Intraperitoneal injection of zymosan (1 mg in 0.5 ml saline) in mice induces a transient writhing response accompanied by the synthesis of small amounts of prostaglandin E2 (PGE2, < 2 ng) and larger amounts of PGI2 (200 ng per mouse), measured as its non‐enzymatic breakdown product, 6‐keto‐PGF1α.
Although both centrally‐acting analgesics (morphine, clonidine) and prostaglandin biosynthesis inhibitors (aspirin, indomethacin, ibuprofen) blocked the writhing response to intraperitoneal injection of zymosan, only the latter reduced prostaglandin levels in the peritoneal cavity.
The writhing response correlated equally well with PGE2 levels and 6‐keto‐PGF1α levels when data from mice treated with centrally‐acting analgesics were excluded. However, intraperitoneal injection of PGI2, but not PGE2, reversed the analgesia induced by indomethacin in zymosan‐injected mice.
Centrally‐acting agents, but not ibuprofen, blocked the ability of PGI2 to reverse the analgesic activity of indomethacin.
PGI2 (2 μg per mouse), injected intraperitoneally in otherwise untreated mice, induced writhing.
These data indicate that PGI2 is the prostaglandin involved in mediation of the writhing response to zymosan and that prostaglandin biosynthesis inhibitors, but not centrally‐acting analgesics, exert their analgesic activity by reducing the peritoneal level of PGI2. It is possible that PGI2 may have the ability to stimulate pain receptors directly in the mouse peritoneal cavity, in addition to its previously recognized ability to sensitize pain receptors to other pain‐producing stimuli.
1 Oral administration of high doses of paracetamol (600mg kg-1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6-keto-PGF1.) 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,. However, inhibition of writhing by paracetamol occurred at higher levels of 6-keto-PGF1, 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 mgkg-', p.o.) but not that induced by oral administration of paracetamol. 4 Paracetamol at 800mgkg-1, p.o., inhibited carbacyclin-induced writhing but indomethacin at lmgkg-1 p.o. did not. Paracetamol administered i.p. at 100mgkg-1 reduced the peritoneal levels of 6-keto-PGF1, and inhibited zymosan-induced but not carbacyclin-induced writhing and did not produce behavioural toxicity.
5The 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.
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