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Am J Physiol Regul Integr Comp Physiol 279: R960-R965, 2000;
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Vol. 279, Issue 3, R960-R965, September 2000

Vagal CCK and 5-HT3 receptors are unlikely to mediate LPS or IL-1beta -induced fever

S. M. Martin1, B. C. Wilson2, X. Chen2, Y. Takahashi2, P. Poulin2, and Q. J. Pittman2

1 Mt. Saint Vincent University, Halifax, Nova Scotia B3M 2J6, 2 Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Previous studies suggested that peripheral immune mediators may involve intermediates acting on the vagus nerve, such as CCK or serotonin (5-HT). We have therefore investigated a possible role for vagal CCK-A and 5-HT3 receptors in the febrile response after intraperitoneal human recombinant interleukin-1beta (IL-1beta ) or lipopolysaccharide (LPS). Unanesthetized, adult male rats instrumented with abdominal thermistors were given intraperitoneal CCK-8 sulfate (100 or 150 µg/kg) or 2-methyl-5-hydroxytryptamine maleate (4 mg/kg). In other experiments, rats were treated with either antagonists to the 5-HT3 receptor (ondansetron HCl; 100 µg/kg) or the CCK-A receptor (L-364,718, 100 or 200 µg/kg) in combination with LPS or IL-1beta . CCK administration caused a short-lived hypothermia, but interference with the action of endogenous CCK at CCK-A receptors was without effect on IL-1beta - or LPS-induced fever. Neither activation of 5-HT3 receptors nor blockade of 5-HT3 receptors affected body temperature or LPS fever. Taken together, our data support the idea that vagal afferents responsive to pyrogenic cytokines may be different from those responsive to CCK or 5-HT.

lipopolysaccharide; interleukin; cholecystokinin; serotonin; 5-hydroxytryptamine


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE MEANS BY WHICH PERIPHERAL inflammatory events are communicated to the brain to activate changes in body temperature regulation such as fever and other host defense and sickness responses have been under investigation for many years. Although early studies focused on circumventricular organs and the cerebral vasculature as possible portals of entry of cytokines to the brain, more recent evidence suggests that the vagus nerve is also involved in signaling the existence of peripheral inflammation to the central nervous system (CNS) (37). In addition to the well-known efferent parasympathetic fibers innervating the viscera, the vagus also contains unmyelinated afferent fibers (21). The electrical activity of these fibers has been shown to increase (27) in response to peripheral injections of interleukin-1beta (IL-1beta ). Presumably this increased activity is due to binding of IL-1beta to receptors, because mRNA for IL-1beta receptors (10) has been identified in vagal sensory neurons and IL-1beta binding sites (15) have been identified in paraganglia associated with vagal afferent fibers. This activation of vagal afferents is also associated with elaboration of Fos immunoreactivity in the nodose ganglion (14) .

In keeping with the activation of vagal afferents by peripheral immune stimuli, a wide range of CNS responses to peripheral lipopolysaccharide (LPS) or IL-1beta injections has now been reported to be blocked or attenuated by vagotomy or chemical destruction of vagal afferents (reviewed in Ref. 12) (2). These effects of vagotomy and capsaicin treatment support the hypothesis that vagal afferents signal the brain regarding peripheral immune activation. However, a number of questions concerning the signal that activates the vagus remains unresolved.

A number of other substances is also known to activate vagal afferents, most notably CCK, acting on CCK-A receptors (8, 29), and 5-hydroxytryptamine (5-HT), acting on 5-HT3 receptors (1, 39). With respect to CCK, it has been reported that peripheral injections of IL-1beta increase plasma CCK concentrations and the action of IL-1beta in increasing vagal afferent nerve activity is partially mediated by CCK receptors (24). Furthermore, CCK and IL-1beta appear to potentiate each other's action on the vagus (5).

These observations raise the possibility that the actions of peripheral immune mediators on body temperature regulation may involve intermediates, such as CCK or 5-HT, that activate vagal afferents. If so, administration of these substances may cause changes in body temperature to mimic those of LPS or IL-1beta and antagonists to these substances should interfere with the alterations in body temperature induced by these pyrogens. To test these hypotheses, we administered CCK-8 and an agonist to the 5-HT3 receptor to determine their effect on body temperature in unanesthetized, unrestrained rats. In addition, we pretreated rats with antagonists to the 5-HT3 receptor and the CCK-A receptor to identify a possible participation of endogenous CCK or 5-HT in the temperature response to LPS and IL-1beta .


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. Fifty-eight male, Sprague-Dawley rats (228-352 g) obtained from the University of Calgary Animal Breeding Colony were used in the experiments. Rats were housed in the vivarium at an ambient temperature of 20-22°C under a 12:12-h light-dark cycle (lights on at 0700) and given food and water ad libitum. All experimental procedures were approved by the University of Calgary Animal Care Committee and were carried out in accordance with the Canadian Council of Animal Care guidelines.

