Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, Gansu, 730000, China; Department of Biochemistry and Molecular Biology, School of Medicine, Shihezi University, Xinjiang Endemic and Ethnic Disease and Education Ministry Key Laboratory, Shihezi, Xinjiang, 832000, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, And Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, Gansu, 730000, China.
Eur J Pharmacol. 2021 Jul 15;903:174139. doi: 10.1016/j.ejphar.2021.174139. Epub 2021 Apr 30.
Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.
烧伤是全球主要的死亡原因之一，常伴有严重且持久的疼痛，从而降低患者的生活质量。多项研究表明，μ-阿片受体（MOR）系统在烧伤疼痛缓解中起着重要作用。在本研究中，我们研究了内源性 MOR 激动剂内吗啡肽诱导的脊髓镇痛作用，并探讨了其在烧伤诱导疼痛模型中的作用机制。结果表明，在烧伤后 3 天，鞘内注射内吗啡肽-1 和 -2 可剂量依赖性地通过 MOR 减轻机械性痛觉过敏和热痛觉过敏，这与 MOR 敲除小鼠的数据一致。Western blot 显示，烧伤后同侧脊髓组织中细胞外信号调节激酶 1/2（ERK1/2）和 p38 丝裂原活化蛋白激酶（p38 MAPK）的磷酸化水平显著上调。鞘内注射内吗啡肽选择性地通过 MOR 抑制烧伤后第 3 天 p38 MAPK 的激活。进一步的研究发现，重复应用特异性 p38 MAPK 抑制剂 SB203580 可剂量依赖性地抑制烧伤疼痛以及脊髓 p38 MAPK 的激活。综上，本研究表明，鞘内注射内吗啡肽通过 MOR 影响脊髓 p38 MAPK 的激活来减轻雄性小鼠的烧伤疼痛。
