Department of Physiology, University of Szeged, Szeged, Hungary.
Department of Anatomy, Physiology and Biophysics, University of Bucharest, Bucharest, Romania.
Eur J Pain. 2020 Feb;24(2):383-397. doi: 10.1002/ejp.1495. Epub 2019 Nov 24.
The α -adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side-effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system.
Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena.
Phenylephrine above 10 mM dose-dependently released calcitonin gene-related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, whereas hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine-evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1-deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre-application of the CGRP receptor antagonist CGRP or the TRPV1 antagonist BCTC.
Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine.
Phenylephrine is used at high concentrations as a mydriaticum and for treating nasal congestion. As adverse side-effects burning sensations and headaches have been described. Phenylephrine at high concentrations causes calcium transients in trigeminal afferents, CGRP release and increased meningeal blood flow upon activation of TRPV1 receptor channels, which is likely underlying the reported pain phenomena.
α-肾上腺素受体激动剂苯肾上腺素以高浓度用作散瞳剂和治疗鼻塞。其不良反应包括短暂的烧灼感，表明激活了三叉神经伤害性系统。
在脑膜伤害性感受的啮齿动物模型中应用神经肽释放、钙成像和脑膜血流记录，以阐明这些疼痛现象潜在的受体机制。
苯肾上腺素在 10mM 以上剂量依赖性地从硬脑膜和分离的三叉神经节释放降钙素基因相关肽 (CGRP)，而 90mM 的高渗甘露醇则无效。苯肾上腺素诱导的释放被瞬时受体电位香草酸 1（TRPV1）拮抗剂 BCTC 阻断，并且在 TRPV1 缺陷型小鼠的三叉神经节中不会发生。苯肾上腺素在 30mM 时引起培养的三叉神经节神经元中的钙瞬变，对 TRPV1 激动剂辣椒素和表达人 TRPV1 的 HEK293T 细胞有反应。局部应用微摩尔浓度的苯肾上腺素到暴露的大鼠硬脑膜减少脑膜血流，而浓度高于 10mM 则导致脑膜血流增加。CGRP 受体拮抗剂 CGRP 或 TRPV1 拮抗剂 BCTC 的预应用可消除这种血流增加。
高毫摩尔浓度的苯肾上腺素激活血管周围传入神经的 TRPV1 受体通道，在钙内流后释放 CGRP，增加脑膜血流。TRPV1 受体的激活可能是三叉神经伤害感受的基础，导致局部烧灼感或头痛等颅痛，这是由于高剂量苯肾上腺素的给药引起的。
苯肾上腺素以高浓度用作散瞳剂和治疗鼻塞。已经描述了不良反应如烧灼感和头痛。高浓度的苯肾上腺素在 TRPV1 受体通道激活时引起三叉神经传入纤维的钙瞬变、CGRP 释放和脑膜血流增加，这可能是报道的疼痛现象的基础。
