scholarly journals The Effect of Epidural Resiniferatoxin in the Neuropathic Pain Rat Model

2012 ◽  
Vol 4;15 (4;8) ◽  
pp. 287-296
Author(s):  
Mi Kyoung Lee
Keyword(s):  
Neuropathic Pain ◽  
Rat Model ◽  
Analgesic Effect ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Thermal Stimulation ◽  
Control Group ◽  
Transient Receptor Potential Vanilloid ◽  
Epidural Administration ◽  
Mechanical Hypersensitivity

Background: Resiniferatoxin (RTX) is a potent synthetic agonist for transient receptor potential vanilloid subtype 1 (TRPV1), which has a selectivity for antinociception. The analgesic effect of epidural RTX in a rat model of neuropathic pain has not yet been studied. Objectives: The purpose of this study was to evaluate the analgesic effect of epidural RTX on neuropathic pain in a rat model to mechanical and thermal stimulation. The dose-related behavior changes and side effects were also studied. Study design: A randomized, experimental trial. Setting: Department of Anesthesiology and Pain Medicine, Korea University Guro Hospital Methods: A spinal nerve ligation model was prepared using male Sprague-Dawley rats (7 weeks old, weight 230-250 g). An epidural catheter was placed at the L4-L5 level. Each study group (n = 6) received a different dose of RTX: 100 ng, 500 ng, 1 µg, 2 µg, 4 µg and 10 µg. All substances were administered in 20 µL volume doses. The control group (n = 6) received 20 µL of normal saline. We evaluated the response to mechanical and thermal stimuli as well as the sedation score at both short-term (3 hours) and long-term (20 days) after the epidural RTX injection. Results: Prolonged analgesia to thermal stimulation was preceded by a transient dose-dependent hyperalgesia (500 ng, 1 µg) or sedation (≥ 2 µg) during the initial 60 minutes after RTX administration. Marked sedation and hyperventilation were noted at higher doses (≥ 2 µg), while 2 out of 6 rats died with a 10 µg dose. ED50 for epidural RTX was 265 ng (95% confidence interval 216.1–324.9 ng). The increased latency to thermal stimulation continued for 20 days at RTX ≥ 1 µg. But the threshold to mechanical stimulation increased only in the acute period and returned to the baseline after 3-5 days, regardless of the administered dose. Limitations: A histological examination by electron-microscopic staining was not performed. The observation period was not very long (20 days). Conclusion: RTX has potential to be used in an epidural route for neuropathic pain in a rat model with a relatively small amount, which produces transitory improvement of mechanical hypersensitivity and prolonged thermal analgesic response. Key words: Epidural administration, mechanical allodynia, mechanical hypersensitivity, resiniferatoxin, sedation, spinal nerve ligation rat model, thermal hyperalgesia.

scholarly journals Three-dimensional analysis of the characteristics of joint motion and gait pattern in a rodent model following spinal nerve ligation

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Takayuki Seto ◽  
Hidenori Suzuki ◽  
Tomoya Okazaki ◽  
Yasuaki Imajo ◽  
Norihiro Nishida ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Pain Intensity ◽  
Rat Model ◽  
Gait Pattern ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Joint Motion ◽  
Behavioral Reactions ◽  
Post Operation ◽  
The Right

