Zoltán Szelényi

Cholecystokinin octapeptide (CCK-8) injected into a cerebral ventricle induces a fever-like thermoregulatory response mediated by type B CCK-receptors in the rat

In conscious female Wistar rats with chronic lateral cerebroventricular cannula, the thermoregulatory effects of CCK-8, ceruletide and prostaglandin E1 (PGE1) were studied. In addition, the possible involvement of type A or type B receptors of CCK-8 in thermoregulatory effects of PGE1 and CCK-8 was also investigated. In the normothermic rat an intracerebroventricular (i.c.v.) injection of CCK-8 or ceruletide induced a thermogenic response with tail-skin vasoconstriction and a resulting rise in colonic temperature (Tc). There was a significant negative correlation between the starting level of Tc and the extent of rise in Tc following an i.c.v. administration of PGE1, CCK-8 or ceruletide. Subcutaneously injected CCK-8 caused decreases in Tc in a cool ambient temperature as also described by others. The fever-like response to i.c.v. injected CCK-8 was attenuated by a CCK type B receptor blocker, but not by a CCK type A receptor blocker. Conversely, the hypothermic response to peripherally administered CCK-8 was attenuated by a type A receptor blocker, but not by a type B receptor blocker. Neither of these CCK-receptor blockers influenced the fever caused by an i.c.v. injection of PGE1. It is concluded that in normothermic rats the thermogenic response observed after i.c.v. injection of CCK-8 and ceruletide is the most likely central thermoregulatory change mediated by CCK type B receptors, while the well-known hypothermic response observed after peripheral injection of these peptides might also be explained by their direct effect on variables influencing some of the thermoregulatory effector mechanisms at the periphery.

Acute, subacute and chronic effects of central neuropeptide Y on energy balance in rats

Central neuropeptide Y (NPY) injection has been reported to cause hyperphagia and in some cases also hypometabolism or hypothermia. Chronic central administration induced a moderate rise of short duration in body weight, without consistent metabolic/thermal changes. In the present studies the acute and subsequent subacute ingestive and metabolic/thermal changes were studied following intracerebroventricular (i.c.v.) injections of NPY in cold-adapted and non-adapted rats, or the corresponding chronic changes following i.c.v. NPY infusion. Besides confirming basic earlier data, we demonstrated novel findings: a temporal relationship for the orexigenic and metabolic/thermal effects, and differences of coordination in acute/subacute/chronic phases or states. The acute phase (30-60 min after injection) was anabolic: coordinated hyperphagia and hypometabolism/hypothermia. NPY evoked a hypothermia by suppressing any (hyper)metabolism in excess of basal metabolic rate, without enhancing heat loss. Thus, acute hypothermia was observed in sub-thermoneutral but not thermoneutral environments. The subsequent subacute catabolic phase exhibited opposite effects: slight increase in metabolic rate, rise in body temperature, reaching a plateau within 3-4 h after injection -- this was maintained for at least 24 h; meanwhile the food intake decreased and the normal daily weight gain stopped. This rebound is only indirectly related to NPY. Chronic (7-day long) i.c.v. NPY infusion induced an anabolic phase for 2-3 days, followed by a catabolic phase and fever, despite continued infusion. In cold-adaptation environment the primary metabolic effect of the infusion induced a moderate hypothermia with lower daytime nadirs and nocturnal peaks of the circadian temperature rhythm, while at near-thermoneutral environments in non-adapted rats the infusion attenuated only the nocturnal temperature rise by suppressing night-time hypermetabolism. Further finding is that in cold-adapted animals, the early feeding effect of NPY-infusion was enhanced, whereas the early hypothermic effect in cold was limited by interference with competing thermoregulatory mechanisms.

Cholecystokinin participates in the mediation of fever

Cholecystokinin of the central nervous system participates in the pathogenesis of lipopolysaccharide- induced fever in rats, contributing mainly to the first phase rise of this fever. The mediatory role is connected to type- B receptors of cholecystokinin.

Energetics of fasting heterothermia in TRPV1-KO and wild type mice.

