Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn

Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-d-aspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

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Liver X Receptor α Is Involved in Counteracting Mechanical Allodynia by Inhibiting Neuroinflammation in the Spinal Dorsal Horn

Anesthesiology ◽

10.1097/aln.0000000000001718 ◽

2017 ◽

Vol 127 (3) ◽

pp. 534-547 ◽

Cited By ~ 4

Author(s):

Jing Xu ◽

Yi-Wei Feng ◽

Ling Liu ◽

Wei Wang ◽

Xiong-Xiong Zhong ◽

...

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Glial Cells ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Liver X Receptor ◽

Spared Nerve Injury ◽

Wild Type ◽

Spinal Dorsal ◽

Liver X Receptor Α

Abstract Background Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown. Methods A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms. Results Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines. Conclusions Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.

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Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

10.21203/rs.3.rs-35728/v1 ◽

2020 ◽

Author(s):

Yaping Wang ◽

Yu Shi ◽

Yongquan Huang ◽

Wei Liu ◽

Guiyuan Cai ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Response ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Intrathecal Administration ◽

Spared Nerve Injury ◽

Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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Glutamate Transporters Prevent Excessive Activation of NMDA Receptors and Extrasynaptic Glutamate Spillover in the Spinal Dorsal Horn

Journal of Neurophysiology ◽

10.1152/jn.91138.2008 ◽

2009 ◽

Vol 101 (4) ◽

pp. 2041-2051 ◽

Cited By ~ 46

Author(s):

Hui Nie ◽

Han-Rong Weng

Keyword(s):

Nmda Receptors ◽

Dorsal Horn ◽

Neural Plasticity ◽

Spinal Dorsal Horn ◽

Plasma Membranes ◽

Glutamate Transporters ◽

Substantia Gelatinosa ◽

Open Probability ◽

Spinal Dorsal ◽

Excessive Activation

Activation of N-methyl-d-aspartate (NMDA) receptors in the spinal dorsal horn neurons is a key process related to sensory transmission, neural plasticity, and pathogenesis of pain. In this study, we investigated how activation of NMDA receptors in spinal substantia gelatinosa neurons is regulated by glutamate re-uptake through glutamate transporters located in the astrocytic and neuronal plasma membranes. Using visualized whole cell patch recording techniques, NMDA excitatory postsynaptic currents evoked by graded peripheral inputs in spinal substantia gelatinosa neurons of spinal slices from young adult rats were analyzed before and after combined inhibition of glial and neuronal glutamate transporters by d-threo-β-benzyloxyaspartate (TBOA). Blockade of glutamate transporters increased the number and duration of NMDA receptors activated by weak and by strong primary afferent inputs as well as by exogenous glutamate. The enhancement in activation of NMDA receptors induced by TBOA was greater in neurons that have weaker synaptic input at baseline. Impaired glutamate uptake increased the open probability of NMDA channels and caused glutamate spillover outside the active synapses, leading to activation of extrasynaptic NMDA receptors and/or receptors located in neighboring synapses. Finally, blockade of glutamate transporters resulted in an increased proportion of NR2B subunit activation induced by peripheral input, and this increase was further augmented by stronger afferent input. These data indicate that glutamate transporters regulate spatiotemporal and intensity coding for sensory input and prevent excessive activation of glutamate receptors in the spinal dorsal horn. It is suggested that remedying dysfunctional glutamate transporters may be a potential new avenue to prevent the pathogenesis of pain.

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Peri-sciatic administration of recombinant rat TNF-α induces mechanical allodynia via upregulation of TNF-α in dorsal root ganglia and in spinal dorsal horn: The role of NF-kappa B pathway

Experimental Neurology ◽

10.1016/j.expneurol.2007.03.012 ◽

2007 ◽

Vol 205 (2) ◽

pp. 471-484 ◽

Cited By ~ 71

Author(s):

Xu-Hong Wei ◽

Ying Zang ◽

Chang-You Wu ◽

Ji-Tian Xu ◽

Wen-Jun Xin ◽

...

