This study evaluated the participation of -opioid-receptor activation in body temperature (T b) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid -receptor-antagonist cyclic D-Phe-Cys-Try-DTrp-Arg-Thr-Pen-Thr-NH2 (CTAP; 0.1-1.0 g) reduced fever induced by LPS (5.0 g/kg) but did not change Tb at ambient temperatures of either 20°C or 28°C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0 -10.0 mg/kg, 3.0 -30.0 g, and 1-100 ng, respectively) produced a dose-dependent increase in Tb. Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 g icv) reduced the fever induced by intracerebroventricular administration of TNF-␣ (250 ng), IL-6 (300 ng), CRF (2.5 g), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF2␣ (500.0 ng) but not the fever induced by IL-1 (3.12 ng) or PGE2 (125.0 ng) or the second phase of the fever induced by PGF2␣. Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE2 levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1 and prostaglandins) recruit the opioid system to cause a -receptor-mediated fever. prostaglandin independent; body temperature; morphine; CTAP THE REGULATION OF BODY TEMPERATURE (T b ) is under the control of a hierarchy of neuronal structures that must first integrate afferent and central information before activating appropriate physiological and behavioral responses. In mammals, T b is regulated with considerable precision, normally varying by only a few degrees Celsius. This is an important adaptation because most biochemical and physiological processes are temperature dependent. In some conditions, adjustments of T b are beneficial. During infection, an increase in T b (fever) enhances immunologic responses and facilitates recovery and survival of an individual (34). In other conditions (such as during hypoxia), a decrease in T b is also beneficial because lower T b increases survival, primarily through a reduction in metabolic rate (13,38). The preoptic area of anterior hypothalamus (POA-AH) is one of the major neuronal structures involved in the control of T b . In addition to receiving afferent input from peripheral thermoreceptors, the POA-AH responds to central changes in hypothalamic temperature (10).Fever is characterized as a controlled elevation in the thermal set point, which is induced initially by exogenous pyrogens. These exogenous pyrogens induce the synthesis and release of a number of endogenous pyrogens, including IL-1, TNF...