Endogenous opioids: Role in prostaglandin-dependent and -independent fever

This study evaluated the participation of μ-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 μ-receptor-antagonist cyclic D-Phe-Cys-Try-D-Trp- Arg-Thr-Pen-Thr-NH₂ (CTAP; 0.1-1.0 μg) reduced fever induced by LPS (5.0 μg/kg) but did not change T_b 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 μg, and 1-100 ng, respectively) produced a dose-dependent increase in T_b. Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 μg icv) reduced the fever induced by intracerebroventricular administration of TNF-α (250 ng), IL-6 (300 ng), CRF (2.5 μg), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF _2α (500.0 ng) but not the fever induced by IL-1β (3.12 ng) or PGE₂ (125.0 ng) or the second phase of the fever induced by PGF_2α. 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-1β and prostaglandins) recruit the opioid system to cause a μ-receptor-mediated fever.