Morphine as an opioid is an important drug in the treatment of moderate to severe pain. Several stress factors via generation of nitric oxide (NO) and oxidative stress (OS) are responsible for the adverse effects of morphine-induced analgesia, addiction, and antinociceptive tolerance, including altered Ca²⁺ concentration, inflammation, OS, and release of apoptotic factors. TRPM2 is a Ca²⁺-permeable cation channel and it is activated by OS and NO. Hence, adverse effect of morphine addiction may occur via the OS and NO-induced TRPM2 activation. Because of the unclear etiology of morphine-induced adverse effects in the hippocampus, investigating the involvement of TRPM2 and NO synthetase (NOS) activations in the treatment of morphine-induced OS, apoptosis, and neuroinflammation is a major challenge. The hippocampal neuron of TRPM2 wild-type (TRPM2-WT) and knockout (TRPM2-KO) mice were divided into control, morphine, NOS inhibitor (L-NAME) + morphine, and TRPM2 channel blockers (ACA and 2-APB) + morphine. The morphine-induced increases of apoptosis, neuron death, OS, lipid peroxidation, caspase-3 and caspase-9, neuroinflammatory cytokines (IL-1β, TNF-α, IL-6), and Ca²⁺ levels in the hippocampal neuron of TRPM2-WT mouse were decreased by the L-NAME, ACA, and 2-APB treatments, although cell viability, neuron count, and reduced glutathione and glutathione peroxidase levels were increased by the treatments. However, the effects of morphine were not observed in the hippocampus of TRPM2-KO mice. Taken together, our data show that neurodegeneration adverse effects of morphine were induced by activation of TRPM2, and excessive generations of NO and OS. Thus, inhibition of TRPM2 may modulate morphine-induced neurodegeneration in the hippocampus.

吗啡作为阿片类药物是治疗中度至重度疼痛的重要药物。通过产生一氧化氮 (NO) 和氧化应激 (OS) 的几种应激因素是造成吗啡诱导的镇痛、成瘾和镇痛耐受的不良影响的原因，包括改变的 Ca ²⁺浓度、炎症、OS 和凋亡释放因素。TRPM2 是一种 Ca ²⁺-渗透性阳离子通道，由 OS 和 NO 激活。因此，吗啡成瘾的不利影响可能通过 OS 和 NO 诱导的 TRPM2 激活发生。由于吗啡诱导的海马不良反应的病因不明，研究 TRPM2 和 NO 合成酶 (NOS) 激活在吗啡诱导的 OS、细胞凋亡和神经炎症的治疗中的作用是一项重大挑战。TRPM2 野生型 (TRPM2-WT) 和敲除 (TRPM2-KO) 小鼠的海马神经元分为对照、吗啡、NOS 抑制剂 (L-NAME) + 吗啡和 TRPM2 通道阻滞剂 (ACA 和 2-APB) +吗啡。吗啡诱导的细胞凋亡、神经元死亡、OS、脂质过氧化、caspase-3 和 caspase-9、神经炎性细胞因子（IL-1β、TNF-α、IL-6）和 Ca ^2+的增加L-NAME、ACA 和 2-APB 治疗降低了 TRPM2-WT 小鼠海马神经元中的水平，尽管治疗增加了细胞活力、神经元计数和降低的谷胱甘肽和谷胱甘肽过氧化物酶水平。然而，在 TRPM2-KO 小鼠的海马体中未观察到吗啡的作用。总之，我们的数据表明吗啡的神经退行性副作用是由 TRPM2 的激活和过量生成的 NO 和 OS 诱导的。因此，TRPM2 的抑制可能会调节吗啡诱导的海马神经变性。