To learn the possible role of TRPV1 in the changes of temperature regulation induced by short-term energy lack, TRPV1-KO and wild type mice were exposed to complete fasting for 2 or 3 days while their core temperature and locomotor activity were recorded using a biotelemetry method. In both types of mice, fasting led to progressive daytime hypothermia with night-time core temperature being maintained at normothermia (collectively called heterothermia). During fasting rises of locomotor activity were observed parallel to night-time normothermia with occasional increases of both parameters recorded every 2 to 3 hours (ultradian rhythms). The daytime fall of core temperature was significantly greater in wild type than in TRPV1-KO mice, in the former an advance of the temperature/activity rhythm having been observed in spite of the presence of a 12/12 hour light/darkness schedule. Re-feeding applied at the beginning of the light-period led to rapid reappearance of normothermia in both types of mice without a large increase in locomotor activity. It is concluded that the TRPV1-gene may have a role in the development of adaptive daytime hypothermia (and hence saving some energy) in mice during complete fasting but still allowing normothermia maintained at night, a strategy probably serving survival under natural conditions in small size rodents such as the mouse. The possible role of muscle thermogenesis either with or without gross bodily movement during fasting or on re-feeding, respectively, may be based on different mechanisms yet to be clarified.

Cholecystokinin and thermoregulation—a minireview

Thermoregulatory effects of cholecystokinin (CCK) peptides are reviewed with special emphasis on two types of responses, that is hypothermia or hyperthermia. In rodents exposed to cold a dose-dependent hypothermia has been observed on peripheral injection of CCK probably acting on CCKA receptors. Central microinjection of CCK in rats induced a thermogenic response that could be attenuated by CCKB receptor antagonists, but some authors observed a hypothermia. It is suggested that neuronal CCK may have a specific role in the development of hyperthermia, and endogenous CCK-ergic mechanisms could contribute to the mediation of fever. Possible connections between thermoregulatory and other autonomic functional changes induced by CCK are discussed.

Orexigenic vs. anorexigenic peptides and feeding status in the modulation of fever and hypothermia.

Prevailing changes in the feeding status or the nutritional status, in general, can modify the expression of many orexigenic and anorexigenic peptides, which influence hypothalamic functions. These peptides usually adjust body temperature according to anabolic (increased appetite with suppressed metabolic rate and body temperature) or catabolic (anorexia with enhanced metabolism and temperature) patterns. It was plausible to presume that such peptides contribute to regulated changes of body temperature (either fever or hypothermia) in systemic inflammation, particularly since anorexia is a common feature in inflammatory processes. No consistent, common, or uniform way of action was, however, demonstrated, which could have described the effects of various peptides. With the exception of cholecystokinin (CCK), all investigated peptides were devoid of real thermoregulatory actions: they influenced the metabolic rate (and consequently body temperature), but not the mechanisms of heat loss. Central CCK is indeed catabolic and may participate in febrigenesis. Leptin may activate various cytokines, catabolic peptides and may inhibit anabolic peptides, but it probably has no direct febrigenic effect and it is not indispensable in fever. Melanocortins and corticotropin-releasing factor provide catabolic adaptive mechanisms to food intake (diet induced thermogenesis) and environmental stress, respectively, but they act rather as endogenous antipyretic substances during systemic inflammation, possibly contributing to the mechanisms of limitation of fever. Bacterial lipopolysaccharides enhance the expression of most of these catabolic peptides. In contrast, neuropeptide Y (NPY) expression may not be changed, only its release is decreased at specific nuclei, a defective NPY effect may also contribute to the febrile rise in body temperature. The data provide no clear-cut explanation for the mechanism of hypothermia seen in systemic inflammation. According to speculations, a presumed, overflow,-type release of NPY from the hypothalamic nuclei, as well as a suppression of the activity of catabolic peptides, could possibly cause hypothermia. There are no cues, however, referring to the identity of factors that could trigger such changes during systemic inflammation in order to induce hypothermia.

