Inhibition of sensory afferents activation and visceral pain by a brominated algal diterpene
Inhibition of sensory afferents activation and visceral pain by a brominated algal diterpene
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DOI：
10.1111/j.1365-2982.2012.01940.x
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发表时间：
2012-07-01
影响因子：
3.5
通讯作者：
Vergnolle, N.
中科院分区：
文献类型：
--
作者：
Chatter, R.;Cenac, N.;Vergnolle, N.
背景在寻找新的治疗疼痛的方法时，从植物提取物中分离和检测次级代谢产物引起了人们的极大关注。我们研究了从地中海红藻Laurencia glandulifera中提取的溴化二萜O 1115- cyclo-14-bromo-14，15-dihydrologiol-3，11-diol（我们将其命名为VLC 5）的影响。方法采用高浓度KCl、瞬时受体电位香草酸（TRPV）1（辣椒素）或TRPV 4激动剂、组胺、蛋白酶激活受体2（PAR 2）激动剂诱发初级传入钙信号。它还在芥子油诱导的结肠超敏反应的小鼠模型中进行了测试。VLC 5在小鼠初级传入中被PAR 2激动剂或组胺诱导的钙动员抑制，但不改变高浓度KCl、TRPV 1或TRPV 4激动剂诱导的钙信号。VLC 5对组胺诱导的初级传入中的钙信号的影响被百日咳毒素预处理抑制，并且依赖于μ-或κ-阿片受体激动剂的激活，因为它被这两种受体的选择性拮抗剂抑制，但不被δ-阿片受体的选择性拮抗剂抑制。腹腔注射VLC 5（10 mg kg-1）可显著降低结肠内注射芥子油诱导的内脏痛行为，且呈阿片受体依赖性。结论与推论我们已经证明了藻类代谢物VLC 5的显着镇痛特性，它能够通过依赖于阿片受体激活的机制直接向初级传入信号。这确定了一种新的天然化合物，能够激活外周阿片系统，发挥镇痛作用。
Background In the search of new therapeutic options for the treatment of pain, isolation, and testing of secondary metabolites from plant extracts has raised significant attention. We have investigated the effects of the brominated diterpene O1115- cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (that we have named VLC5), extracted from the Mediterranean red algae Laurencia glandulifera. Methods The pure extract was tested on primary afferent calcium signals induced by high concentration of KCl, transcient receptor potential vanilloid (TRPV)1 (capsaicin) or TRPV4 agonists, histamine, or protease-activated receptor-2 (PAR2) agonist. It was also tested in mice in a model of mustard oil-induced colonic hypersensitivity. Key Results VLC5 was inhibited PAR2 agonist or histamine-induced calcium mobilization in mouse primary afferents, but did not modify calcium signals induced by high concentrations of KCl, TRPV1 or TRPV4 agonists. The effect of VLC5 on histamine-induced calcium signal in primary afferent was inhibited by pertussis toxin pretreatment and was dependent on the activation of mu- or kappa-opioid receptor agonists, as it was inhibited by selective antagonists of those two receptors, but not by selective antagonist of the delta-opioid receptor. Intraperitoneal treatment of mice with VLC5 (10 mg kg-1) significantly reduced visceral pain behaviors induced by the intracolonic administration of mustard oil, in an opioid receptor-dependent manner. Conclusions & Inferences We have demonstrated significant analgesic properties for the algal metabolite VLC5, which is able to signal directly to primary afferents, through a mechanism dependent on the activation of opioid receptors. This identifies a new natural compound capable of activating peripheral opioidergic systems, exerting analgesic properties.