Physiology and Pharmacology of Temperature Regulation Neuronal CCK and thermoregulation : two receptors with different functions

THE EARLY DAYS OF THE DISCOVERY and identification of different forms of CCK in the GI tract and the abdominal vagus (20), on the one hand, and in the central nervous system (CNS; 7, 17), on the other hand, might have already anticipated important roles of the peptide in various aspects of energy homeostasis, ranging from regulation of feeding behavior and body mass to body temperature control. Indeed, centrally or peripherally administered CCK has proven to be a satiety agent in animal experiments (10) and, as such, this peptide or some of its derivatives have raised hopes of representing an effective candidate of a genuine antiobesity medicine for humans. The CCK peptide family has been characterized in the literature as consisting of two receptor sets, forming a more comprehensive picture of the mechanisms of their action. The availability of specific antagonists for these two receptors, now called CCK1 and CCK2 receptors—corresponding to the peripheral type and central type receptors, respectively—and some more-or-less selectively acting agonists, offered means to study various aspects of energetics. As a result of these developments, the relatively long history of the function of CCK-ergic system in satiety has gradually become straightforward: as supported by experiments carried out in rats on the satiety action of the peptide, CCK1 receptors now appear indispensable (19, 24), while the CCK2 receptors do not take part in this regulation. Interest in the regulation of body temperature, another aspect of energetics in animals, used to be less intensive in investigations on CCK-dependent functions. In particular, the first data indicated a monotonous CCK-induced hypothermia in rats (22) and were later supported by several authors showing a robust dose-dependent hypothermia (14, 15, 38). Even central administration of CCK-octapeptide was reported to result in hypothermia that was also accompanied by thermoregulatory effector responses known to contribute to decreases of core temperature (18). Although the mechanism of hypothermic action of CCK peptides was still unknown in the 1980s, this thermoregulatory effect seemed to have fitted well into a general negative imbalance of energetics, which also included decreased energy (food) intake, thus leading to a slowing down of general metabolism (regarded as a coordinated response to conserve energy). However, some published research showed slight rises of body core temperature in some species after central administration of CCK (8, 13). In fact, through applying more controlled experimental conditions and antagonists to the two CCK receptors, it could be shown that in rats exposed to a range of ambient temperature, an intracerebroventricular microinjection of CCK-8 led to a rise in core temperature that resembled the fever response induced by the established pyrogen mediator, PGE (33). Furthermore, pretreating rats with the CCK2 receptor antagonist L365,260 given either peripherally or centrally could attenuate that feverlike response, while the CCK1-receptor antagonist devazepide—otherwise able to antagonize the hypothermic effect of a large dose of CCK-8 given peripherally—failed to attenuate the fever response to intracerebroventricular CCK-8. Similar results were later reported by other authors (9, 31), showing also a dose dependency of the size of CCK-induced fever. A rise in core temperature, however, cannot necessarily be regarded as a fever, unless it is accompanied by appropriate thermoregulatory changes, such as a rise in heat production and evidence for decreased heat loss (33) and other, nonthermoregulatory changes as components of the sickness behavior, the latter resulting from efferents from some CNS areas and leading to a coordinated set of symptoms (11). The development of two or more of the established components of the sickness behavior (e.g., inactivity, anorexia, sleepiness, social isolation, decreased grooming behavior), together with a rise in body core temperature is regarded as a strong argument for a febrile nature of the response, whereas a rise of core temperature alone may also be a simple passive hyperthermia. In the latter case, thermoregulatory compensations (i.e., skin vasodilatation, signs of increased evaporation aiming at increasing heat loss) are evoked in defense of normothermia, just the opposite of what can be observed during genuine fever (vasoconstriction, shivering, etc.). The role of a CCK-ergic mechanism in fever could be clarified further by using the established LPS fever model (25) to see whether specific antagonists could modify that response. In fact, an attempt in this direction was published showing that a CCK2-receptor antagonist was able to attenuate at least the first phase of LPS fever in rats ( 32 ). Availabilty of genetically modified mice and rats lacking or overexpressing receptor(s) of CCK has improved our understanding about functional aspects of biologically active peptides. In this line, experiments using mice lacking the CCK2 receptor indicated a minor but significant role of that receptor in normal thermoregulation (36). In this issue of the American Journal of Physiology— Regulatory, Integrative, and Comparative Physiology, data have been published of detailed analysis of fever response observed in three different doses of LPS in mice lacking functional CCK2 receptors and in their wild-type counterparts (37). According to the study’s results, which were carried out using biotelemetry, all parameters of sickness behavior monitored (decreases in activity, body weight, and food intake, as well as the rise of body core temperature), showed reduced response to 500 or 2,500 g/kg intraperitoneal injection of Escherichia coli LPS compared with the same responses of wild-type mice. As emphasized by these authors, their results do not exclude the role of vagal afferents in the initiation of the fever responses observed, but the parallel changes of fever with all three parameters of sickness behavior monitored having Am J Physiol Regul Integr Comp Physiol 292: R109–R111, 2007; doi:10.1152/ajpregu.00620. 2006.