Keyword(s):

Dorsal Horn ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Nf Kappa B ◽

Spinal Dorsal ◽

Tnf Α

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https://painphysicianjournal.com/current/pdf?article=MTgwMw%3D%3D&journal=71

January 2018 - Pain Physician ◽

10.36076/ppj.2012/15/e995 ◽

2012 ◽

Vol 6;15 (6;12) ◽

pp. E995-E1006

Author(s):

Prof. Yun-Qing Li

Keyword(s):

Neuropathic Pain ◽

Dorsal Horn ◽

Inflammatory Cytokines ◽

Glial Cells ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Pain Behavior ◽

Repeated Treatment ◽

Single Bolus ◽

Spinal Dorsal

Background: Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells. Objective: In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide. Study Design: A randomized, double blind, controlled animal trial. Methods: Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 μg/kg, 100 μg/kg, 300 μg/kg) or vehicle during the period of days 11–20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study. Results: A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide. Limitations: The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia. Conclusions: Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn. Key words: Triptolide, neuropathic pain, spinal dorsal horn, astrocyte, microglia, MAPK.

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NFATc2-dependent epigenetic upregulation of CXCL14 is involved in the development of neuropathic pain induced by paclitaxel

10.21203/rs.3.rs-35729/v1 ◽

2020 ◽

Author(s):

Meng Liu ◽

Su-Bo Zhang ◽

Yu-Xuan Luo ◽

Yan-Ling Yang ◽

Xiang-Zhong Zhang ◽

...

Keyword(s):

Binding Site ◽

Dorsal Horn ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Molecular Mechanisms ◽

Target Genes ◽

Painful Neuropathy ◽

Withdrawal Threshold ◽

Spinal Dorsal ◽

Paclitaxel Treatment

Abstract Background: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat solid tumor, is painful neuropathy. However, the molecular mechanisms underlying paclitaxel-induced painful neuropathy are largely unclarified. Methods: Paw withdrawal threshold was measured in the rats following intraperitoneal injection of paclitaxel. The qPCR, western blotting, protein or chromatin immunoprecipitation, ChIP-seq identification of NFATc2 binding sites, microarray analysis were performed to explore the molecular mechanism. Results: We found that paclitaxel treatment increased the expression of NFATc2 in the spinal dorsal horn, and knockdown of NFATc2 with NFATc2 siRNA significantly attenuated the mechanical allodynia induced by paclitaxel. Further binding site analysis utilizing ChIP-seq assay combining with gene expression profile revealed a shift of NFATc2 binding site closer to TSS of target genes in dorsal horn after paclitaxel treatment. We further found that NFATc2 occupancy directly upregulated the chemokine CXCL14 expression in dorsal horn, which was mediated by enhanced interaction between NFATc2 and p300 and consequently increased acetylation of histone H4 in CXCL14 promoter region. Also, knockdown of CXCL14 in dorsal horn significantly attenuated mechanical allodynia induced by paclitaxel. Conclusion: These results suggested that enhanced interaction between p300 and NFATc2 mediated the epigenetic upregulation of CXCL14 in the spinal dorsal horn, which contributed to the chemotherapeutic paclitaxel-induced chronic pain.

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Peripheral inflammation increased the synaptic expression of NMDA receptors in spinal dorsal horn

Pain ◽

10.1016/j.pain.2009.04.005 ◽

2009 ◽

Vol 144 (1) ◽

pp. 162-169 ◽

Cited By ~ 39

Author(s):

Xian Yang ◽

Hong-Bin Yang ◽

Qin-Jian Xie ◽

Xiao-Hua Liu ◽

Xiao-Dong Hu

Keyword(s):

Nmda Receptors ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Peripheral Inflammation ◽

Spinal Dorsal

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The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats

BioMed Research International ◽

10.1155/2014/251785 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Li Li ◽

Rong Luo ◽

Yuan Guo ◽

Fanrong Yao ◽

Dongyuan Cao ◽

...

Keyword(s):

Dorsal Horn ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Somatostatin Receptor ◽

Thermal Hyperalgesia ◽

Receptor Activation ◽

Bee Venom ◽

Spinal Dorsal ◽

Nociceptive Responses ◽

Lumbar Spinal

The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.

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