Salas Margaux M, McIntyre Matthew K, Petz Lawrence N, Korz Walter, Wong Donald, Clifford John L
US Army Institute of Surgical Research, 3698 Chambers Pass, Bldg 3611, JBSA Fort Sam Houston, TX 78234-6315, USA.
WEX Pharmaceuticals Inc., Suite 420, 1090 West Pender Street, Vancouver, BC V6E 2N7, Canada.
Neurosci Lett. 2015 Oct 21;607:108-113. doi: 10.1016/j.neulet.2015.09.031. Epub 2015 Sep 28.
Burn injuries have been identified as the primary cause of injury in 5% of U.S. military personnel evacuated from Operations Iraqi Freedom and Enduring Freedom. Severe burn-associated pain is typically treated with opioids such as fentanyl, morphine, and methadone. Side effects of opioids include respiratory depression, cardiac depression, decrease in motor and cognitive function, as well as the development of hyperalgesia, tolerance and dependence. These effects have led us to search for novel analgesics for the treatment of burn-associated pain in wounded combat service members. Tetrodotoxin (TTX) is a selective voltage-gated sodium channel blocker currently in clinical trials as an analgesic. A phase 3 clinical trial for cancer-related pain has been completed and phase 3 clinical trials on chemotherapy-induced neuropathic pain are planned. It has also been shown in mice to inhibit the development of chemotherapy-induced neuropathic pain. TTX was originally identified as a neurotoxin in marine animals but has now been shown to be safe in humans at therapeutic doses. The antinociceptive effects of TTX are thought to be due to inhibition of Na(+) ion influx required for initiation and conduction of nociceptive impulses. One TTX sensitive sodium channel, Nav1.7, has been shown to be essential in lowering the heat pain threshold after burn injuries. To date, the analgesic effect of TTX has not been tested in burn-associated pain. Male Sprague-Dawley rats were subjected to a full thickness thermal injury on the right hind paw. TTX (8 μg/kg) was administered once a day systemically by subcutaneous injection beginning 3 days post thermal injury and continued through 7 days post thermal injury. Thermal hyperalgesia and mechanical allodynia were assessed 60 and 120 min post injection on each day of TTX treatment. TTX significantly reduced thermal hyperalgesia at all days tested and had a less robust, but statistically significant suppressive effect on mechanical allodynia. These results suggest that systemic TTX may be an effective, rapidly acting analgesic for battlefield burn injuries and has the potential for replacing or reducing the need for opioid analgesics.
烧伤已被确定为从伊拉克自由行动和持久自由行动中撤离的5%美国军事人员受伤的主要原因。严重的烧伤相关疼痛通常用阿片类药物治疗，如芬太尼、吗啡和美沙酮。阿片类药物的副作用包括呼吸抑制、心脏抑制、运动和认知功能下降，以及痛觉过敏、耐受性和依赖性的发展。这些影响促使我们寻找新型镇痛药来治疗受伤战斗人员的烧伤相关疼痛。河豚毒素（TTX）是一种选择性电压门控钠通道阻滞剂，目前正作为镇痛药进行临床试验。一项针对癌症相关疼痛的3期临床试验已经完成，计划开展关于化疗引起的神经性疼痛的3期临床试验。在小鼠中也已证明它能抑制化疗引起的神经性疼痛的发展。TTX最初在海洋动物中被鉴定为一种神经毒素，但现在已证明在治疗剂量下对人类是安全的。TTX的镇痛作用被认为是由于抑制了伤害性冲动起始和传导所需的Na(+)离子内流。一种对TTX敏感的钠通道Nav1.7已被证明在降低烧伤后的热痛阈值方面至关重要。迄今为止，TTX的镇痛效果尚未在烧伤相关疼痛中进行测试。雄性Sprague-Dawley大鼠右后爪遭受全层热损伤。从热损伤后3天开始，每天一次通过皮下注射全身给予TTX（8μg/kg），持续至热损伤后7天。在TTX治疗的每一天，注射后60分钟和120分钟评估热痛觉过敏和机械性异常性疼痛。在所有测试日，TTX均显著降低热痛觉过敏，并且对机械性异常性疼痛有较弱但具有统计学意义的抑制作用。这些结果表明，全身给予TTX可能是一种治疗战场烧伤的有效、快速起效的镇痛药，并且有可能替代或减少对阿片类镇痛药的需求。
