The antinociceptive activity of paracetamol in zymosan-induced peritonitis in mice: the role of prostacyclin and reactive oxygen species.
1. Oral administration of high doses of paracetamol (600 mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1 alpha) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing. 2. The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6-keto-PGF1 alpha. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1 alpha than was previously observed with acidic non-steroidal anti-inflammatory agents. 3. When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mg kg-1, p.o.) but not that induced by oral administration of paracetamol. 4. Paracetamol at 800 mg kg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at 1 mg kg-1 p.o. did not. Paracetamol administered i.p. at 100 mg kg-1 reduced the peritoneal levels of 6-keto-PGF1 alpha and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity. 5. The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan-injected mice. 6. Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol. 7. The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.
Doherty
N S
NS
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Beaver
T H
TH
Chan
K Y
KY
Dinerstein
R J
RJ
Diekema
K A
KA
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000082:Acetaminophen / Q000494:pharmacology*; D000700:Analgesics; D000818:Animals; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005609:Free Radicals; D016285:Iloprost / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism; D008163:Luminescent Measurements; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D015054:Zymosan
D000700:Analgesics; D005609:Free Radicals; D008054:Lipid Peroxides; D010975:Platelet Aggregation Inhibitors; D013481:Superoxides; D000082:Acetaminophen; D015121:6-Ketoprostaglandin F1 alpha; C026678:carboprostacyclin; D015054:Zymosan; D011464:Epoprostenol; D016285:Iloprost; D015232:Dinoprostone