Pidoux Ludivine, Delanoe Kevin, Barbier Julie, Marchand Fabien, Lingueglia Eric, Deval Emmanuel
Université Côte d'Azur, CNRS, IPMC, LabEx ICST, FHU InovPain, Valbonne, France.
Université Clermont Auvergne, Inserm U1107 Neuro-Dol, Pharmacologie Fondamentale et Clinique de la Douleur, Clermont-Ferrand, France.
Front Mol Neurosci. 2022 Jun 14;15:880651. doi: 10.3389/fnmol.2022.880651. eCollection 2022.
Lysophosphatidyl-choline (LPC), a member of the phospholipid family, is an emerging player in pain. It is known to modulate different pain-related ion channels, including Acid-Sensing Ion Channel 3 (ASIC3), a cationic channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH. Very recently, LPC has been associated to chronic pain in patients suffering from fibromyalgia or osteoarthritis. Accordingly, repetitive injections of LPC within mouse muscle or joint generate both persistent pain-like and anxiety-like behaviors in an ASIC3-dependent manner. LPC has also been reported to generate acute pain behaviors when injected intraplantarly in rodents. Here, we explore the mechanism of action of a single cutaneous injection of LPC by studying its effects on spinal dorsal horn neurons. We combine pharmacological, molecular and functional approaches including patch clamp recordings and recordings of spinal neuronal activity. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway, inducing an ASIC3-dependent sensitization of nociceptive fibers that leads to hyperexcitabilities of both high threshold (HT) and wide dynamic range (WDR) spinal neurons. ASIC3 is involved in LPC-induced increase of WDR neuron's windup as well as in WDR and HT neuron's mechanical hypersensitivity, and it participates, together with TRPV1, to HT neuron's thermal hypersensitivity. The nociceptive input induced by a single LPC cutaneous rather induces short-term sensitization, contrary to previously described injections in muscle and joint. If the effects of peripheral LPC on nociceptive pathways appear to mainly depend on peripheral ASIC3 channels, their consequences on pain may also depend on the tissue injected. Our findings contribute to a better understanding of the nociceptive signaling pathway activated by peripheral LPC ASIC3 channels, which is an important step regarding the ASIC3-dependent roles of this phospholipid in acute and chronic pain conditions.
溶血磷脂酰胆碱（LPC）是磷脂家族的一员，在疼痛领域正逐渐崭露头角。已知它可调节多种与疼痛相关的离子通道，包括酸敏感离子通道3（ASIC3），这是一种主要在外周感觉神经元中表达的阳离子通道。LPC可增强轻度酸化诱发的ASIC3电流，但在生理pH值下也能激活该通道。最近，LPC已被发现与纤维肌痛或骨关节炎患者的慢性疼痛有关。相应地，在小鼠肌肉或关节内重复注射LPC会以ASIC3依赖的方式产生持续的疼痛样和焦虑样行为。据报道，在啮齿动物足底注射LPC也会产生急性疼痛行为。在此，我们通过研究LPC对脊髓背角神经元的影响，探索单次皮肤注射LPC的作用机制。我们结合了药理学、分子生物学和功能学方法，包括膜片钳记录和脊髓神经元活动记录。我们发现，单次皮肤注射LPC仅影响伤害性感受通路，诱导伤害性纤维的ASIC3依赖的敏化，导致高阈值（HT）和广动力范围（WDR）脊髓神经元的兴奋性增高。ASIC3参与LPC诱导的WDR神经元的windup增加以及WDR和HT神经元的机械性超敏反应，并且它与TRPV1一起参与HT神经元的热超敏反应。与之前在肌肉和关节中描述的注射情况相反，单次LPC皮肤注射诱导的伤害性输入反而引起短期敏化。如果外周LPC对伤害性感受通路的影响似乎主要取决于外周ASIC3通道，那么它们对疼痛的影响可能也取决于注射的组织。我们的研究结果有助于更好地理解外周LPC-ASIC3通道激活的伤害性感受信号通路，这是了解这种磷脂在急性和慢性疼痛状态下ASIC3依赖作用的重要一步。
