Oral acetaminophen-induced spinal 5-hydroxytriyptamine release produces analgesic effects in the rat formalin test

• Published in: Biomedicine & pharmacotherapy 2022-02, Vol.146, p.112578-112578, Article 112578
• Main Authors: Nakamura, Shingo, Nonaka, Takahiro, Komatsu, Shuji, Yamada, Toshihiko, Yamamoto, Tatsuo
• Format: Article
• Language: English
• Subjects: 5-HT; Acetaminophen; AM404; Analgesia; Inflammatory pain; Spinal cord
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112578

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-HT1A receptor antagonist) and SB269970 (a 5-HT7 receptor 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. [Display omitted] •Mechanisms underlying acetaminophen-induced analgesia are not fully understood.•Oral acetaminophen administration induced spinal 5-HT release.•ICV AM404, a metabolite of acetaminophen, induced spinal 5-HT release.•Spinal 5-HT release induced by oral acetaminophen and ICV AM404 produced analgesic effects.•The role of spinal 5-HT-induced release of oral acetaminophen differs from that of ICV AM404.