Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors

Abstract

Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A1 receptors (A1Rs) and serotonin 5-HT7 receptors (5-HT7Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT7R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A1R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT7R antagonist SB269970 3μg. In mice lacking A1Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT7R and A1R mechanisms. We also explored potential roles of peripheral A1Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A1R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A1R wild type mice, but not in those lacking A1Rs. In summary, we demonstrate a link between spinal 5-HT7Rs and A1Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A1Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen.