Singh Tahim A, Sántha P, Nagy I
Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
Neuroscience. 2005;136(2):539-48. doi: 10.1016/j.neuroscience.2005.08.005. Epub 2005 Sep 28.
The endogenous ligand, anandamide activates at least two receptors on nociceptors; the excitatory vanilloid type 1 transient receptor potential receptor, the activity of which is indispensable for the development and maintenance of inflammatory heat hyperalgesia, and the inhibitory cannabinoid 1 receptor, the activity of which reduces that pathological pain sensation. Recent data are equivocal on whether increasing anandamide levels at the peripheral terminals of nociceptors in pathological conditions increases or decreases inflammatory heat hyperalgesia. Here, by using the cobalt-uptake technique we examined whether vanilloid type 1 transient receptor potential receptor activity evoked by 10 nM-100 microM anandamide is increased or decreased in inflammatory conditions. An inflammatory milieu for cultured rat primary sensory neurons was established by incubating the cells in the presence of the inflammatory mediators, bradykinin and prostaglandin E2. Anandamide, similarly to the archetypical vanilloid type 1 transient receptor potential receptor agonist, capsaicin induced concentration-dependent cobalt-uptake in a proportion of neurons. However, the potency of anandamide was significantly lower than that of capsaicin. While pre-incubation of cultures with bradykinin and prostaglandin E2 alone did not evoke cobalt-entry, the inflammatory mediators potentiated the effect of both capsaicin and anandamide. Application of the competitive vanilloid type 1 transient receptor potential receptor antagonist, capsazepine, or inhibitors of protein kinase A, protein kinase C or phospholipase C inhibited the anandamide-evoked cobalt-uptake both in the presence and absence of bradykinin and prostaglandin E2. These findings show that inflammatory mediators significantly increase the excitatory potency and efficacy of anandamide on vanilloid type 1 transient receptor potential receptor, thus, increasing the anandamide concentration in, or around the peripheral terminals of nociceptors might rather evoke than decrease inflammatory heat hyperalgesia.
内源性配体花生四烯乙醇胺可激活伤害性感受器上至少两种受体；兴奋性香草酸受体1型瞬时受体电位受体，其活性对于炎症性热痛觉过敏的发生和维持不可或缺，以及抑制性大麻素1型受体，其活性可减轻病理性疼痛感觉。关于在病理条件下提高伤害性感受器外周终末的花生四烯乙醇胺水平会增加还是降低炎症性热痛觉过敏，近期数据并不明确。在此，我们通过钴摄取技术研究了在炎症条件下，10 nM - 100 μM花生四烯乙醇胺诱发的香草酸受体1型瞬时受体电位受体活性是增加还是降低。通过在炎症介质缓激肽和前列腺素E2存在的情况下培养大鼠原代感觉神经元，建立了培养大鼠原代感觉神经元的炎症环境。与典型的香草酸受体1型瞬时受体电位受体激动剂辣椒素类似，花生四烯乙醇胺在一部分神经元中诱导了浓度依赖性的钴摄取。然而，花生四烯乙醇胺的效力明显低于辣椒素。虽然单独用缓激肽和前列腺素E2预孵育培养物不会诱发钴内流，但炎症介质增强了辣椒素和花生四烯乙醇胺的作用。应用竞争性香草酸受体1型瞬时受体电位受体拮抗剂辣椒平或蛋白激酶A、蛋白激酶C或磷脂酶C的抑制剂，在有或没有缓激肽和前列腺素E2的情况下，均抑制了花生四烯乙醇胺诱发的钴摄取。这些发现表明，炎症介质显著增加了花生四烯乙醇胺对香草酸受体1型瞬时受体电位受体的兴奋效力和功效，因此，提高伤害性感受器外周终末或其周围的花生四烯乙醇胺浓度可能会引发而非减轻炎症性热痛觉过敏。
