Behavioral, cellular and molecular maladaptations covary with exposure to pyridostigmine bromide in a rat model of gulf war illness pain
Behavioral, cellular and molecular maladaptations covary with exposure to pyridostigmine bromide in a rat model of gulf war illness pain
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DOI：
10.1016/j.taap.2018.05.023
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发表时间：
2018-08-01
影响因子：
3.8
通讯作者：
Nutter, T. J.
中科院分区：
文献类型：
--
作者：
Cooper, B. Y.;Flunker, L. D.;Nutter, T. J.
许多沙漠风暴行动（ODS）的退伍军人与海湾战争疾病（GWI）的慢性疼痛作斗争。暴露于杀虫剂和溴化吡啶斯的明（PB）已牵连在这种多症状疾病的病因。本文研究了3种避蚊胺（DEET）、氯菊酯、毒死蜱（Chlorpyrifos）和4种GW制剂（DEET、氯菊酯、毒死蜱、溴化吡啶斯的明（PB））暴露后对大鼠行走和静息行为的影响。在三项独立研究中，暴露于所有4种药物的大鼠持续出现即时和延迟性行走障碍，并在暴露停止后持续至少16周。暴露于3种药物方案（PB除外）的大鼠未出现任何行走障碍。对从16WP（暴露后周）大鼠收获的伤害感受器的细胞和分子研究表明，血管伤害感受器Na（v）1.9介导的电流在4种药物方案后长期增强，但在3种药物方案后不增强。毒蕈碱连接到肌肉伤害感受器TRPA1也加强了4剂，但不是3剂，PB排除，协议。虽然K（v）7活性变化与行为数据不同，但K（v）7开放剂瑞替加滨可短暂逆转Ambasso缺陷。我们得出结论，PB在GWI大鼠模型中疼痛样体征的发展中起着关键作用，Na（v）1.9和TRPA1活性的变化对这些疼痛行为的表达至关重要。
Many veterans of Operation Desert Storm (ODS) struggle with the chronic pain of Gulf War Illness (GWI). Exposure to insecticides and pyridostigmine bromide (PB) have been implicated in the etiology of this multisymptom disease. We examined the influence of 3 (DEET (N,N-diethyl-meta-toluamide), permethrin, chlorpyrifos) or 4 GW agents (DEET, permethrin, chlorpyrifos, pyridostigmine bromide (PB)) on the post-exposure ambulatory and resting behaviors of rats. In three independent studies, rats that were exposed to all 4 agents consistently developed both immediate and delayed ambulatory deficits that persisted at least 16 weeks after exposures had ceased. Rats exposed to a 3 agent protocol (PB excluded) did not develop any ambulatory deficits. Cellular and molecular studies on nociceptors harvested from 16WP (weeks post-exposure) rats indicated that vascular nociceptor Na(v)1.9 mediated currents were chronically potentiated following the 4 agent protocol but not following the 3 agent protocol. Muscarinic linkages to muscle nociceptor TRPA1 were also potentiated in the 4 agent but not the 3 agent, PB excluded, protocol. Although K(v)7 activity changes diverged from the behavioral data, a K(v)7 opener, retigabine, transiently reversed ambulation deficits. We concluded that PB played a critical role in the development of pain-like signs in a GWI rat model and that shifts in Na(v)1.9 and TRPA1 activity were critical to the expression of these pain behaviors.