González-Cano Rafael, Tejada Miguel Ángel, Artacho-Cordón Antonia, Nieto Francisco Rafael, Entrena José Manuel, Wood John N, Cendán Cruz Miguel
Department of Pharmacology, Biomedical Research Centre and Institute of Neuroscience, Faculty of Medicine, University of Granada, 18016 Granada, Spain.
Biosanitary Research Institute, University Hospital Complex of Granada, 18012 Granada, Spain.
Mar Drugs. 2017 Jun 21;15(6):188. doi: 10.3390/md15060188.
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Na1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Na1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.
内脏痛非常常见，是临床上一个尚未得到充分满足的重大需求，目前的药物治疗往往效果不佳。河豚毒素（TTX）是一种强效神经毒素，在不同的躯体疼痛条件下，对人类和啮齿动物均有镇痛作用，但其在内脏痛方面的作用尚未得到探索。因此，我们测试了全身性TTX在结肠化学刺激（结肠内注入辣椒素和芥子油）和腹腔注射环磷酰胺诱导的膀胱炎等内脏特异性小鼠模型中的作用。皮下注射TTX剂量依赖性地抑制了所有评估疼痛模型中与疼痛相关的行为数量，并逆转了由辣椒素和环磷酰胺诱导的牵涉性机械性痛觉过敏（通过用von Frey细丝刺激腹部来检测），但对芥子油诱导的牵涉性机械性痛觉过敏无效。吗啡在所有测试中均抑制了疼痛反应和牵涉性机械性痛觉过敏。用TTX处理的条件性伤害感受器特异性Na1.7基因敲除小鼠在给予致痛剂后表现出与同窝对照相同的反应。未观察到TTX给药后出现运动不协调。这些结果表明，全身性给予TTX阻断TTX敏感的钠通道，而不仅仅是Na1.7亚型，可能是治疗内脏痛的一种潜在治疗策略。
