The purpose of these studies was to assess the involvement of β-adrenoceptors in the development of psychological stress-induced elevation in body temperature (Tb) and rise in circulating interleukin-6 (IL-6). We selected three drugs to attempt to block the rise in body temperature and plasma IL-6; L-propranolol, D-propranolol and nadolol. Both stereoisomers of propranolol have ‘local anesthetic’ membrane-stabilizing activity and are capable of penetrating into the brain. However, D-propranolol has significantly lower β-blocking activity than L-propranolol. Nadolol has β-blocking activity similar to L-propranolol without membrane-stabilizing activity. Furthermore, nadolol does not cross the blood-brain barrier. All β-blockers were injected intraperitoneally (i.p. 7.5 mg/kg) or into the third cerebral ventricle (i.c.v., 5 or 50 µg/animal), 20 min or just before exposure of rats to an open field, respectively. Blood samples for measurement of plasma IL-6 activity (IL-6-dependent B9 cell bioassay) were taken from rats immediately following exposure to the open field. After exposure to the open field, rats not treated with β-blockers responded with a rapid rise in Tb measured by biotelemetry as well as with an increase in plasma IL-6 activity. The increase in Tb of open field-exposed rats was significantly suppressed by L-propranolol injected i.p. (ΔTmax = 0.14 ± 0.15°C for L-propranolol vs. 0.78 ± 0.15°C for vehicle-treated rats). Neither i.p. injection of D-propranolol nor nadolol had any effect on the increase in Tb induced by exposure to the open field. Both i.c.v. doses of L-propranolol and nadolol markedly attenuated the open field-induced rise in Tb. The large i.c.v. dose of D-propranolol (50 µg) did, whereas the lower dose (5 µg) did not suppress the elevation in Tb in open field exposed rats. The open field-exposed rats injected with L-propranolol (both i.p. or i.c.v.) had lower plasma IL-6 activity than that of open field-exposed rats injected with vehicle (for i.p. injection: 5.2 ± 1.3 U/ml for L-propranolol vs. 17.4 ± 3.8 U/ml for vehicle; for i.c.v. injection: 3.5 ± 2.3 U/ml for L-propranolol vs. 24.4 ± 7.2 U/ml for vehicle). Nadolol blocked the open field-induced rise in plasma IL-6 only when injected i.c.v. but not i.p. Neither i.p. nor i.c.v. D-propranolol injection had an effect on plasma IL-6 activity in open field-exposed rats. These data show that β-adrenoceptors in the central nervous system are involved in the psychological stress-induced elevation in Tb and rise in plasma IL-6 activity caused by expo