A selective inhibitor of cyclooxygenase-2 reverses endotoxin-induced pyretic responses in non-human primates.

The anti-pyretic effect of a selective cyclooxygenase-2 inhibitor, DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furano ne), was examined in conscious, un-restrained squirrel monkeys (Saimiri sciureus) using a radio telemetric system. Injection of bacterial endotoxin (lipopolysaccharide, 6 microg kg(-1), i.v.) in squirrel monkeys caused a gradual increase in core body temperature reaching a plateau of 2.07 +/- 0.17 degrees C above baseline at 2 h post-injection. Oral administration of DFU (1 mg kg(-1)) reduced, and DFU (3 mg kg(-1)) completely reversed the lipopolysaccharide-induced pyretic responses. The onset of action of DFU (about 30 min) is in good agreement with the pharmacokinetic profile of this compound in squirrel monkeys. The effect of DFU is comparable to that of a conventional non-selective non-steroidal anti-inflammatory drug (NSAID), diclofenac (3 mg kg(-1)). Since the plasma levels achieved for DFU at the dose employed in the present study are below the threshold required for inhibition of cyclooxygenase-1, it is concluded that the anti-pyretic effect of DFU can be attributed predominantly to an inhibitory action on cyclooxygenase-2. Thus, lipopolysaccharide-induced pyresis in squirrel monkeys can be used as a model for evaluation of anti-pyretic activity of cyclooxygenase inhibitors.

The organization of reticulo-olivo-cerebellar circuits in the North American opossum.

By employing the autoradiographic method we have determined that the inferior olivary nucleus receives input from the reticular formation of the midbrain, pons and, probably, the medulla. The remarkable thing about such connections is that they are not diffuse, but targeted in large part on restricted portions of the caudal acessory nuclei. From our previous studies it is clear that some of the olivary regions receiving reticular input also receive projections from the cerebral cortex, the spinal cord and the dorsal column nuclei. In addition, the HRP technique reveals that these same olivary regions relay to parts of the spinal cerebellum, i.e. to restricted zones of the anterior lobe (present study). Taken together these observations suggest that some reticulo-olivo-cerebellar connections provide indirect routes through which cortical and spinal information gains access to the spinal cerebellum. Such circuits have also been suggested by the physiological literature. Of particular interest, however, was our finding that several reticular areas of the midbrain and pons project to the portion of the medial acessory nucleus which relays in turn to auditory-visual areas of the cerebellar vermis (declive, folium and tuber). It would appear that at least some reticulo-olivo-cerebellar circuits are significant in the organization of motor responses to visual and/or auditory stimuli.