scholarly journals Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Guo-Chuang Deng ◽  
Ming Lu ◽  
Ya-Yu Zhao ◽  
Ying Yuan ◽  
Gang Chen
Keyword(s):  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Chronic Prostatitis ◽  
Connexin 43 ◽  
Intrathecal Injection ◽  
Neutralizing Antibody ◽  
Spinal Cord Dorsal Horn ◽  
Enzyme Linked Immunosorbent Assay ◽  
Carrageenan Injection ◽  
Later Phase

Abstract Background Prostatodynia is the main symptom of chronic prostatitis and the main reason that patients go to the hospital for treatment. Although a variety of factors, including inflammatory immune response, nervous system sensitization, and psychological factors, have been shown to play important roles in the induction and development of chronic pain in prostatitis, the underlying cause of chronic prostatodynia maintenance in prostatitis patients remains unclear. Methods A mouse model of chronic prostatitis induced by carrageenan injection was used. The von Frey test was used to measure pain behavior. The microglial and astrocyte activations were immunohistochemically demonstrated with antibodies against Iba1 and GFAP. The expression of cytokine or signaling pathway was detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Results In this study, we provide several lines of evidence to demonstrate that activated spinal astrocytes contribute to the later phase (5 weeks after carrageenan injection) of carrageenan-induced prostatitis pain. First, activation of spinal astrocytes but not microglia was found in the spinal cord dorsal horn at 5 weeks. Second, intrathecal injection of the astroglial toxin L-2-Aminoadipate acid (L-AA) but not microglial inhibitor minocycline reduced mechanical allodynia at 5 weeks. Third, chronic prostatitis induced a profound and persistent upregulation of connexin-43 hemichannels in spinal astrocytes, and spinal injection of the connexin-43 inhibitor carbenoxolone (CBX) effectively reduced pain symptoms. Fourth, increased expression and release of chemokine C-X-C motif ligand 1 (CXCL1) in the spinal dorsal horn and intrathecal injection of a CXCL1 neutralizing antibody or the CXCR2 (a major receptor of CXCL1) antagonist SB225002 significantly reduced mechanical allodynia at 5 weeks. Conclusions In this study, we found that a novel mechanism of activated spinal astrocytes plays a crucial role in maintaining chronic prostatitis-induced persistent pain via connexin-43-regulated CXCL1 production and secretion.

scholarly journals Intrathecal Injection of the ς1Receptor Antagonist BD1047 Blocks Both Mechanical Allodynia and Increases in Spinal NR1 Expression during the Induction Phase of Rodent Neuropathic Pain

2008 ◽  
Vol 109 (5) ◽  
pp. 879-889 ◽  
Author(s):  
Dae-Hyun Roh ◽  
Hyun-Woo Kim ◽  
Seo-Yeon Yoon ◽  
Hyoung-Sig Seo ◽  
Young-Bae Kwon ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Maintenance Phase ◽  
Spinal Cord Dorsal Horn ◽  
Induction Phase ◽  
Receptor Subunit ◽  
Aspartate Receptor ◽  
Spinal Cord Dorsal

Background Selective blockade of spinal sigma(1) receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. Methods Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. Results BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation. Conclusions These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.

scholarly journals Interleukin-17 is Involved in Neuropathic Pain and Spinal Synapse Plasticity on Mice

2021 ◽  
Author(s):  
Jia-Lu Sun ◽  
Wen-Jing Dai ◽  
Xin-Yuan Shen ◽  
Yu-Qiu Zhang ◽  
Ning Lü
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Intrathecal Injection ◽  
Neutralizing Antibody ◽  
Interleukin 17 ◽  
Field Potentials ◽  
Spinal Dorsal ◽  
Synapse Plasticity ◽  
Evoked Field Potentials ◽  
C Fiber

