 diabetic mice

Food Research International ◽

10.1016/j.foodres.2022.110945 ◽

2022 ◽

pp. 110945

Author(s):

Yongli Zhang ◽

Yanni Xu ◽

Ling Zhang ◽

Yijun Chen ◽

Tao Wu ◽

...

Keyword(s):

Gut Microbiota ◽

Signaling Pathway ◽

Diabetic Mice ◽

Licorice Extract ◽

Type 2 Diabetic ◽

Microbiota Structure

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

Microscopy and Microanalysis ◽

10.1017/s1431927612012688 ◽

2012 ◽

Vol 18 (S5) ◽

pp. 5-6 ◽

Cited By ~ 3

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.

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