Inhibition of Spinal Prostaglandin Synthesis Early after L5/L6 Nerve Ligation Prevents the Development of Prostaglandin-dependent and Prostaglandin-independent Allodynia in the Rat

2003 ◽  
Vol 99 (5) ◽  
pp. 1180-1188 ◽  
Author(s):  
Michael P. Hefferan ◽  
Darren D. O'Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Glutamate Release ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Sprague Dawley ◽  
Nociceptive Transmission ◽  
Withdrawal Threshold ◽  
Sham Surgery ◽  
Cyclooxygenase 1 ◽  
Sprague Dawley Rats ◽  
Spinal Segments

Background Prostaglandins, synthesized in the spinal cord in response to noxious stimuli, are known to facilitate nociceptive transmission, raising questions about their role in neuropathic pain. The current study tested the hypothesis that spinal nerve ligation-induced allodynia is composed of an early prostaglandin-dependent phase, the disruption of which prevents allodynia. Methods Male Sprague-Dawley rats, fitted with intrathecal drug delivery or microdialysis catheters, underwent left L5-L6 spinal nerve ligation or sham surgery. Paw withdrawal threshold, brush-evoked behavior, and the concentration of prostaglandin E2 (PGE2) in spinal cerebrospinal fluid ([PGE2]dialysate) were determined for up to 24 days. PGE2-evoked glutamate release from spinal slices was also determined. Results Paw withdrawal threshold decreased from at least 15 g (control) to less than 4 g, beginning 1 day after ligation. Brushing the affected hind paw evoked nociceptive-like behavior and increased [PGE2]dialysate (up to 257 +/- 62% of baseline). There was no detectable change in basal [PGE2]dialysate from preligation values. The EC50 of PGE2-evoked glutamate release (2.4 x 10-11 M, control) was significantly decreased in affected spinal segments of allodynic rats (8.9 x 10-15 M). Treatment with intrathecal S(+)-ibuprofen or SC-560, beginning 2 h after ligation, prevented the decrease in paw withdrawal threshold, the brush-evoked increase in [PGE2]dialysate, and the change in EC50 of PGE2-evoked glutamate release. R(-)-ibuprofen or SC-236 had no effect. Conclusions The results of this study provide solid evidence that spinal prostaglandins, synthesized by cyclooxygenase-1 in the first 4-8 h after ligation, are critical in the pathogenesis of prostaglandin-dependent and prostaglandin-independent allodynia and that their early pharmacologic disruption affords protection against this neuropathic state in the rat.

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

2006 ◽  
Vol 104 (2) ◽  
pp. 328-337 ◽  
Author(s):  
Darren D. O’Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Glutamate Release ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Withdrawal Threshold ◽  
Enhanced Sensitivity ◽  
Sham Surgery ◽  
Inducible Nos

Background Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Results Allodynia (paw withdrawal threshold < or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P > 0.05) from baseline (> 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). Conclusion The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

Neuropathic Allodynia Involves Spinal Neurexin-1β-dependent Neuroligin-1/Postsynaptic Density-95/NR2B Cascade in Rats

2015 ◽  
Vol 123 (4) ◽  
pp. 909-926 ◽  
Author(s):  
Tzer-Bin Lin ◽  
Cheng-Yuan Lai ◽  
Ming-Chun Hsieh ◽  
Jian-Lin Jiang ◽  
Jen-Kun Cheng ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Small Interfering Rna ◽  
Postsynaptic Density ◽  
Spinal Nerve ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Withdrawal Threshold ◽  
Sprague Dawley Rats ◽  
Rna Targeting ◽  
Interfering Rna

