KST5468, a new T-type calcium channel antagonist, has an antinociceptive effect on inflammatory and neuropathic pain models.
The T-type Ca(2+) channel is a low-voltage-activated Ca(2+) channel related to nociceptive stimuli. Increases in Ca(2+) 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 30min after a 10mg/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.
Lee
Min Ju
MJ
Department of Dental Anesthesiology and Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-768, Republic of Korea.
Shin
Teo Jeon
TJ
Lee
Jie Eun
JE
Choo
Hyunah
H
Koh
Hun Yeong
HY
Chung
Hye Jin
HJ
Pae
Ae Nim
AN
Lee
Sang Chul
SC
Kim
Hyun Jeong
HJ
D000700:Analgesics; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005557:Formaldehyde; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D006358:Hot Temperature; D007249:Inflammation / Q000150:complications*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000378:metabolism* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects*; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics; D004856:Postural Balance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects
D000700:Analgesics; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D007555:Isoxazoles; C555515:KST 5468; D010879:Piperazines; D005557:Formaldehyde; D048049:Extracellular Signal-Regulated MAP Kinases; D015740:Calcitonin Gene-Related Peptide