Jin Hua, Sun Ying-Tong, Guo Guang-Qiong, Chen Da-Lin, Li Yu-Jin, Xiao Gao-Peng, Li Xin-Nan
Department of Anesthesiology, Kunhua Hospital, The First People's Hospital of Yunnan Province, Kunming 650032, China.
Medical Faculty, Kunming University of Science and Technology, Kunming 650500, China.
Neurosci Lett. 2017 Feb 3;639:138-145. doi: 10.1016/j.neulet.2016.12.062. Epub 2016 Dec 26.
The chronic administration of opioids results in the development of morphine analgesic tolerance and withdrawl-induced hyperalgesia, which limits their clinical utility in pain treatment. However, the cellular mechanisms underlying opioid-induced tolerance and hyperalgesia are not fully understood. The transient receptor potential canonical channel TRPC6 is important for brain development and function, as it regulates cytosolic, endoplasmic reticulum, and mitochondrial Ca levels in neural cells. Here, we report that TRPC6 expression in the spinal cord was up-regulated after chronic morphine treatment. Furthermore, inhibition of TRPC6 in the spinal cord blocked the induction of morphine tolerance and hyperalgesia without affecting basal pain perception. These effects were attributed to the attenuation of morphine-induced neuroimmune activation and increased levels of CaMKIIα and nNOS in the spinal cord. This data suggests that specific TRPC6 inhibitors could be utilized for the prevention of morphine-induced antinociceptive tolerance and hyperalgesia in chronic pain management.
长期使用阿片类药物会导致吗啡镇痛耐受性的产生以及戒断诱导的痛觉过敏，这限制了它们在疼痛治疗中的临床应用。然而，阿片类药物诱导的耐受性和痛觉过敏背后的细胞机制尚未完全明确。瞬时受体电位经典通道TRPC6对大脑发育和功能很重要，因为它调节神经细胞中的细胞质、内质网和线粒体钙水平。在此，我们报告慢性吗啡治疗后脊髓中TRPC6的表达上调。此外，脊髓中TRPC6的抑制可阻断吗啡耐受性和痛觉过敏的诱导，而不影响基础痛觉。这些作用归因于吗啡诱导的神经免疫激活的减弱以及脊髓中CaMKIIα和nNOS水平的升高。该数据表明，特异性TRPC6抑制剂可用于预防慢性疼痛管理中吗啡诱导的抗伤害感受耐受性和痛觉过敏。