Surgery. Rats were anesthetized with pentobarbital sodium (50-60 mg/kg ip). Under aseptic conditions, a telemetry thermistor (Minimitter, Sun River, OR) was inserted in the abdomen. Animals, housed in individual cages, were allowed a minimum of 6 days recovery from surgery before the start of the experiments.

Experimental procedures. All experiments were conducted in a temperature-controlled room (22°C) during the light phase. Rats were conditioned to the room before the time of the experiment and were provided with food and water during the experiments. Body temperatures were recorded using antenna plates under each rat's home cage. These picked up the signal from the telemetry device and directed that signal to a computer for continuous online recording of body temperature. Online data acquisition and analysis were done with Dataquest III (Data Sciences, St. Paul, MN) on an IBM AT computer. Body temperature was measured for 1 h before and 6 h postinjection. All injections were given intraperitoneally in a 0.3-ml saline volume for each compound (except for the CCK-A receptor antagonist, which was given in 0.5% BSA in saline) and were administered between 1130 and 1330. Only one injection of LPS was given to any animal. Because ondansetron (5-HT3 receptor antagonist) and L-364,718 (CCK-A receptor antagonist) are short-acting blockers, in some experiments a second injection of each was given ~2.25-2.5 h after the initial injections to ensure correct concentration of the antagonist during the endotoxin-induced fever experiments. Animals participated in anywhere from one to four experiments, including control studies; intervals of 3-9 days separated any given set of experiments, and experiments were carried out using a crossover design to control for order effects.

Four sets of experiments were conducted to investigate 1) the effect of CCK on body temperature; 2) the effect of CCK-A receptor antagonist (L-364,718) on body temperature, LPS fever, and IL-1beta fever; 3) the effect of the 5-HT3 receptor agonist (2-methyl-5-hydroxytryptamine maleate) on body temperature; and 4) the effect of the 5-HT3 receptor antagonist ondansetron on LPS fever.

Drugs. We used the following compounds: CCK (CCK-8 sulfated; 100 or 150 µg/kg, Bachem, Torrance, CA); CCK-A receptor antagonist, L-364,718 (100 or 200 µg/kg dissolved in 10 µl DMSO, Merck, Rathway, NJ); 5-HT3 receptor antagonist (ondansetron HCl; 100 µg/kg, Glaxo, obtained from Foothills Hospital pharmacy); 5-HT3 receptor agonist (2-methyl-5-hydroxytryptamine maleate; 4 mg/kg, Research Biochem International, Natick, MA); LPS (derived from Escherichia coli; 50 µg/kg, Sigma, St. Louis, MO); human recombinant IL-1beta (1.0 µg/kg, 108 U/mg, Immunex, Seattle WA).

Data analysis. Mean ± SE body temperatures were calculated at 5-min intervals for 1 h before and up to 6 h after the injections. The temperatures of the respective groups at the time of injection were compared using Student's t-test. Postinjection body temperatures and statistical comparisons were made using repeated-measures ANOVA followed by Student-Newman-Keuls post hoc when significance was indicated by group ANOVA. Statistical significance was set at P <=  0.05.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effect of CCK on body temperature. The body temperatures in the vehicle and CCK-treated groups were similar at the time of injection (36.7 ± 0.1 and 36.9 ± 0.2°C; respectively, P>= 0.5). Intraperitoneal injection of vehicle (n = 7) led to a transient increase in body temperature that returned to the pretreatment value by the next hour (Fig. 1). This initial slight elevation of body temperature was observed in some but not all experimental groups and is thought to be associated with the behavioral response to the injection procedure. In contrast to the control injections, when these same rats were injected with 100 µg/kg of CCK, they displayed a significant drop in body temperature (F1,12 = 8.089, P = 0.016) during the first hour postinjection without initial elevation in body temperature. The hypothermia reached its minimum (36.2 ± 0.3°C; a drop of approximately -0.7°C) 30-45 min after the injection and returned to the pretreatment value by the second hour after the injection (Fig. 1). This experiment was repeated in seven other rats using a higher dose of CCK (150 µg/kg ip), and similar hypothermic values were obtained (data not shown) in the hour after CCK injection.


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  		Fig. 1.   Body temperature responses (means ± SE) in male rats (n = 7) in response to intraperitoneal injection (arrow) of CCK (100 µg/kg) or vehicle (0.9% saline) * P <=  0.05, ANOVA, Student-Newman-Keuls.

Effect of CCK-A receptor antagonist (L-364,718) on body temperature. The initial values of body temperature in the vehicle and CCK-A receptor antagonist-treated groups were similar (37.3 ± 0.2 and 37.4 ± 0.2°C, respectively, P>= 0.5; n = 5). Intraperitoneal injection of vehicle or 200 µg/kg CCK-A receptor antagonist led to similar small transient increases in body temperature that returned to the pretreatment value by the next hour. Overall temperature responses were identical between the two groups, indicating that the antagonist was without effect on normal body temperature (Fig. 2A).


