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Neuroimmunomodulation. 2001;9(5):263-75.

Differential inhibition by nimesulide of the early and late phases of intravenous- and intracerebroventricular-LPS-induced fever in guinea pigs.

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Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.



The findings that inducible cyclooxygenase (COX)-2, but not constitutive COX-1, is upregulated in the brain of conscious rats approximately 1.5 h after intraperitoneal pyrogen administration, that the systemic administration of COX-2 inhibitors abolishes fever, and that COX-2-deficient mice do not develop fever in response to intraperitoneal lipopolysaccharide (LPS) have strongly implicated COX-2 in the mediation of the febrile response. However, the biosynthesis of COX-2 is significantly slower than the onset of the fever produced by intravenously injected LPS. It consequently seems improbable that inducible COX-2 could play a role in the initiation of this febrile response, but a role for COX-1 has not yet been categorically ruled out; or, alternatively, a constitutive isoform of COX-2 could have such a role. We have studied, therefore, the effects of the non-selective COX inhibitor indomethacin, the COX-1-selective inhibitor SC-560, and the COX-2-selective inhibitor nimesulide on the characteristically biphasic fever induced by intravenous LPS in conscious guinea pigs; it has an onset latency of approximately 10 min.


We injected the inhibitors 30 min before LPS, in various combinations of doses and routes; their respective vehicles were the control solutions. Core temperatures (T(c)) were monitored continuously, and plasma and brain PGE(2) levels were measured before and at 2-hour intervals after LPS administration.


Intraperitoneal indomethacin at 10 mg kg(-1) attenuated both phases of intravenous LPS (2 microg kg(-1)) fever, but the first more so than the second; at 50 mg kg(-1), it inhibited the febrile response completely. Intraperitoneal SC-560 (5 mg kg(-1)) did not affect the febrile response to intravenous LPS (2 microg kg(-1)). Intraperitoneal nimesulide (0.3, 1.0, and 3.0 mg kg(-1)) dose dependently attenuated intravenous LPS (0.1 and 2 microg kg(-1)) fever; the second phase of the biphasic T(c) rise was affected significantly more than the first. Intraperitoneal nimesulide also prevented the associated rises in plasma and brain PGE(2) levels. Intracerebroventricular LPS (150 ng kg(-1)) evoked a monophasic fever with a long onset latency ( approximately 30 min); it was accompanied by a rise in brain PGE(2) only, implying that the febrigenic PGE(2) was generated directly in the brain. This response, however, was completely abolished by intraperitoneal nimesulide (3 mg kg(-1)), indicating that nimesulide crosses the blood-brain barrier. Intracerebroventricular nimesulide at 0.3 mg kg(-1) prevented the rise in plasma PGE(2) after intravenous LPS (2 microg kg(-1)) and again attenuated the second febrile peak significantly more than the first.


COX-1 is not involved in intravenous LPS fever production, and COX-2 appears to play a greater role in the late than in the early phase of intravenous LPS fever in guinea pigs. The involvement of a constitutive COX-2 is inferred in the early phase.

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