Abstract Background: Neuropathic pain seriously affects people’s life, but its mechanism is not clear. Interleukin-17 (IL-17) is a proinflammation cytokine and involved in pain regulation. Our previous study found that IL-17 markedly enhanced the excitatory activity of spinal dorsal neurons in mice spinal slices. The present study attempts to explore if IL-17 contributes to neuropathic pain and spinal synapse plasticity.Methods：A model of spared nerve injury (SNI) was established in C57BL/6J mice and IL-17a mutant mice. The pain-like behaviors was tested, and the expression of IL-17 and its receptor, IL-17RA, was detected. C-fiber evoked field potentials were recorded in vivo. Results: In the spinal dorsal horn, IL-17 predominantly expressed in the superficial spinal astrocytes and IL-17RA expressed mostly in neurons and slightly in astrocytes. The SNI-induced static and dynamic allodynia was significantly prevented by pretreatment of neutralizing IL-17 antibody (intrathecal injection, 2 μg/10 μL) and attenuated in IL-17a mutant mice. Post-treatment of IL-17 neutralizing antibody also partially relieved the established mechanical allodynia. Moreover, spinal long-term potentiation (LTP) of C-fiber evoked field potentials, a substrate for central sensitization, was suppressed by IL-17 neutralizing antibody. Intrathecal injection of IL-17 recombinant protein (0.2 μg/10 μL) mimicked the mechanical allodynia and facilitated the spinal LTP. Conclusions: These data implied that IL-17 in the spinal cord played a crucial role in neuropathic pain and central sensitization.

scholarly journals Involvement of Interleukin-10 in Analgesia of Electroacupuncture on Incision Pain

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Wen-jing Dai ◽  
Jia-lu Sun ◽  
Chao Li ◽  
Wei Mao ◽  
Yun-ke Huang ◽  
...  
Keyword(s):  
Central Sensitization ◽  
Mechanical Allodynia ◽  
Intrathecal Injection ◽  
Neutralizing Antibody ◽  
Long Term Potentiation ◽  
Interleukin 10 ◽  
Immunohistochemical Method ◽  
Intraplantar Injection ◽  
Neuroprotective Effects

Objective. Postincision pain often occurs after surgery and is an emergency to be treated in clinic. Electroacupuncture (EA) is a Chinese traditional treatment widely used to cure acute or chronic pain, but its mechanism is not clear. Interleukin-10 (IL-10) is a powerful anti-inflammatory cytokine that shows neuroprotective effects in inflammation and injury in the CNS. The present study attempts to reveal that IL-10 is crucial for EA analgesia on postincision pain. Methods. A model of incision pain was established in C57BL/6J mice. The pain threshold was detected by behavioral test, and the expression of IL-10 and its receptor was detected by an immunohistochemical method. C-fiber-evoked field potentials were recorded by in vivo analysis. Results. The mechanical allodynia induced by paw incision was significantly inhibited by pretreatment of EA in mice. Intrathecal injection of IL-10 neutralizing antibody (2 µg/10 µL) but not intraplantar injection (10 µg/10 µL) reversed the analgesia of EA. The upregulations of IL-10 mRNA and protein were induced by EA at 6 h and 1 d after incision, respectively. Spinal long-term potentiation (LTP), a substrate for central sensitization, was also suppressed by EA with IL-10. IL-10 recombinant protein (1 µg/10 µL, i.t.) mimicked the analgesia of EA on mechanical allodynia and inhibition on the spinal LTP. Posttreatment of EA after incision also transitorily relieved the mechanical allodynia, which can be blocked by spinal IL-10 antibody. IL-10 and its receptor, IL-10RA, are predominantly expressed in the superficial spinal astrocytes. Conclusions. These results suggested that pretreatment of EA effectively prevented postincision pain and IL-10 in spinal astrocytes was critical for the analgesia of EA and central sensitization.

scholarly journals Urotensin II inhibitor eases neuropathic pain by suppressing the JNK/NF-κB pathway