Abstract Background: Neuroligin-1 (NL1) forms a complex with the presynaptic neurexin-1β (Nrx1b), regulating clustering of N-methyl-d-aspartate receptors with postsynaptic density-95 (PSD-95) to underlie learning-/memory-associated plasticity. Pain-related spinal neuroplasticity shares several common features with learning-/memory-associated plasticity. The authors thereby investigated the potential involvement of NL1-related mechanism in spinal nerve ligation (SNL)–associated allodynia. Methods: In 626 adult male Sprague–Dawley rats, the withdrawal threshold and NL1, PSD-95, phosphorylated NR2B (pNR2B) expressions, interactions, and locations in dorsal horn (L4 to L5) were compared between the sham operation and SNL groups. A recombinant Nrx1b Fc chimera (Nrx1b Fc, 10 μg, 10 μl, i.t., bolus), antisense small-interfering RNA targeting to NL1 (10 μg, 10 μl, i.t., daily for 4 days), or NR2B antagonist (Ro 25-6981; 1 μM, 10 μl, i.t., bolus) were administered to SNL animals to elucidate possible cascades involved. Results: SNL-induced allodynia failed to affect NL1 or PSD-95 expression. However, pNR2B expression (mean ± SD from 13.1 ± 2.87 to 23.1 ± 2.52, n = 6) and coexpression of NL1–PSD-95, pNR2B–PSD-95, and NL1-total NR2B were enhanced by SNL (from 10.7 ± 2.27 to 22.2 ± 3.94, 11.5 ± 2.15 to 23.8 ± 3.32, and 8.9 ± 1.83 to 14.9 ± 2.27 at day 7, n = 6). Furthermore, neuron-localized pNR2B PSD-95–pNR2B double-labeled and NL1/PSD-95/pNR2B triple-labeled immunofluorescence in the ipsilateral dorsal horn was all prevented by Nrx1b Fc and NL1-targeted small-interfering RNA designed to block and prevent NL1 expression. Without affecting NL1–PSD-95 coupling, Ro 25-6981 decreased the SNL-induced PSD-95–pNR2B coprecipitation (from 18.7 ± 1.80 to 14.7 ± 2.36 at day 7, n = 6). Conclusion: SNL-induced allodynia, which is mediated by the spinal NL1/PSD-95/pNR2B cascade, can be prevented by blockade of transsynaptic Nrx1b–NL1 interactions.

Peripheral Nerve Injury Sensitizes the Response to Visceral Distension but Not Its Inhibition by the Antidepressant Milnacipran

2004 ◽  
Vol 100 (3) ◽  
pp. 671-675 ◽  
Author(s):  
Sang-Wook Shin ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Visceral Pain ◽  
Spinal Nerve ◽  
Reflex Response ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Withdrawal Threshold ◽  
Sprague Dawley Rats ◽  
Lumbar Spinal

Background Manipulations that cause hypersensitivity to visceral stimuli have been shown to also result in hypersensitivity to somatic stimuli coming from convergent dermatomes, but the converse has not been examined. The authors tested whether lumbar spinal nerve ligation in rats, a common model of neuropathic pain that results in hypersensitivity to somatic stimuli, also leads to hypersensitivity to visceral stimuli coming from convergent dermatomes and whether pharmacology of inhibition differed between these two sensory modalities. Methods Female Sprague-Dawley rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Animals received either intrathecal saline or milnacipran (0.1-3 microg), and withdrawal thresholds to mechanical testing in the left hind paw, using von Frey filaments, and visceral testing, using balloon colorectal distension, were determined. Results Nerve ligation resulted in decreases in threshold to withdrawal to somatic mechanical stimulation (from 13 +/- 1.8 g to 2.7 +/- 0.7 g) and also in decreases in threshold to reflex response to visceral stimulation (from 60 mmHg to 40 mmHg). Intrathecal milnacipran increased withdrawal threshold to somatic stimulation in a dose-dependent manner but failed to alter the response to noxious visceral stimulation. Conclusions Injury of nerves innervating somatic structures enhances nociception from stimulation of viscera with convergent input from nearby dermatomes, suggesting that somatic neuropathic pain could be accompanied by an increased likelihood of visceral pain. Lack of efficacy of the antidepressant milnacipran against visceral stimuli suggests that visceral hypersensitivity may not share the same pharmacology of inhibition as somatic hypersensitivity after nerve injury.

scholarly journals Spinal Prostaglandins Facilitate Exaggerated A- and C-fiber-mediated Reflex Responses and Are Critical to the Development of Allodynia Early after L5-L6 Spinal Nerve Ligation

2007 ◽  
Vol 106 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Darren D. O'Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Spinal Cord ◽  
Prostaglandin E2 ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Reflex Responses ◽  
Withdrawal Threshold ◽  
Sham Surgery ◽  
C Fiber ◽  
Cox 2 ◽  
Cox 1

