201 HCN Channels Blockade Attenuates Chemotherapy-Induced Pain

Neurosurgery ◽  
2017 ◽  
Vol 64 (CN_suppl_1) ◽  
pp. 254-254
Author(s):  
Kun Hu ◽  
Zerong You ◽  
Weihua Ding ◽  
Jianren Mao
Keyword(s):  
Peripheral Neuropathy ◽  
Rat Model ◽  
Dorsal Root ◽  
Mechanical Hyperalgesia ◽  
Hcn Channels ◽  
Oxaliplatin Treatment ◽  
Gene Transcripts ◽  
Pre Treatment ◽  
Chemotherapy Agents ◽  
Therapeutic Avenue

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.

scholarly journals Antiallodynic and anti-inflammatory effects of intrathecal R-PIA in a rat model of vincristine-induced peripheral neuropathy

2020 ◽  
Vol 73 (5) ◽  
pp. 434-444 ◽  
Author(s):  
Kyungmi Kim ◽  
Wonyeong Jeong ◽  
In Gu Jun ◽  
Jong Yeon Park
Keyword(s):  
Peripheral Neuropathy ◽  
Rat Model ◽  
Thermal Hyperalgesia ◽  
Mechanical Hyperalgesia ◽  
Cold Allodynia ◽  
Adenosine A1 Receptors ◽  
Tnf Α ◽  
Adenosine A1 ◽  
Α Level ◽  
Antiallodynic Effect

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.

scholarly journals Preventing the induction of acid saline-induced fibromyalgia pain in mice by electroacupuncture or APETx2 injection

2020 ◽  
Vol 38 (3) ◽  
pp. 188-193
Author(s):  
Liang-Ta Yen ◽  
Ching-Liang Hsieh ◽  
Hsin-Cheng Hsu ◽  
Yi-Wen Lin
Keyword(s):  
Spinal Cord ◽  
Murine Model ◽  
Dorsal Root ◽  
Morning Stiffness ◽  
Mechanical Hyperalgesia ◽  
Signalling Pathways ◽  
Clinical Use ◽  
Over Expression ◽  
Pre Treatment ◽  
Sleep Difficulties

Background: Fibromyalgia (FM) is a syndrome involving chronic pain, fatigue, sleep difficulties, morning stiffness and muscle cramping lasting longer than 3 months. The epidemiological prevalence is approximately 3–5% in women and increases with age. Antagonism of acid-sensing ion channel 3 (ASIC3) reportedly attenuates acid saline-induced FM pain in mice. Aims: Whether pre-treatment with electroacupuncture (EA) or APETx2 can attenuate mechanical hyperalgesia in this murine model remains unknown. Methods: Accordingly, we examined the analgesic effect of EA in a murine model of FM pain induced by dual injections of acid saline and investigated whether EA or APETx2 can attenuate FM pain via the ASIC3 channel. Results: EA significantly reduced mechanical hyperalgesia in this model. ASIC3 antagonism, induced by injecting APETx2, also significantly reduced mechanical hyperalgesia. The expression of ASIC3 in the dorsal root ganglia, spinal cord and thalamus was increased after FM model induction. Over-expression of these nociceptive channels was attenuated by pre-treatment with EA or an ASIC3 antagonist. Conclusion: Our data reveal that both EA and ASIC3 blockade significantly reduce FM pain in mice via the ASIC3, Nav1.7 and Nav1.8 signalling pathways. Moreover, our findings support the potential clinical use of EA for the treatment of FM pain.

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
Keyword(s):  
Peripheral Neuropathy ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Negative Impact ◽  
Mechanical Hyperalgesia ◽  
Essential Medicines ◽  
World Health ◽  
Lumbar Spinal Cord ◽  
Glycine Transporter ◽  
Glycine Transporter 2

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.

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