scholarly journals The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain

2006 ◽  
Vol 2 (4) ◽  
pp. 279-291 ◽  
Author(s):  
Annemarie Ledeboer ◽  
Tongyao Liu ◽  
Jennifer A. Shumilla ◽  
John H. Mahoney ◽  
Sharmila Vijay ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Cell Activation ◽  
Therapeutic Agent ◽  
Chronic Constriction Injury ◽  
Phosphodiesterase Inhibitor ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Glial Cell Activation ◽  
Medical Need

AbstractControlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol¯). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.

Effect of Methylprednisolone on Neuropathic Pain and Spinal Glial Activation in Rats

2004 ◽  
Vol 100 (5) ◽  
pp. 1249-1257 ◽  
Author(s):  
Kenji Takeda ◽  
Shigehito Sawamura ◽  
Hiroshi Sekiyama ◽  
Hisayoshi Tamai ◽  
Kazuo Hanaoka
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Day Treatment ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Glial Activation ◽  
Pain State ◽  
Protein Immunoreactivity ◽  
Neuropathic Pain State

Background Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. Methods Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg x kg(-1) x day(-1)) or intrathecal (80 microg x kg(-1) x day(-1)) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. Results Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. Conclusion : Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.

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.

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.

Role for Cyclooxygenase 2 in the Development and Maintenance of Neuropathic Pain and Spinal Glial Activation

2005 ◽  
Vol 103 (4) ◽  
pp. 837-844 ◽  
Author(s):  
Kenji Takeda ◽  
Shigehito Sawamura ◽  
Hisayoshi Tamai ◽  
Hiroshi Sekiyama ◽  
Kazuo Hanaoka
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Cyclooxygenase 2 ◽  
Glial Activation ◽  
Protein Immunoreactivity ◽  
Intrathecal Infusion ◽  
Lines Of Evidence

Background Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats. Methods Continuous intrathecal infusion of meloxicam (32 or 320 mug . kg . day) or saline was started immediately after L5-L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg . kg . day) on existing neuropathic pain and glial activation were examined. Results Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation. Conclusions Spinal cyclooxygenase 2 mediates the development but not the maintenance of neuropathic pain and glial activation in rats. Peripheral cyclooxygenase 2 plays a part in the maintenance of neuropathic pain.

scholarly journals Tongluo Zhitong Prescription Alleviates Allodynia, Hyperalgesia, and Dyskinesia in the Chronic Constriction Injury Model of Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Zhiyong Wang ◽  
Jianwei Wang ◽  
Lihua Qin ◽  
Weiguang Zhang
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Catgut Suture ◽  
Cold Allodynia ◽  
Injury Model ◽  
Neuropathic Pain Model ◽  
Gait Function ◽  
Chronic Constriction Injury Model ◽  
Heat Hyperalgesia

Neuropathic pain is common in clinical practice. Exploration of new drug therapeutics has always been carried out for more satisfactory effects and fewer side-effects. In the present study, we aimed to investigate effects of Tongluo Zhitong Prescription (TZP), a compounded Chinese medicine description, on neuropathic pain model of rats with chronic constriction injury (CCI). The CCI model was established by loosely ligating sciatic nerve with catgut suture, proximal to its trifurcation. The static and dynamic allodynia, heat hyperalgesia, mechanical allodynia, cold allodynia, and gait were assessed. Our results showed that TZP alleviated CCI-induced static and dynamic allodynia, suppressed heat hyperalgesia and cold and mechanical allodynia, and improved gait function. These results suggest that TZP could alleviate neuropathic pain. Further experiments are needed to explore its mechanisms.

Sign in / Sign up

Export Citation Format

Share Document