Kumar Rakesh, Geron Matan, Hazan Adina, Priel Avi
Institute for Drug Research (IDR), School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Front Pharmacol. 2020 Jun 12;11:903. doi: 10.3389/fphar.2020.00903. eCollection 2020.
Neuronal signals are processed along the nociceptive pathway to convey discriminative information, which would manifest in the produced pain sensation. The transient receptor potential vanilloid 1 (TRPV1), an important signaling complex in nociceptors termini, is activated by different noxious stimuli that underlie distinct pain sensations. For example, while endovanilloids are associated with inflammatory pain and hypersensitivity through TRPV1 activation, the exovanilloid toxin, capsaicin, evokes an acute pain by activating this channel. Differences in the TRPV1 activation profile evoked by exogenous and endogenous vanilloids were suggested to underlie this disparity in pain sensations. However, the cellular processes that lead to these differences in pain sensation mediated by the same channel are not fully understood. Here, we sought to describe the neuronal response of TRPV1-expressing nociceptors to exo-and endovanilloids. To this end, we performed current-clamp recordings in rat trigeminal neurons exposed to either capsaicin or intracellular endovanilloids produced downstream of the bradykinin receptor BK2. Our results show that lipoxygenase metabolites generate persistent TRPV1-dependent action potential firing while capsaicin evokes robust depolarization and high-frequency firing that is quickly terminated by depolarization block. Additionally, we found that a weak TRPV1 activation prolongs action potential firing. Overall, our results indicate different firing patterns evoked by inflammatory mediators and capsaicin TRPV1 that correlate with the respective subsequent pain sensation. These findings also suggest that differences in neuronal activation stem from the variable degree of TRPV1 activation they produce.
神经信号沿着伤害性感受通路进行处理，以传递辨别性信息，这会在产生的痛觉中表现出来。瞬时受体电位香草酸受体1（TRPV1）是伤害感受器终末中的一种重要信号复合体，它被不同的有害刺激激活，这些刺激是不同痛觉的基础。例如，内源性香草酸类物质通过激活TRPV1与炎症性疼痛和超敏反应相关，而外源性香草酸毒素辣椒素则通过激活该通道引发急性疼痛。外源性和内源性香草酸类物质诱发的TRPV1激活模式的差异被认为是这种痛觉差异的基础。然而，由同一通道介导的导致这些痛觉差异的细胞过程尚未完全了解。在这里，我们试图描述表达TRPV1的伤害感受器对外源性和内源性香草酸类物质的神经元反应。为此，我们在暴露于辣椒素或缓激肽受体BK2下游产生的细胞内内源性香草酸类物质的大鼠三叉神经元中进行了电流钳记录。我们的结果表明，脂氧合酶代谢产物产生持续的TRPV1依赖性动作电位发放，而辣椒素引发强烈的去极化和高频发放，这种发放会因去极化阻滞而迅速终止。此外，我们发现弱的TRPV1激活会延长动作电位发放。总体而言，我们的结果表明炎症介质和辣椒素激活TRPV1会引发不同的发放模式，这与各自随后的痛觉相关。这些发现还表明，神经元激活的差异源于它们产生的TRPV1激活程度的不同。