Background Spinal prostaglandins are important in the early pathogenesis of spinal nerve ligation (SNL)-induced allodynia. This study examined the effect of SNL on the expression of cyclooxygenase (COX)-1, COX-2, and prostaglandin E2 receptors in the rat lumbar spinal cord, and the temporal and pharmacologic relation of these changes to the exaggerated A- and C-fiber-mediated reflex responses and allodynia, 24 h after injury. Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery. Paw withdrawal threshold, electromyographic analysis of the biceps femoris flexor reflex, and immunoblotting of the spinal cord were used. Results Both allodynia (paw withdrawal threshold of < or = 4 g) and exaggerated A- and C-fiber-mediated reflex responses (i.e., decrease in activation threshold, increase in evoked activity, including windup; P < 0.05) were evident 24 h after SNL but not sham surgery. Allodynic animals exhibited significant increases in prostaglandin E2 receptor (subtypes 1-3) and COX-1 (but not COX-2) expression in the ipsilateral lumbar dorsal horn. The corresponding ventral horns and contralateral dorsal horn were unchanged from sham controls. Exaggerated A- and C-fiber-mediated reflex responses were significantly attenuated by intrathecal SC-560 or SC-51322, but not SC-236, given 24 h after SNL. Conclusion These results provide further evidence that spinal prostaglandins, derived primarily from COX-1, are critical in the exaggeration of A- and C-fiber input and allodynia, 24 h after SNL.

Modulation of Nerve Injury–induced HDAC4 Cytoplasmic Retention Contributes to Neuropathic Pain in Rats

2015 ◽  
Vol 123 (1) ◽  
pp. 199-212 ◽  
Author(s):  
Tzer-Bin Lin ◽  
Ming-Chun Hsieh ◽  
Cheng-Yuan Lai ◽  
Jen-Kun Cheng ◽  
Yat-Pang Chau ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Histone Deacetylases ◽  
Spinal Nerve ◽  
Sprague Dawley ◽  
Withdrawal Threshold ◽  
Dorsal Horn Neurons ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Interfering Rna

Abstract Background: The histone deacetylases (HDACs) have been implicated in pain hypersensitivity. This study investigated the potential involvement of an HDAC4-related mechanism in the spinal nerve ligation (SNL)-induced nociceptive hypersensitivity. Methods: The left L5 to L6 spinal nerves of 627 adult male Sprague–Dawley rats were surgically ligated. The withdrawal threshold of hind paws and the abundances, cellular location, and interactions of proteins in the dorsal horn were assayed before and after surgery. The 14-3-3β-targeting small-interfering RNA, a serum- and glucocorticoid-inducible kinase 1 (SGK1) antagonist, or an HDAC inhibitor was spinally injected to elucidate the role of 14-3-3β, SGK1, and HDAC4. Results: Without affecting the HDAC4 level, SNL provoked SGK1 phosphorylation (mean ± SEM from 0.24 ± 0.02 to 0.78 ± 0.06 at day 7, n = 6), HDAC4 phosphorylation (from 0.38 ± 0.03 to 0.72 ± 0.06 at day 7, n = 6), 14-3-3β expression (from 0.53 ± 0.09 to 0.88 ± 0.09 at day 7, n = 6), cytoplasmic HDAC4 retention (from 1.18 ± 0.16 to 1.92 ± 0.11 at day 7, n = 6), and HDAC4-14-3-3β coupling (approximately 2.4-fold) in the ipsilateral dorsal horn in association with behavioral allodynia. Knockdown of spinal 14-3-3β expression prevented the SNL-provoked HDAC4 retention (from 1.89 ± 0.15 to 1.32 ± 0.08 at day 7, n = 6), HDAC4-14-3-3β coupling (approximately 0.6-fold above SNL 7D), and behavioral allodynia (from 0.16 ± 0.3 to 6 ± 1.78 at day 7, n = 7), but not SGK1 (from 0.78 ± 0.06 to 0.71 ± 0.04 at day 7, n = 6) or HDAC4 (from 0.75 ± 0.15 to 0.68 ± 0.11 at day 7, n = 6) phosphorylation. Conclusion: Neuropathic pain maintenance involves the spinal SGK1 activation–dependent HDAC4 phosphorylation and its subsequent association with 14-3-3β that promotes cytoplasmic HDAC4 retention in dorsal horn neurons.

Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats

Pharmacology ◽  
2018 ◽  
Vol 102 (5-6) ◽  
pp. 332-338 ◽  
Author(s):  
Hyung Gon Lee ◽  
Ji A Song ◽  
Dong Soo Han ◽  
Kyeong Wan Woo ◽  
Myung Ha Yoon
Keyword(s):  
Neuropathic Pain ◽  
Adrenergic Receptors ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Areca Nut ◽  
Sprague Dawley ◽  
Once Daily ◽  
Spinal Nerves ◽  
Sprague Dawley Rats ◽  
Von Frey Filaments

This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and α2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective α2-adrenoceptor (yohimbine), α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (‡ p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (‡ p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and α2A, α2B, and α2C-adrenoceptors contributed to the antiallodynic effects of areca nut.

