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

Abstract

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...

Brain IL-6- and PG-dependent actions of IL-1β and lipopolysaccharide in avian fever

“…Nevertheless, it is clear from the results of our study and from the results of mammalian studies that IL-6 and PGs are not exclusively responsible for LPS-induced fevers. Macrophage inflammatory protein-1␤, corticotropin-releasing factor, and endothelin-1 have been identified as PG-independent mediators of fever in mammals (11,12). In addition, Fraga et al (12) showed that, in mammals, LPS and endogenous pyrogens (except IL-1␤ and PGs) recruit the opioid system to cause a -receptor-mediated fever independent of PG.…”

Central mediators of the zymosan-induced febrile response

“…injected zymosan. We previously found that eOPs participate in the febrile response that is induced by ET-1 and CRF but not prostaglandins [20]. Kanashiro et al [24] reported that ET-1 and CRF do not participate in the febrile response induced by i.a.…”

“…The CRF/ET-1 pathway is not involved in i.a. zymosan-induced fever [24], indicating that the eOPs are not released through the CRF or ET-1 during the febrile response; instead, they appear to be released through cytokines, such as TNF-α and IL-6 [20,21].…”

“…The first study that suggested that endogenous opioids (eOPs) also participated in the LPS-induced febrile response was published by Blatteis et al [19]. Fraga et al [20] further confirmed these results by proving that μ-opioid receptors (MORs) are involved in modulating fever. Some redundancy in the pathways that lead to the release of these central mediators (i.e.…”

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats

“…POMC peptide is a precursor for several biologically active neuropeptides including ␣-MSH, ␤-endorphin, and ACTH (40). Of particular interest to the current study is ␤-endorphin as blockade of -opioid receptor, one of the receptors for ␤-endorphin either by specific antagonists or genetic mutation abrogates the fever response induced by classical pyrogens including LPS (4,5,16,44,61) via several different mechanisms, including a central hypothermic action, peripheral vasodilation, and peripheral antipyretic activity (44).…”