KST5468, a new T-type calcium channel antagonist, has an antinociceptive effect on inflammatory and neuropathic pain models |
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Authors: | Min Ju Lee Jie Eun Lee Hyunah Choo Hye Jin Chung Sang Chul Lee |
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Affiliation: | a Department of Dental Anesthesiology and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-768, Republic of Koreab Life Science Division, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Republic of Koreac Department of Chemistry, Inha University, Nam-gu, Incheon 402-751, Republic of Koread Department of Anesthesiology and Pain Medicine and Institute of Complementary and Integrative Medicine, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea |
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Abstract: | The T-type Ca2+ channel is a low-voltage-activated Ca2+ channel related to nociceptive stimuli. Increases in Ca2+ due to calcium channel activation enhance pain sensitivity through both peripheral and central pain pathways. We have developed a novel compound, KST5468, which is a T-type calcium channel antagonist. The new synthetic compound may have an antinociceptive effect, and thus we evaluated KST5468 as a putative analgesic in a hot plate test, a formalin test, and two neuropathic pain models. KST5468 caused a significant increase in latency in the hot plate test at 30 min after a 10 mg/kg peritoneal injection of the compound. Interestingly, in the second phase of formalin test, KST5468 decreased pain behaviors in a dose-dependent manner. Moreover, in two neuropathic pain models induced by chronic constriction and spared nerve injury, KST5468 significantly increased the mechanical pain threshold. Using immunohistochemistry, expression of two well known pain-related molecular markers, c-Fos and calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-related kinase (p-ERK) were found to be decreased in the laminae I-II layers of the ipsilateral L4-L5 spinal dorsal horn in KST5468 treated mice. Taken together, the results of this study suggest that KST5468 may be an effective antinociceptive agent for neuropathic pain. |
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Keywords: | Formalin test Hot plate test Low-voltage-activated T-type Ca2+ channel Mice Neuropathy Pain |
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