Abstract Background The spinal nerve ligation (SNL) rat is well known as the most common rodent model of neuropathic pain without motor deficit. Researchers have performed analyses using only the von Frey and thermal withdrawal tests to evaluate pain intensity in the rat experimental model. However, these test are completely different from the neurological examinations performed clinically. We think that several behavioral reactions must be observed following SNL because the patients with neuropathic pain usually have impaired coordination of the motions of the right–left limbs and right–left joint motion differences. In this study, we attempted to clarify the pain behavioral reactions in SNL rat model as in patients. We used the Kinema-Tracer system for 3D kinematics gait analysis to identify new characteristic parameters of each joint movement and gait pattern. Results The effect of SNL on mechanical allodynia was a 47 ± 6.1% decrease in the withdrawal threshold during 1–8 weeks post-operation. Sagittal trajectories of the hip, knee and ankle markers in SNL rats showed a large sagittal fluctuation of each joint while walking. Top minus bottom height of the left hip and knee that represents instability during walking was significantly larger in the SNL than sham rats. Both-foot contact time, which is one of the gait characteristics, was significantly longer in the SNL versus sham rats: 1.9 ± 0.15 s vs. 1.03 ± 0.15 s at 4 weeks post-operation (p = 0.003). We also examined the circular phase time to evaluate coordination of the right and left hind-limbs. The ratio of the right/left circular time was 1.0 ± 0.08 in the sham rats and 0.62 ± 0.15 in the SNL rats at 4 weeks post-operation. Conclusions We revealed new quantitative parameters in an SNL rat model that are directly relevant to the neurological symptoms in patients with neuropathic pain, in whom the von Frey and thermal withdrawal tests are not used at all clinically. This new 3D analysis system can contribute to the analysis of pain intensity of SNL rats in detail similar to human patients’ reactions following neuropathic pain.

Peripheral Nerve Injury Reduces Analgesic Effectsof Systemic Morphine via Spinal 5-Hydroxytryptamine 3 Receptors

2014 ◽  
Vol 121 (2) ◽  
pp. 362-371 ◽  
Author(s):  
Masafumi Kimura ◽  
Hideaki Obata ◽  
Shigeru Saito
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Noradrenaline Release ◽  
Peripheral Nerve Injury ◽  
Analgesic Effect ◽  
Spinal Dorsal Horn ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Analgesic Effects ◽  
Spinal Dorsal

Abstract Background: Morphine produces powerful analgesic effects against acute pain, but it is not effective against neuropathic pain, and the mechanisms underlying this reduced efficacy remain unclear. Here, the authors compared the efficacy of systemic morphine between normal rats and rats with peripheral nerve injury, with a specific focus on descending serotonergic mechanisms. Methods: After L5 spinal nerve ligation injury, male Sprague–Dawley rats were subjected to behavioral testing, in vivo microdialysis of the spinal dorsal horn to determine serotonin (5-hydroxytryptamine [5-HT]) and noradrenaline release, and immunohistochemistry (n = 6 in each group). Results: Intraperitoneal administration of morphine (1, 3, or 10 mg/kg) produced analgesic effects in normal and spinal nerve ligation rats, but the effects were greater in normal rats (P < 0.001). Morphine increased 5-HT release (450 to 500% of the baseline), but not noradrenaline release, in the spinal dorsal horn via activation of serotonergic neurons in the rostral ventromedial medulla. Intrathecal pretreatment with ondansetron (3 μg), a 5-HT3 receptor antagonist, or 5,7-dihydroxytryptamine creatinine sulfate (100 μg), a selective neurotoxin for serotonergic terminals, attenuated the analgesic effect of morphine (10 mg/kg) in normal rats but increased the analgesic effect of morphine in spinal nerve ligation rats (both P < 0.05). Conclusions: Systemic administration of morphine increases 5-HT levels in the spinal cord, and the increase in 5-HT contributes to morphine-induced analgesia in the normal state but attenuates that in neuropathic pain through spinal 5-HT3 receptors. The plasticity of the descending serotonergic system may contribute to the reduced efficacy of systemic morphine in neuropathic pain.

scholarly journals Low Frequency Electroacupuncture Alleviated Spinal Nerve Ligation Induced Mechanical Allodynia by Inhibiting TRPV1 Upregulation in Ipsilateral Undamaged Dorsal Root Ganglia in Rats

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Yong-Liang Jiang ◽  
Xiao-Hu Yin ◽  
Ya-Fang Shen ◽  
Xiao-Fen He ◽  
Jian-Qiao Fang
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Pain Threshold ◽  
Transient Receptor Potential ◽  
Low Frequency ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Transient Receptor Potential Vanilloid

