title: 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 A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) 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-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs 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 A(1)R 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 A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen.
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Jean
authors: J
authors: Liu
authors: Allison R
authors: AR
authors: Reid
authors: Jana
authors: J
authors: Sawynok
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology* / Q000627:therapeutic use; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D018712:Analgesics, Non-Narcotic; D043682:Receptor, Adenosine A1; D011985:Receptors, Serotonin; D014970:Xanthines; C104425:serotonin 7 receptor; D000082:Acetaminophen; C051360:1,3-dipropyl-8-cyclopentylxanthine