scholarly journals Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 940
Author(s):  
Andy Kuo ◽  
Laura Corradini ◽  
Janet R. Nicholson ◽  
Maree T. Smith

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation’s List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3–30 mg/kg), pregabalin (3–100 mg/kg), duloxetine (3–100 mg/kg), indomethacin (1–10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose–response curve warrants further translational considerations.

1998 ◽  
Vol 86 (3) ◽  
pp. 584-587 ◽  
Author(s):  
Masahiko Shibata ◽  
Satoshi Wakisaka ◽  
Takaya Inoue ◽  
Tadao Shimizu ◽  
Ikuto Yoshiya

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 254-254
Author(s):  
Kun Hu ◽  
Zerong You ◽  
Weihua Ding ◽  
Jianren Mao

Abstract INTRODUCTION Painful peripheral neuropathy is a common dose-limiting side effect caused by chemotherapy agents, such as oxaliplatin. Mechanisms underlying this devastating condition are largely unknown. METHODS We established a rat model of chemotherapy induced pain by administering oxaliplatin at 2 mg/Kg for 5 consecutive days. Mechanical hyperalgesia, a typical nociceptive pain behavior, developed after treatment with oxaliplatin. We investigated the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the dorsal root ganglia (DRG) at both gene transcripts level (real-time PCR) and protein level (immunofluorescence). In addition, we examined the functional significance of HCN upregulation after oxaliplatin treatment by using a pan HCN channels blocker-ZD 7288. RESULTS >DRG HCN 1 and HCN 2 were higher in oxaliplatin- treated rats than saline-treated controls, both for gene transcripts and proteins. ZD7288, when administered intrathecally, was able to alleviate, albeit not abrogate, oxaliplatin induced-pain. Interestingly, pre-treatment with ZD7288 prior to oxaliplatin administration did not prevent the development of mechanical hyperalgesia. CONCLUSION Taken together, HCN1 and HCN2 channels are upregulated by oxaliplatin treatment, and that HCN blockade alleviates oxaliplatin-induced pain. Therefore, targeting HCN channels may provide a therapeutic avenue to treat chemotherapy induced-pain.


2000 ◽  
Vol 92 (6) ◽  
pp. 1740-1745 ◽  
Author(s):  
Tiina Onttonen ◽  
Antti Pertovaara

Background MPV-2426 is a novel alpha2-adrenoceptor agonist developed for spinal pain therapy. It has proved to be effective in physiologic and neuropathic conditions. In the current study its effectiveness on mechanical hyperalgesia was assessed in a rat model of postoperative pain. Methods Rats with intrathecal catheters were anesthetized with pentobarbital, and a 1-cm incision was made in the plantar aspect of the foot and closed. During postoperative days 1 and 2 the antihyperalgesic effects induced by intrathecal MPV-2426, clonidine, and dexmedetomidine were determined by assessing the hind limb withdrawal threshold to calibrated von Frey hairs applied to the skin of the hind paw adjacent to the wound. Results MPV-2426 administered into the lumbar spinal cord produced a dose-dependent (0.3-10 microg) attenuation of the mechanical hyperalgesia, and this antihyperalgesic effect was completely reversed by yohimbine (1 mg/kg, subcutaneous), an alpha2-adrenoceptor antagonist. Dexmedetomidine (1-3 microg) produced an equipotent antihyperalgesic effect, whereas the effect of clonidine (1-10 microg) was markedly weaker. MPV-2426 (10 microg in 20 microl) administered adjacent to the wound did not produce any effect. Preoperative treatment with an antihyperalgesic dose of MPV-2426 did not prevent the development of hyperalgesia. Conclusions Intrathecal MPV-2426 dose-dependently attenuates postoperative hyperalgesia to mechanical stimulation because of an action on alpha2 adrenoceptors. Its antihyperalgesic action is as effective as that produced by dexmedetomidine and is considerably stronger than that produced by clonidine. However, preoperative treatment with MPV-2426 does not prevent the development of postoperative hyperalgesia.


1998 ◽  
Vol 86 (3) ◽  
pp. 584-587 ◽  
Author(s):  
Masahiko Shibata ◽  
Satoshi Wakisaka ◽  
Takaya Inoue ◽  
Tadao Shimizu ◽  
Ikuto Yoshiya

Pain ◽  
2006 ◽  
Vol 123 (1) ◽  
pp. 117-126 ◽  
Author(s):  
Seung Keun Back ◽  
Jaehee Lee ◽  
Seung Kil Hong ◽  
Heung Sik Na

2020 ◽  
Vol 73 (5) ◽  
pp. 434-444 ◽  
Author(s):  
Kyungmi Kim ◽  
Wonyeong Jeong ◽  
In Gu Jun ◽  
Jong Yeon Park

Background: Studies investigating the correlation between spinal adenosine A1 receptors and vincristine-induced peripheral neuropathy (VIPN) are limited. This study explored the role of intrathecal N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) in the rat model of VIPN. Methods: Vincristine (100 μg/kg) was intraperitoneally administered for 10 days (two 5-day cycles with a 2-day pause) and VIPN was induced in rats. Pain was assessed by evaluating mechanical hyperalgesia, mechanical dynamic allodynia, thermal hyperalgesia, cold allodynia, and mechanical static allodynia. Biochemically, tumor necrosis factor-alpha (TNF-α) level and myeloperoxidase (MPO) activity were measured in the tissue from beneath the sciatic nerve.Results: Vincristine administration resulted in the development of cold allodynia, mechanical hyperalgesia, thermal hyperalgesia, mechanical dynamic allodynia, and mechanical static allodynia. Intrathecally administered R-PIA (1.0 and 3.0 μg/10 μl) reversed vincristine-induced neuropathic pain (cold and mechanical static allodynia). The attenuating effect peaked 15 min after intrathecal administration of R-PIA after which it decreased until 180 min. However, pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 μg/10 μl) 15 min before intrathecal R-PIA administration significantly attenuated the antiallodynic effect of R-PIA. This antiallodynic effect of intrathecal R-PIA may be mediated through adenosine A1 receptors in the spinal cord. Intrathecally administered R-PIA also attenuated vincristine-induced increases in TNF-α level and MPO activity. However, pretreatment with intrathecal DPCPX significantly reversed this attenuation.Conclusions: These results suggest that intrathecally administered R-PIA attenuates cold and mechanical static allodynia in a rat model of VIPN, partially due to its anti-inflammatory actions.


2018 ◽  
Vol 34 (04) ◽  
pp. 264-269 ◽  
Author(s):  
Chenlong Liao ◽  
Min Yang ◽  
Pengfei Liu ◽  
Wenxiang Zhong ◽  
Wenchuan Zhang

Background Preclinical studies involving animal models are essential for understanding the underlying mechanisms of diabetic neuropathic pain. Methods Rats were divided into four groups: two controls and two experimental. Diabetes mellitus was induced by streptozotocin (STZ) injection in two experimental groups. The first group involved one sham operation. The second group involved one latex tube encircling the sciatic nerve. The vehicle-injection rats were used as two corresponding control groups: sham operation and encircled nerves. By the third week, STZ-injected rats with encircled nerves were further divided into three subgroups: one involving continuing observation and the other two involving decompression (removal of the latex tube) at different time points (third week and fifth week). Weight and blood glucose were monitored, and behavioral analysis, including paw withdrawal threshold (PWT) and latency, was performed every week during the experimental period (7 weeks). Results Hyperglycemia was induced in all STZ-injected rats. A significant increase in weight was observed in the control groups when compared with the experimental groups. By the third week, more STZ-injected rats with encircled nerves developed mechanical allodynia than those without (P < 0.05), while no significant difference was noted (P > 0.05) on the incidence of thermal hyperalgesia. Mechanical allodynia, but not thermal hyperalgesia, could be ameliorated by the removal of the latex tube at an early stage (third week). Conclusion With the combined use of a latex tube and STZ injection, a stable rat model of painful diabetic peripheral neuropathy (DPN) manifesting both thermal hyperalgesia and mechanical allodynia has been established.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Kangwook Lee ◽  
Jin Mo Ku ◽  
Yu-Jeong Choi ◽  
Hyun Ha Hwang ◽  
Miso Jeong ◽  
...  

Docetaxel-based therapy has been applied to kill cancers including lung and breast cancers but frequently causes peripheral neuropathy such as mechanical allodynia. Lack of effective drugs for chemotherapy-induced peripheral neuropathy (CIPN) treatment leads us to find novel drugs. Here, we investigated whether and how novel anticancer herbal prescription SH003 alleviates mechanical allodynia in mouse model of docetaxel-induced neuropathic pain. Docetaxel-induced mechanical allodynia was evaluated using von Frey filaments. Nerve damage and degeneration in paw skin of mice were investigated by immunofluorescence staining. Neuroinflammation markers in bloodstream, lumbar (L4-L6) spinal cord, and sciatic nerves were examined by ELISA or western blot analysis. Docetaxel (15.277 mg/kg) was intravenously injected into the tail vein of C57BL/6 mice, and mechanical allodynia was followed up. SH003 (557.569 mg/kg) was orally administered at least 60 min before the mechanical allodynia test, and von Frey test was performed twice. Docetaxel injection induced mechanical allodynia, and SH003 administration restored withdrawal threshold. Meanwhile, degeneration of intraepidermal nerve fibers (IENF) was observed in docetaxel-treated mice, but SH003 treatment suppressed it. Moreover, docetaxel injection increased levels of TNF-α and IL-6 in plasma and expressions of phospho-NF-κB and phospho-STAT3 in both of lumbar spinal cord and sciatic nerves, while SH003 treatment inhibited those changes. Taken together, it is worth noting that TNF-α and IL-6 in plasma and phospho-NF-κB and phospho-STAT3 in spinal cord and sciatic nerves are putative biomarkers of docetaxel-induced peripheral neuropathy (DIPN) in mouse models. In addition, we suggest that SH003 would be beneficial for alleviation of docetaxel-induced neuropathic pain.


2020 ◽  
Vol 72 (5) ◽  
pp. 1418-1425
Author(s):  
Mohammad Zafar Imam ◽  
Andy Kuo ◽  
Janet R. Nicholson ◽  
Laura Corradini ◽  
Maree T. Smith

2019 ◽  
Vol 62 (5) ◽  
pp. 2466-2484 ◽  
Author(s):  
Shannon N. Mostyn ◽  
Tristan Rawling ◽  
Sarasa Mohammadi ◽  
Susan Shimmon ◽  
Zachary J. Frangos ◽  
...  

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