Neuropathic pain is an intractable problem in clinical practice. Accumulating evidence shows that electroacupuncture (EA) with low frequency can effectively relieve neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1) plays a key role in neuropathic pain. The study aimed to investigate whether neuropathic pain relieved by EA administration correlates with TRPV1 inhibition. Neuropathic pain was induced by right L5 spinal nerve ligation (SNL) in rats. 2 Hz EA stimulation was administered. SNL induced mechanical allodynia in ipsilateral hind paw. SNL caused a significant reduction of TRPV1 expression in ipsilateral L5 dorsal root ganglia (DRG), but a significant up-regulation in ipsilateral L4 and L6 DRGs. Calcitonin gene-related peptide (CGRP) change was consistent with that of TRPV1. EA alleviated mechanical allodynia, and inhibited TRPV1 and CGRP overexpressions in ipsilateral L4 and L6 DRGs. SNL did not decrease pain threshold of contralateral hind paw, and TRPV1 expression was not changed in contralateral L5 DRG. 0.001, 0.01 mg/kg TRPV1 agonist 6′-IRTX fully blocked EA analgesia in ipsilateral hind paw. 0.01 mg/kg 6′-IRTX also significantly decreased pain threshold of contralateral paw. These results indicated that inhibition of TRPV1 up-regulation in ipsilateral adjacent undamaged DRGs contributed to low frequency EA analgesia for mechanical allodynia induced by spinal nerve ligation.

Opioid Self-administration in the Nerve-injured Rat

2007 ◽  
Vol 106 (2) ◽  
pp. 312-322 ◽  
Author(s):  
Thomas J. Martin ◽  
Susy A. Kim ◽  
Nancy L. Buechler ◽  
Frank Porreca ◽  
James C. Eisenach
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Intrathecal Administration ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Drug Intake ◽  
Spontaneous Pain ◽  
Self Administration ◽  
Mechanical Hypersensitivity ◽  
Opioid Sparing

Background Neuropathic pain is associated with several sensory abnormalities, including allodynia as well as spontaneous pain. Opioid intake in neuropathic pain patients is motivated by alleviation of both pain and allodynia. However, laboratory animal studies rely almost exclusively on reflexive withdrawal measures of allodynia. The authors examined the pharmacology of self-regulated intake of opioids in rats with or without nerve injury and compared the rate of drug intake to reversal of allodynia. Methods Rats were implanted with intravenous catheters, and the L5 and L6 spinal nerves were ligated in half of these animals. Rats were then trained to self-administer a commonly abused opioid (heroin) and commonly prescribed opioids (morphine, fentanyl, hydromorphone, and methadone). In addition, rats trained to self-administer heroin were given either clonidine or adenosine spinally before self-administration sessions to assess opioid-sparing effects. Results Nerve injury significantly decreased the reinforcing effects of low doses of opioids, and only doses of each opioid that reduced mechanical hypersensitivity maintained self-administration after spinal nerve ligation. The rate of drug consumption was correlated with the duration of the antiallodynic effect for each dose of opioid. Intrathecal administration of clonidine or adenosine reversed mechanical hypersensitivity, but only clonidine reduced heroin self-administration in rats with spinal nerve ligation. Conclusion Opioid self-administration is significantly altered by nerve injury, with rate of drug intake being correlated with reversal of allodynia. Intrathecal clonidine, but not adenosine, produces opioid-sparing effects in self-administering rats. The neurobiologic mechanisms that regulate opioid consumption in rats therefore seem to be altered after nerve injury.

scholarly journals Effect of two-week continuous epidural administration of 2% lidocaine on mechanical allodynia induced by spinal nerve ligation in rats

2020 ◽  
Vol 15 (3) ◽  
pp. 334-343
Author(s):  
Yuseon Cheong ◽  
Minsoo Kim ◽  
Namyoong Kim ◽  
Byeongmun Hwang
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Epidural Administration ◽  
Drug Infusion ◽  
Continuous Epidural Infusion ◽  
Withdrawal Threshold ◽  
Lidocaine Administration ◽  
The Difference