Cholecystokinin: Role in thermoregulation and other aspects of energetics

Cholecystokinin (CCK) has long been implicated in body energetics, first as a gastrointestinal hormone assisting fat utilization and later as a neuropeptide acting either peripherally or centrally in the regulation of body mass. In the present review the thermoregulatory role of CCK peptides is reviewed with special emphasis on two types of responses, that is hyperthermia (fever) or hypothermia. Central microinjection of CCK in rats induces a thermogenic response that can be attenuated by CCK2 receptor antagonists, but some authors observed a mild hypothermia. By contrast to its central fever-inducing effect, CCK-8 elicits a dose-dependent hypothermia on peripheral injection probably acting on CCK1 receptors in rodents exposed to cold. It is suggested that neuronal CCK may have a specific role in the development of hyperthermia and endogenous CCK-ergic mechanisms could contribute to the mediation of fever. Recent evidence in rodents lacking either of the CCK receptors appears to support the fever-mediating role of the peptide. In particular, CCK2 receptors seem to be involved in the development of endotoxin fever, while the role of CCK1 receptors could be more complex. In line with that idea, rats lacking functional CCK1 receptors show an exaggerated fever response, a phenomenon that may be associated with a trait different from the absence of this receptor set. The relationship between the putative CCK-ergic febrile mechanism and the established central prostaglandin mediation is also discussed.

Sickness behavior in fever and hypothermia.

Sickness behavior has become a common expression in the description of general symptoms of diseases and regarded as partly or fully advantageous for the patient to combat infection or other disturbance acting on the body. Several components of sickness behavior such as anorexia, sleepiness and inactivity have significant energetic connotations and hence may affect body mass and/or body temperature. Thermoregulatory accompaniments of sickness behavior could be either fever or hypothermia depending on the nature and severity of disease. A survey of the relevant literature has identified afferent, central and efferent mechanisms that may allow separate or coordinated appearance of behavioral and/or thermoregulatory aspects of these symptoms occurring under different experimental conditions. An attempt has been made to find some biological logic in the appearance of various components of sickness behavior and changes in body temperature that could explain the purported positive value of sickness behavior in disease survival.

CCK-8 and PGE1: central effects on circadian body temperature and activity rhythms in rats

Cholecystokinin-octapeptide (CCK-8) has been shown to possess an acute thermogenic and hyperthermic action when given intracerebroventricularly in slightly restrained rats. To substantiate the febrile nature of that hyperthermia freely moving animals should be used and together with body core temperature, at least one behavioral parameter, such as general activity, should also be recorded. In the present studies, Wistar rats (N=34) exposed to thermoneutral (26-28 degrees C) or cold (4 degrees C) ambient temperature and to a 12:12-h light/darkness schedule were infused intracerebroventricularly with CCK-8 or prostaglandin E1 (PGE1) for several days using ALZET minipump and changes in body core temperature and general activity were recorded by biotelemetry (Minimitter). In rats exposed to a thermoneutral ambient temperature, low doses of CCK-8 induced slight but significant rises of day minima of circadian body temperature rhythm (CBTR) and with a high dose (1 microg/h) of the peptide--infused either at thermoneutrality or during cold exposure--an increase of acrometron could also be recorded. All of these changes were observed only during the first 2-4 days of 7-day-long infusions. Intracerebroventricular infusion of PGE1 administered at thermoneutrality in a dose of 1 microg/h for 7 days induced a marked rise in body core temperature with a disappearance of CBTR in some rats for 2-3 days or with rises of day minima/acrometron in others. General activity--running parallel with CBTR in periods without infusions--tended to be decreased when core temperature rose during the first couple of days of intracerebroventricular infusion of higher doses of CCK-8 or of PGE1. The decreased general activity--one component of sickness behavior--together with an increased body core temperature found in the present study, supports the view that they are components of a genuine fever induced by the central effect of the two mediators used.

Autonomic cold- and heat-defence of rats during a febrile rise in core temperature induced by intracerebroventricular infusion of prostaglandin E1

Abstract Body core temperature of rats is elevated during intracerebroventricular infusions of prostaglandin E 1 . In the course of concurrent acute cold- or warm-exposure this new elevated temperature is defended to the same extent as is normal temperature in control animals. Skin vasomotor changes — reflected by oscillations of tail-skin temperature — suggest, however, a decreased regulatory accuracy (or sensitivity) during PGE 1 infusion, at least when measured at thermoneutral ambient temperature.