2017 ◽  
Vol 232 (2) ◽  
pp. 165-174 ◽  
Author(s):  
Jing Li ◽  
Pan-Pan Zhao ◽  
Ting Hao ◽  
Dan Wang ◽  
Yu Wang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Cyclic Peptide ◽  
Intrathecal Injection ◽  
Thermal Hyperalgesia ◽  
Nuclear Factor Κb ◽  
Neurosecretory System ◽  
Urotensin Ii ◽  
Caudal Neurosecretory System

Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4–6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.

scholarly journals Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain

2013 ◽  
Vol 119 (3) ◽  
pp. 687-697 ◽  
Author(s):  
Marie-Christine Ross-Huot ◽  
André Laferrière ◽  
Mina Khorashadi ◽  
Terence J. Coderre
Keyword(s):  
Reperfusion Injury ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Normal Feeding

Abstract Background: Ischemia–reperfusion injury causes chronic postischemia pain (CPIP), and rats with higher glycemia during ischemia–reperfusion injury exhibit increased allodynia. Glycemia-induced elevation of nuclear factor κB (NFκB) may contribute to increased allodynia. Methods: Glycemia during a 3-h ischemia–reperfusion injury was manipulated by: normal feeding; or normal feeding with administration of insulin; dextrose; or insulin/dextrose. In these groups, NFκB was measured in ipsilateral hind paw muscle and spinal dorsal horn by enzyme-linked immunosorbent assay (ELISA), and SN50, an NFκB inhibitor, was administered to determine its differential antiallodynic effects depending on glycemia. Results: CPIP fed/insulin rats (12.03 ± 4.9 g, N = 6) had less allodynia than fed, fed/insulin/dextrose, and fed/dextrose rats (6.29 ± 3.37 g, N = 7; 4.57 ± 3.03 g, N = 6; 2.95 ± 1.10 g, N = 9), respectively. Compared with fed rats (0.209 ± 0.022 AU, N = 7), NFκB in ipsilateral plantar muscles was significantly lower for fed/insulin rats, and significantly higher for fed/dextrose rats (0.152 ± 0.053 AU, N = 6; 0.240 ± 0.057 AU, N = 7, respectively). Furthermore, NFκB in the dorsal horn of fed, fed/insulin/dextrose, and fed/dextrose rats (0.293 ± 0.049 AU; 0.267 ± 0.037 AU; 0.315 ± 0.015 AU, respectively, N = 6 for each) was significantly higher than in fed/insulin animals (0.267 ± 0.037 AU, N = 6). The antiallodynic SN50 dose–response curves of CPIP rats in the fed/insulin/dextrose, fed/dextrose, and fed conditions exhibited a rightward shift compared with the fed/insulin group. The threshold SN50 dose of CPIP fed/dextrose, fed/insulin/dextrose, and fed rats (328.94 ± 92.4 ng, 77.80 ± 44.50 ng, and 24.89 ± 17.20 ng, respectively) was higher than that for fed/insulin rats (4.06 ± 7.04 ng). Conclusions: NFκB was activated in a glycemia-dependent manner in CPIP rats. Hypoglycemic rats were more sensitive to SN50 than rats with higher glycemia. The finding that SN50 reduces mechanical allodynia suggests that NFκB inhibitors might be useful for treating postischemia pain.

Comparison of the Effects of Treatment with Intrathecal Lidocaine Given before and after Formalin on Both Nociception and Fos Expression in the Spinal Cord Dorsal Horn 

1998 ◽  
Vol 88 (1) ◽  
pp. 157-164 ◽  
Author(s):  
Kiran Yashpal ◽  
Patrick Mason ◽  
John E. McKenna ◽  
Sushil K. Sharma ◽  
James L. Henry ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Intrathecal Injection ◽  
Post Treatment ◽  
Spinal Cord Dorsal Horn ◽  
Formalin Injection ◽  
Second Phase ◽  
Nociceptive Responses ◽  
Spinal Cord Dorsal ◽  
Fos Expression

