TRPC1/4/5 channels contribute to morphine-induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity
TRPC1/4/5 channels contribute to morphine-induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity
复制标题
TRPC1/4/5通道通过增强脊髓突触增强和结构可塑性来促进吗啡诱导的镇痛耐受和痛觉过敏
DOI：
10.1096/fj.202000154rr
复制
发表时间：
2020-05-02
期刊：
影响因子：
4.8
通讯作者：
Luo, Ceng
中科院分区：
文献类型：
--
作者：
Chu, Wen-Guang;Wang, Fu-Dong;Luo, Ceng
阿片类镇痛药仍然是治疗顽固性慢性疼痛的主要药物，但其使用受到镇痛耐受和痛觉过敏等有害副作用的限制。钙依赖性突触可塑性是阿片耐受和痛觉过敏的关键决定因素。然而，这种钙依赖性突触可塑性在介导这些适应不良的过程中的确切底物在很大程度上是未知的。经典瞬时受体电位1、4和5（TRPC 1、4、5）蛋白组装成具有高Ca 2+渗透性的异源多聚体非选择性阳离子通道，并影响各种神经元功能。然而，TRPC 1/4/5通道是否以及如何促进阿片耐受和痛觉过敏的发展仍然是一个谜。在这里，我们表明TRPC 1/4/5通道有助于产生吗啡耐受和痛觉过敏。慢性吗啡暴露导致脊髓中TRPC 1/4/5通道的上调。脊髓表达TRPC 1，TPRC 4和TRPC 5是慢性吗啡诱导的突触长时程增强（LTP）以及背角突触棘重塑所必需的，从而在吗啡诱导的痛觉过敏和耐受过程中协调功能和结构可塑性。这些作用归因于TRPC 1/4/5介导的慢性吗啡处理诱导的脊髓背角中的Ca 2+升高。本研究将TRPC 1/4/5通道作为一个很有前途的新靶点，以防止不必要的吗啡耐受和痛觉过敏。
Opioid analgesics remain the mainstay for managing intractable chronic pain, but their use is limited by detrimental side effects such as analgesic tolerance and hyperalgesia. Calcium-dependent synaptic plasticity is a key determinant in opiates tolerance and hyperalgesia. However, the exact substrates for this calcium-dependent synaptic plasticity in mediating these maladaptive processes are largely unknown. Canonical transient receptor potential 1, 4, and 5 (TRPC1, 4, 5) proteins assemble into heteromultimeric nonselective cation channels with high Ca2+ permeability and influence various neuronal functions. However, whether and how TRPC1/4/5 channels contribute to the development of opiates tolerance and hyperalgesia remains elusive. Here, we show that TRPC1/4/5 channels contribute to the generation of morphine tolerance and hyperalgesia. Chronic morphine exposure leads to upregulation of TRPC1/4/5 channels in the spinal cord. Spinally expressed TRPC1, TPRC4, and TRPC5 are required for chronic morphine-induced synaptic long-term potentiation (LTP) as well as remodeling of synaptic spines in the dorsal horn, thereby orchestrating functional and structural plasticity during the course of morphine-induced hyperalgesia and tolerance. These effects are attributed to TRPC1/4/5-mediated Ca2+ elevation in the spinal dorsal horn induced by chronic morphine treatment. This study identifies TRPC1/4/5 channels as a promising novel target to prevent the unwanted morphine tolerance and hyperalgesia.