Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test
Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test
复制标题
大鼠福尔马林试验中口服对乙酰氨基酚诱导的脊髓 5-羟三胺释放产生镇痛作用
DOI：
10.1016/j.biopha.2021.112578
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发表时间：
2022
影响因子：
7.5
通讯作者：
Tatsuo Yamamoto
中科院分区：
文献类型：
--
作者：
Shingo Nakamura;Takahiro Nonaka;Shuji Komatsu;Toshihiko Yamada;Tatsuo Yamamoto
对乙酰氨基酚产生止痛作用的机制尚不完全清楚。一个可能的机制是激活脊髓5-羟色胺(5-HT)受体，尽管尚未有直接证据表明脊髓5-HT释放。扑热息痛的代谢物N-花生四氢酚胺(AM404)被认为是参与扑热息痛镇痛作用的关键物质。在这项研究中，我们研究了对乙酰氨基酚和AM404是否诱导脊髓5-羟色胺的释放，以及脊髓5-羟色胺受体激活在大鼠福尔马林炎症疼痛模型中发挥镇痛作用的机制。用鞘内微透析法测定清醒和自由活动大鼠脊髓5-羟色胺的释放。对乙酰氨基酚口服，AM404脑室注射。在大鼠福尔马林实验中，口服对乙酰氨基酚和侧脑室注射AM404可引起显著的脊髓5-羟色胺释放，并产生镇痛作用。鞘内注射5-HT1受体拮抗剂WAY100135和5-HT7受体拮抗剂SB269970可部分拮抗对乙酰氨基酚的镇痛作用。WAY100135可完全拮抗侧脑室注射AM404的镇痛作用，而SB269970则无此作用。我们的数据表明，当口服对乙酰氨基酚和脑室注射AM404激活脊髓5-羟色胺系统时，口服对乙酰氨基酚激活的脊髓5-羟色胺系统的作用与脑室注射AM404激活的作用不同。
The mechanism by which acetaminophen produces its analgesic effects is not fully understood. One possible mechanism is the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, although direct evidence of spinal 5-HT release has not yet been reported. N-arachidonoylphenolamine (AM404), a metabolite of acetaminophen, is believed to be the key substance that contributes to the analgesic effects of acetaminophen. In this study, we examined whether acetaminophen and AM404 induce spinal 5-HT release and the mechanism through which spinal 5-HT receptor activation exerts analgesic effects in a rat formalin test in an inflammatory pain model. Spinal 5-HT release was examined by intrathecal microdialysis in conscious and freely moving rats. Acetaminophen was administered orally, and AM404 was administered intracerebroventricularly. In rat formalin tests, oral acetaminophen and intracerebroventricular AM404 induced significant spinal 5-HT release and produced analgesic effects. The analgesic effect of oral acetaminophen was partially antagonized by intrathecal administration of WAY100135 (a 5-HT1Areceptor antagonist) and SB269970 (a 5-HT7receptor antagonist). In contrast, the analgesic effect of intracerebroventricular AM404 was completely antagonized by WAY100135, while SB269970 had no effect. Our data suggest that while oral acetaminophen and intracerebroventricular AM404 activate the spinal 5-HT system, the role of the spinal 5-HT system activated by oral acetaminophen differs from that activated by intracerebroventricular AM404.