Background It has been proposed that the measure of noxious stimulus-induced Fos (the protein product of the immediate early gene c-fos) expression in the spinal cord dorsal horn of laboratory animals may provide an estimate of the potential of specific treatments to produce preemptive analgesia. The present study examined this hypothesis by comparing the effects of intrathecal lidocaine given before and after hindpaw formalin injection on persistent nociceptive responses and Fos expression in spinal cord dorsal horn of rats. Methods Formalin-induced nociception and Fos expression in the spinal cord, in response to a 50-microl injection of 2.5% formalin into the hind paw, were assessed in rats given an intrathecal injection of 50 microl 2% lidocaine by lumbar puncture between the L5 and L6 vertebrae, either 3 min before (pretreatment) or 5 min after (post-treatment) formalin injection. Results Pain behaviors (hindpaw licking, elevation, and favoring) in the second phase of the formalin test were significantly reduced by pretreatment, but were unaffected by post-treatment. The number of immunocytochemically stained Fos-positive cells and the immunoprecipitation of the Fos antibodies were reduced by pretreatment, and were also reduced, to a lesser extent, by post-treatment. Conclusions The finding that persistent nociceptive behaviors and Fos expression were suppressed by intrathecal lidocaine pretreatment suggests that nociception in the second phase of the formalin test depends on increases in central hyperexcitability generated during the first phase. On the other hand, the finding that the intrathecal injection of lidocaine after formalin treatment reduced Fos expression but not nociceptive responses indicates an uncoupling of the behavioral and Fos protein responses to formalin and suggests that changes in Fos expression may not be a good predictor of the ability of agents to produce preemptive analgesia.

Intrathecal α2-Adrenergic Agonists Stimulate Acetylcholine and Norepinephrine Release from the Spinal Cord Dorsal Horn in Sheep 

1997 ◽  
Vol 87 (1) ◽  
pp. 110-116 ◽  
Author(s):  
W. Klimscha ◽  
C. Tong ◽  
J. C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Dorsal Horn ◽  
Intrathecal Injection ◽  
Intrathecal Administration ◽  
Spinal Cord Dorsal Horn ◽  
Adrenergic Agonists ◽  
Norepinephrine Release ◽  
Effect Analysis ◽  
Cholinergic Activation

Background Intrathecal injection of clonidine and dexmedetomidine produce behavioral analgesia by an alpha 2-adrenergic mechanism. Functional and anatomic studies suggest that this analgesia is mediated by cholinergic activation. This hypothesis was directly tested by measuring extracellular acetylcholine concentrations in spinal cord interstitial fluid by means of microdialysis after intrathecal injection of these alpha 2-adrenergic agonists in sheep. Methods Twelve sheep with chronically implanted thoracic intrathecal catheters were anesthetized with halothane. Multiple 200-micron-diameter dialysis fibers were inserted surgically at a mid-thoracic level through the dorsal horn and perfused with artificial cerebrospinal fluid. After baseline sampling, either clonidine (100 micrograms), dexmedetomidine (100 micrograms), or saline were injected intrathecally. Microdialysis samples were analyzed by high-pressure liquid chromatography for acetylcholine and norepinephrine. Results Both alpha 2-adrenergic agonists increased acetylcholine in microdialysate, whereas intrathecal saline had no effect. Analysis of the raw data showed that all groups differed significantly, with greater levels of acetylcholine following administration of dexmedetomidine than clonidine or saline. Unexpectedly, intrathecal clonidine also increased microdialysate norepinephrine levels. Conclusions These data are consistent with previous experiments measuring acetylcholine concentrations in cerebrospinal fluid and support analgesia from alpha 2-adrenergic agonists mediated in part by cholinergic activation. In addition, the increase in norepinephrine concentrations after intrathecal administration of clonidine suggest stimulation of norepinephrine release by this agent.

