Laboratory of Pharmacology, Lutheran University of Brazil (ULBRA), Av. Farroupilha, no 8001, Bairro São José, Canoas, Rio Grande do Sul, CEP 92425-900, Brazil.
Program of Postgraduation in Cellular and Molecular Biology Applied To Health, Lutheran University of Brazil (ULBRA), Canoas, RS, Brazil.
Pharmacol Rep. 2020 Jun;72(3):600-611. doi: 10.1007/s43440-020-00108-z. Epub 2020 May 12.
Orofacial pain is clinically challenging, having therapeutic failures and side effects. This study evaluated the antinociceptive activities of the CTK 01512-2 toxin, the TRPA1 channel antagonist, and the selective inhibitor of the N-type voltage-gated calcium channels (N-type VGCC), in different pain models.
The trigeminal ganglia were stimulated in vitro with capsaicin. The in vivo models received subcutaneous (sc) injections of formalin into the upper lip of the rats, Freund's Complete Adjuvant (FCA) into the temporomandibular joint (TMJ), and infraorbital nerve constrictions (IONC). CTK 01512-2 at concentrations of 30, 100, and 300 pmol/site, intrathecally (ith), and MVIIA at 10, 30, and 100 pmol/site in the formalin test, guided the doses for the models. The glutamate levels in the CSF of the rats that were submitted to IONC were analyzed.
CTK 01512-2 decreased the nociceptive behavior in the inflammatory phase of the formalin test (65.94 ± 7.35%) and MVIIA in the neurogenic phase (81.23 ± 3.36%). CTK 01512-2 reduced facial grooming with FCA in the TMJ (96.7 ± 1.6%), and in the IONC neuropathy model, it decreased heat hyperalgesia (100%) and cold hyperalgesia (81.61 ± 9.02%). The levels of glutamate in the trigeminal ganglia in vitro (81.40 ± 8.59%) and in the CSF in vivo (70.0 ± 9.2%) were reduced.
The roles of TRPA1 in pain transduction and the performance of CTK 01512-2 in the inhibition of the N-type VGCCs were reinforced. This dual activity may represent an advantage in clinical treatments.
口腔颌面疼痛具有临床挑战性，存在治疗失败和副作用。本研究评估了 CTK 01512-2 毒素（TRPA1 通道拮抗剂）和 N 型电压门控钙通道（N 型 VGCC）选择性抑制剂在不同疼痛模型中的抗伤害作用。
在体外用辣椒素刺激三叉神经节。体内模型接受皮下（sc）注射到大鼠上唇的福尔马林、颞下颌关节（TMJ）的完全弗氏佐剂（FCA）和眶下神经缩窄（IONC）。CTK 01512-2 以 30、100 和 300 pmol/部位的浓度鞘内（ith）给药，MVIIA 以 10、30 和 100 pmol/部位的浓度在福尔马林试验中指导剂量。分析接受 IONC 的大鼠脑脊液中的谷氨酸水平。
CTK 01512-2 降低了福尔马林试验炎症期的伤害性行为（65.94±7.35%），MVIIA 降低了神经原性期的伤害性行为（81.23±3.36%）。CTK 01512-2 减少了 TMJ 中 FCA 引起的面部梳理（96.7±1.6%），在 IONC 神经病变模型中，它降低了热痛觉过敏（100%）和冷痛觉过敏（81.61±9.02%）。体外三叉神经节（81.40±8.59%）和体内脑脊液（70.0±9.2%）中的谷氨酸水平降低。
TRPA1 在疼痛转导中的作用和 CTK 01512-2 抑制 N 型 VGCC 的作用得到了加强。这种双重作用在临床治疗中可能具有优势。