Morphine-induced Spinal Release of Adenosine Is Reduced in Neuropathic Rats

2001 ◽  
Vol 95 (6) ◽  
pp. 1455-1459 ◽  
Author(s):  
Andreas Sandner-Kiesling ◽  
Xinhui Li ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Lumbar Spinal Cord ◽  
Sprague Dawley ◽  
Dorsal Spinal Cord ◽  
Adenosine Release ◽  
Sprague Dawley Rats ◽  
Lumbar Spinal

Background Spinally administered opioids show decreased potency and efficacy in the treatment of neuropathic pain. As reported previously, morphine stimulates spinal opioid receptors to effect adenosine release, which acts at adenosine receptors to produce analgesia. The authors hypothesized that morphine induces less adenosine release in neuropathic compared with normal rats, explaining its reduced potency and efficacy. Methods Sprague-Dawley rats (200-250 g) were divided into three groups: no surgery (n = 52), sham surgery (n = 20), or left L5 and L6 spinal nerve ligation (n = 64). Two weeks after surgery, mechanical hypersensitivity of the left hind paw was verified. For each experiment, a crude synaptosomal P2 suspension was prepared by homogenizing cervical and lumbar dorsal spinal cord halves from four rats, followed by differential centrifugation, and aliquots incubated with morphine sulfate from 10(-8) to 10(-4) m alone or in presence of 10(-5) m dipyridamole. Extrasynaptosomal concentrations of adenosine were analyzed by high-pressure liquid chromatography. Results Synaptosomal release of adenosine in the absence of morphine was similar between groups. Morphine produced a concentration-dependent adenosine release, which was less in synaptosomes from dorsal lumbar spinal cord in spinal nerve ligation compared with normal or sham animals. This reduction was removed by adding dipyridamole. Conclusion Morphine normally stimulates spinal release of adenosine, a potent antihypersensitivity compound. Because this effect of morphine is diminished in spinal nerve ligation animals, one explanation for decreased efficacy and potency of opioids in the treatment of neuropathic pain may be a dipyridamole-sensitive disruption in the opioid-adenosine link in the spinal cord.

Adenosine Reduces Glutamate Release in Rat Spinal Synaptosomes

2005 ◽  
Vol 103 (5) ◽  
pp. 1060-1065 ◽  
Author(s):  
Xinhui Li ◽  
James C. Eisenach
Keyword(s):  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Dependent Manner ◽  
A1 Adenosine Receptor ◽  
Adenosine Receptor Antagonist ◽  
Adenosine A1

Background A1 adenosine receptor activation reduces hypersensitivity in animal models of chronic pain, but intrathecal adenosine does not produce analgesia to acute noxious stimuli. Here, the authors test whether increased inhibition by adenosine of glutamate release from afferents after injury accounts for this difference. Methods Synaptosomes were prepared from the dorsal half of the lumbar spinal cord of normal rats or those with spinal nerve ligation. Glutamate release evoked by the TRPV-1 receptor agonist, capsaicin, was measured. Adenosine with or without adenosine A1 and A2 receptor antagonists was applied to determine the efficacy and mechanism of adenosine to reduce capsaicin-evoked glutamate release. Results Capsaicin produced a concentration-dependent glutamate release similarly in normal and nerve-injured rats. Capsaicin-evoked glutamate release was inhibited by adenosine or R-PIA (R-N6-(2- phenylisopropyl)-adenosine) in a concentration-dependent manner, with a threshold of 10 nm in both normal and nerve-ligated synaptosomes. Blockade of capsaicin-evoked glutamate release by adenosine was reversed similarly in synaptosomes from normal and spinal nerve-ligated animals by an A1 adenosine receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) but not by an A2 adenosine receptor antagonist DMPX (3'7-dimethyl-1-proparaglyxanthine). Capsaicin-evoked glutamate release, as well as its inhibition by adenosine, did not differ between synaptosomes prepared from tissue ipsilateral and contralateral to spinal nerve ligation. Conclusion These observations confirm previous neurophysiologic studies that presynaptic adenosine A1 receptor activation inhibits glutamate release from primary afferents. This effect is unaltered after peripheral nerve injury and thereby is unlikely to account for the enhanced analgesic efficacy of intrathecal adenosine in this setting.

Cellular sources of cyclooxygenase-1 and -2 up-regulation in the spinal dorsal horn after spinal nerve ligation

2014 ◽  
Vol 40 (4) ◽  
pp. 452-463 ◽  
Author(s):  
Yee Man Lau ◽  
Shing Chau Wong ◽  
Sin Wah Tsang ◽  
Wai Kit Lau ◽  
Ai Ping Lu ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Spinal Dorsal ◽  
Cyclooxygenase 1
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