scholarly journals Electroacupuncture Inhibits the Activity of Astrocytes in Spinal Cord in Rats with Visceral Hypersensitivity by Inhibiting P2Y1 Receptor-Mediated MAPK/ERK Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Jingming Zhao ◽  
Hui Li ◽  
Chong Shi ◽  
Tiezheng Yang ◽  
Baoshi Xu
Keyword(s):  
Spinal Cord ◽  
Acetic Acid ◽  
Dorsal Horn ◽  
Molecular Mechanisms ◽  
Intrathecal Injection ◽  
Inhibitory Effect ◽  
Visceral Hypersensitivity ◽  
Spinal Cord Dorsal Horn ◽  
Male Rats ◽  
Spinal Cord Dorsal

Background. Irritable bowel syndrome (IBS) is a chronic functional bowel disease characterized by abdominal pain and changes in bowel habits in the absence of organic disease. Electroacupuncture (EA) has been shown to alleviate visceral hypersensitivity (VH) in IBS rat models by inhibiting the activation of astrocytes in the spinal cord. However, the underlying molecular mechanisms mediated by P2Y1 receptor of this effect of electroacupuncture remain unclear. Aim. To explore whether EA inhibits the activity of astrocytes in the spinal cord dorsal horn of rat with visceral hypersensitivity by inhibiting P2Y1 receptor and its downstream mitogen activated protein kinase/extracellular regulated kinase 1 (MAPK/ERK) pathway. Methods. Ten-day-old Sprague-Dawley (SD) male rats were given an intracolonic injection of 0.2 ml of 0.5% acetic acid (AA) to establish a visceral hypersensitivity model. EA was performed at Zusanli (ST 36) and Shangjuxu (ST 37) at 100 Hz for 1.05 s and 2 Hz for 2.85 s alternately, pulse width for 0.1 ms, 1 mA, 30 min/d, once a day, for 1 week. Cytokines IL-6, IL-1β, and TNF-α were analyzed by ELISA. The expressions of the P2Y1 receptor and pERK1/2 were analyzed by Western Blot and real-time PCR in the model and EA treated animals to explore the molecular mechanism of EA in inhibiting the activity of spinal cord dorsal horn (L6-S2 segment) astrocytes in rats with IBS visceral hypersensitivity. Results. EA significantly reduced the behavioral abdominal withdrawal reflex score (AWRs) of IBS rats with visceral hypersensitivity induced by AA. For comparison, intrathecal injection of astrocytes activity inhibitor fluorocitrate (FCA) also reduced visceral hypersensitivity in IBS rats. EA at Zusanli and Shangjuxu inhibited the mRNA and protein expression of the glial fibrillary acidic protein (GFAP) and in rat spinal cord and reduced the release of inflammatory cytokines IL-6, IL-1, and TNF-α from astrocytes. EA also inhibited acetic acid-induced expression of the P2Y1 receptor in the spinal cord. Adenosine 5′-[β-thio]diphosphate trilithium salt (ADP), a selective agonist of the P2Y1 receptor, reversed the inhibitory effect of EA on visceral hypersensitivity. ADP also overrode the downregulation of GFAP by EA. Conversely, MRS2179 (MRS), a selective antagonist of the P2Y1 receptor, inhibited visceral hypersensitivity suggesting that EA negatively regulated the P2Y1 receptor in astrocytes. Acetic acid also upregulated the expression of pERK1/2 protein and mRNA in the spinal cord of rats with visceral hypersensitivity, which was inhibited by EA and the inhibitory effect of EA on pERK1/2 was reversed by ADP. We also found that SCH772984 (SCH), an ERK1/2 inhibitor (10 μg, 10 μl), reduced the AWRs. Compared to the SCH group, AWR scores in SCH + EA group were decreased. The application of P2Y1 agonists failed to increase the AWR scores after the intrathecal injection of SCH. GFAP level in the spinal cord in the SCH group was significantly reduced when compared to the Model group. The GFAP expression was further reduced in the SCH + EA group. Conclusion. EA inhibited astrocyte activity in the spinal cord dorsal horn of rat with IBS visceral hypersensitivity by inhibiting the P2Y1 receptor and its downstream, PKC, and MAPK/ERK1/2 pathways.

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