Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model

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.

Download Full-text

CDK5, CRMP2 and NR2B in spinal dorsal horn and dorsal root ganglion have different role in pain signaling between neuropathic pain model and inflammatory pain model

European Journal of Anaesthesiology ◽

10.1097/00003643-201306001-00669 ◽

2013 ◽

Vol 30 ◽

pp. 214-214 ◽

Cited By ~ 7

Author(s):

Y. Kamiya ◽

K. Saeki ◽

M. Takiguchi ◽

K. Funakoshi

Keyword(s):

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Inflammatory Pain ◽

Dorsal Root ◽

Spinal Dorsal Horn ◽

Pain Model ◽

Spinal Dorsal ◽

Neuropathic Pain Model

Download Full-text

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.

Download Full-text

Phosphorylation of ERK in Neurokinin 1 Receptor-Expressing Neurons in Laminae III and IV of the Rat Spinal Dorsal Horn Following Noxious Stimulation

Molecular Pain ◽

10.1186/1744-8069-3-4 ◽

2007 ◽

Vol 3 ◽

pp. 1744-8069-3-4 ◽

Cited By ~ 33

Author(s):

Erika Polgár ◽

Annie D Campbell ◽

Lynsey M MacIntyre ◽

Masahiko Watanabe ◽

Andrew J Todd

Keyword(s):

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Noxious Stimulation ◽

Neurokinin 1 Receptor ◽

Spinal Dorsal ◽

Neurokinin 1

Download Full-text

Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model

Scientific Reports ◽

10.1038/srep11555 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 27

Author(s):

Enji Zhang ◽

Min-Hee Yi ◽

Nara Shin ◽

Hyunjung Baek ◽

Sena Kim ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Neuropathic Pain ◽

Endoplasmic Reticulum Stress ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Pain Model ◽

Spinal Dorsal ◽

Neuropathic Pain Model

Download Full-text

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

Download Full-text

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

BMC Gastroenterology ◽

10.1186/1471-230x-12-148 ◽

2012 ◽

Vol 12 (1) ◽

Cited By ~ 32

Author(s):

Feng Quan-Xin ◽

Feng Fan ◽

Feng Xiang-Ying ◽

Li Shu-Jun ◽

Wang Shi-Qi ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Nmda Receptors ◽

Dorsal Horn ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Resolvin D1 ◽

Spinal Dorsal ◽

Thoracic Spinal

Download Full-text

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.

Download Full-text