To determine why intrahypothalamic microinjections of pyrogen-free saline (PFS) often induce core temperature (Tco) rises, guide cannulas were implanted bilaterally into the preoptic-anterior hypothalamus (POA) of guinea pigs; 1 week later, injectors were inserted to 1 mm beyond the guides and either no injection or 1 microliter PFS was administered. Injector insertion without injection evoked a 0.5 degrees C Tco rise within 40 min, culminating in 3.7 hr. PFS microinjection elicited a 0.9 degrees C Tco rise within 10 min, culminating in 3.8 hr. PFS injected 4 hr later caused a further Tco rise. Indomethacin (10 mg/kg, IM), given 30 min before, prevented these effects. To determine whether microdialysis obviates them, a guide cannula was implanted unilaterally into the POA; 1 week later, a dialysis probe (nominal cutoff, 10kD) was inserted to 1 mm beyond the guide. PFS or prostaglandin E2 (PGE2, 1 microgram/microliter) was perfused 2 days later (2 microliter/min for 3 hr). Tco was unchanged during PFS perfusion but increased during PGE2 perfusion to 1.5 degrees C in 1.6 hr, and plateaued until 2 hr after dialysis. These results indicate the Tco rise induced by PFS microinjection is mediated by prostaglandins, probably released due to tissue puncture by the injectors and injury by the PFS droplet. Microdialysis prevents these effects. It should, therefore, be preferred over microinjection for intracerebral drug administration.