Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research Division for Life Sciences, Kumamoto Health Science University, Kumamoto, Japan; Nogata Nakamura Hospital, Fukuoka, Japan.
Neuropharmacology. 2019 Dec 1;160:107753. doi: 10.1016/j.neuropharm.2019.107753. Epub 2019 Sep 4.
Persistent pain is associated with negative affect originating from hypersensitivity and/or allodynia. The spinal cord is a key area for nociception as well as chronic pain processing. Specifically, the dorsal horn neurons in lamina II (substantia gelatinosa: SG) receive nociceptive inputs from primary afferents such as C fibers and/or Aδ fibers. Transient receptor potential vanilloid 1 (TRPV1) is a major receptor to sense heat as well as nociception. TRPV1 are expressed in the periphery and the central axon terminals of C fibers and/or Aδ fibers in the spinal cord. Activating TRPV1 enhances the release of glutamate in the spinal cord from naïve rodents. Here, we studied whether or not chronic pain could alter the response of TRPV1 channels to exogenous, capsaicin through study of synaptic transmission and neural activity in rat SG neurons. Using in vitro whole-cell patch-clamp recording, we found that bath application of capsaicin facilitated both the frequency and amplitude of miniature and spontaneous excitatory postsynaptic currents beyond a nerve injury and a complete Freund's adjuvant injection observed in the naïve group. Strikingly, capsaicin produced larger amplitudes of inward currents in pain models than compared to the naïve group. By contrast, the proportions of neurons that show capsaicin-induced inward currents were similar among naïve and pain groups. Importantly, the capsaicin-induced inward currents were conducted by TRPV1 and required calcium influx that was independent of voltage-gated calcium channels. Our study provides fundamental evidence that chronic inflammation and neuropathic pain models amplify the release of glutamate through the activation of TRPV1 in central axon terminals, and that facilitation of TRPV1 function in rat spinal SG neurons may contribute to enhanced capsaicin-induced inward currents.
持续性疼痛与源自过敏和/或痛觉过敏的负性情绪有关。脊髓是伤害感受和慢性疼痛处理的关键区域。具体来说，II 层（胶状质：SG）的背角神经元接收来自初级传入纤维（如 C 纤维和/或 Aδ 纤维）的伤害性输入。瞬时受体电位香草酸 1 型（TRPV1）是一种主要的受体，可感知热和伤害性。TRPV1 在周围组织和脊髓 C 纤维和/或 Aδ 纤维的中央轴突末端表达。激活 TRPV1 可增强从幼稚啮齿动物的脊髓中释放谷氨酸。在这里，我们通过研究 TRPV1 通道对鞘内注射辣椒素的反应，研究慢性疼痛是否会改变 TRPV1 通道对鞘内注射辣椒素的反应，以研究大鼠 SG 神经元的突触传递和神经活动。使用体外全细胞膜片钳记录，我们发现，与未受伤和完全弗氏佐剂注射的对照组相比，辣椒素浴液给药可促进神经损伤后 SG 神经元的微小和自发性兴奋性突触后电流的频率和幅度增加。引人注目的是，与对照组相比，疼痛模型中辣椒素产生的内向电流幅度更大。相比之下，在对照组和疼痛组中，显示辣椒素诱导内向电流的神经元比例相似。重要的是，辣椒素诱导的内向电流由 TRPV1 介导，需要钙内流，而钙内流与电压门控钙通道无关。我们的研究提供了基本证据，表明慢性炎症和神经病理性疼痛模型通过激活中央轴突末端的 TRPV1 放大谷氨酸的释放，并且大鼠脊髓 SG 神经元中 TRPV1 功能的易化可能有助于增强辣椒素诱导的内向电流。