Background: Lidocaine is an effective against certain types of neuropathic pain. This study aimed to investigate whether timing of initiating continuous epidural infusion of lidocaine affected the glial activation and development of neuropathic pain induced by L5/6 spinal nerve ligation (SNL) in rats. Methods: Following L5/6 SNL, rats were epidurally infused 2% lidocaine (drug infusion initiated on days 1, and 7 post SNL model establishment) or saline (saline infusion initiated on day 1 post SNL model establishment) continuously for 14 days. Mechanical allodynia of the hind paw to von Frey filament stimuli was determined prior to surgery, postoperative day 3, and once weekly after SNL model establishment. At 7 days after the infusion of saline or lidocaine ended, spinal activation of proinflammatory cytokines and astrocytes was evaluated immunohistochemically, using antibodies to interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP).Results: Continuous epidural administration of 2% lidocaine for 14 days increased the mechanical withdrawal threshold regardless of the difference in timing of initiating lidocaine administration. Epidurally infusing 2% lidocaine inhibited nerve ligation-induced IL-6 and GFAP activation. In the 2% lidocaine infusion group, rats maintained the increased mechanical withdrawal threshold even at 7 days after the discontinuation of 2% lidocaine infusion. Conclusions: Continuous epidural administration of 2% lidocaine inhibited the development of SNL-induced mechanical allodynia and suppressed IL-6 and GFAP activation regardless of the difference in timing of initiating lidocaine administration.

scholarly journals Biomarker Analysis of Orally Dosed, Dual Active, Matrix Metalloproteinase (MMP)-2 and MMP-9 Inhibitor, AQU-118, in the Spinal Nerve Ligation (SNL) Rat Model of Neuropathic Pain

2019 ◽  
Vol 20 (4) ◽  
pp. 811 ◽  
Author(s):  
Mei Kwan ◽  
Anthony Choo ◽  
Taleen Hanania ◽  
Afshin Ghavami ◽  
Jose Beltran ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root Ganglion ◽  
Rat Model ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Caspase 3 ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Oral Dosing ◽  
Protein Levels

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG.

Inhibition of Spinal Microglia and Astrocytes Contributes to the Anti-Allodynic Effect of Electroacupuncture in Neuropathic Pain Induced by Spinal Nerve Ligation

2016 ◽  
Vol 34 (1) ◽  
pp. 40-47 ◽  
Author(s):  
Yi Liang ◽  
Yujie Qiu ◽  
Junying Du ◽  
Jin Liu ◽  
Junfan Fang ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Spinal Cord Dorsal Horn ◽  
Control Group ◽  
Sprague Dawley ◽  
Astrocyte Activation ◽  
Gfap Immunoreactivity ◽  
Underlying Mechanisms

Objective Besides neurons, activated microglia and astrocytes in the spinal cord dorsal horn (SCDH) contribute to the pathogenesis of chronic pain. Electroacupuncture (EA) has been used widely to treat various chronic pain diseases, however, the underlying mechanisms of EA are still not fully understood. Methods Male Sprague-Dawley rats were randomly divided into four groups, including an untreated healthy Control group (n=14), a True-spinal nerve ligation (SNL) group that underwent SNL and remained untreated (n=25), a True-SNL+EA group that underwent SNL followed by EA treatment (n=25), and a Sham-SNL group that underwent sham surgery and remained untreated (n=15). SNL was performed unilaterally at L5 and EA was applied to ST36 and BL60 bilaterally once per day. Paw withdrawal thresholds (PWTs) were measured ipsilaterally at baseline and 1, 3, 7, and 14 days after ligation. Activation of microglia and astrocytes in the SCDH were examined bilaterally by immunofluorescence staining, and concentrations of interleukin-1β (IL-1β) and interleukin (IL-6) were measured in the ipsilateral SCDH by ELISA. Results SNL significantly decreased PWTs and activated glial cells in the superficial laminae of the ipsilateral SCDH. In rats with SNL, glial fibrillary acidic protein (GFAP) immunoreactivity peaked at 7 days and was maintained until 14 days post-ligation, while anti-integrin alphaM (OX-42) immunoreactivity peaked at 3 days and declined gradually. EA significantly alleviated SNL-induced mechanical allodynia. Furthermore, EA reduced microglial activation (OX-42 positive ratios) in the lumbar SCDH at 3 days post-ligation and suppressed astrocyte activation (GFAP positive ratios) at all time points observed. Conclusions EA stimulation alleviates SNL-induced neuropathic pain, at least in part through inhibition of spinal glial activation. Moreover, inhibition of spinal microglia and astrocyte activation may contribute to the immediate effects and maintenance of EA analgesia, respectively.

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