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  		Fig. 2.   Body temperature responses (means ± SE) in male rats in response to intraperitoneal injection (arrow) of CCK-A receptor antagonist (CCK-ANT; 200 µg/kg) or vehicle (0.9% saline); n = 5, with each rat receiving 2 injections in a counterbalanced order (A); CCK-A receptor antagonist (200 µg/kg) plus lipopolysaccharide (LPS) (50 µg/kg; n = 5) or vehicle (0.9% saline) plus LPS (50 µg/kg; n = 5; B); CCK-A receptor antagonist (200 µg/kg) plus interleukin (IL)-1beta (1.0 µg/kg) or vehicle (0.9% saline) plus IL-1beta (1.0 µg/kg); n = 10, with each rat receiving 2 counterbalanced treatments (C).

Effect of CCK-A receptor antagonist on LPS fever. The initial values of body temperature in the LPS- and LPS + CCK-A receptor antagonist-treated groups were similar (37.1 ± 0.1; n = 5 and 37.1 ± 0.1°C; n = 5, respectively, P>= 0.5). The administration of LPS (50 µg/kg ip) resulted in a fever that began to rise ~90 min after injection. The fever reached a peak of 38.7 ±0.2°C ~150 min after the injection; the body temperature remained elevated over the duration of the 6 h postinjection recording period (Fig. 2B). In the other group of animals receiving an identical dose of LPS, along with the CCK-A receptor antagonist (200 µg/kg), a similar fever profile developed with no significant differences between the two groups (P>= 0.5). This experiment was repeated in an additional 12 rats, using a dose of 100 µg/kg of the CCK-A receptor antagonist (or vehicle) and 50 µg/kg LPS; the antagonist was given twice, both at the time of LPS administration and again 2.5 h later. At this dose and treatment regimen, we also observed similar fever development between rats receiving LPS and vehicle (n = 6) and other rats receiving LPS with the antagonist (n = 6; data not shown). Thus, under all conditions tested, the CCK-A receptor antagonist was without effect on LPS fever.

Effect of CCK-A receptor antagonist on IL-1beta fever. The initial values of body temperature in the IL-1beta and IL-1beta  + CCK-A receptor antagonist-treated groups were similar (37.2 ± 0.1 and 37.1 ± 0.9°C, respectively, P>= 0.5). The administration of IL-1beta (1 µg/kg ip) resulted in a fever that peaked ~135 min after the injection at a body temperature of 38.2 + 0.2°C and defervescence proceeded for the next 3 h. (Fig. 2C). Treatment with the CCK-A receptor antagonist (200 µg/kg ip) in these same animals on a different occasion in conjunction with IL-1beta (1 µg/kg ip) resulted in a fever almost identical (P>= 0.05; n = 10) to that induced by IL-1beta alone. Thus the CCK-A receptor antagonist was also without effect on IL-1beta fever.

Effect of 5-HT3 receptor agonist (2-methyl-5-HT) on body temperature. The initial values of body temperature in the vehicle or the 2-methyl-5-HT-treated groups were similar (37.3 ± 0.1 and 37.1 ± 0.1°C, respectively, P>= 0.5). Intraperitoneal injection of either vehicle or the 2-methyl-5-HT (4 mg/kg ip) into the same animals (n = 10) on different occasions caused no significant changes in body temperature (Fig. 3).


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  		Fig. 3.   Body temperature responses (means ± SE) in male rats in response to intraperitoneal injection (arrow) of the 5-hydroxytryptamine type 3 (5-HT3) receptor agonist [2-methyl-5-hydroxytryptamine maleate (2-M-5HT); 4 mg/kg] or vehicle (0.9% saline). n = 10, with each rat receiving both vehicle and drug in a counterbalanced order.

5-HT3 receptor antagonist (ondansetron) and fever. The initial values of body temperature in the vehicle or ondansetron-treated groups were identical (37.0 ± 0.1 and 37.0 ± 0.1°C, respectively, P>= 0.5). The administration of LPS (50 µg/kg ip) resulted in a fever similar to that observed in the experiments reported above. The fever peaked ~165 min after the injection, with body temperature reaching 38.6 + 0.2°C; the hyperthermic body temperature values were observed during the next 4-5 h (Fig. 4). In the presence of the 5-HT3 receptor antagonist ondansetron (100 µg/kg; n = 6), LPS-induced fever was identical to that seen in the control group (P>= 0.05, ANOVA).


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  		Fig. 4.   Body temperature responses (means ± SE) in male rats in response to intraperitoneal injection (arrow) of the 5-HT3 receptor antagonist (ondansetron, 100 µg/kg) plus LPS (50 µg/kg; n = 6) or vehicle (0.9% saline) plus LPS (50 µg/kg; n = 3).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Our results show that direct activation of the peripheral serotoninergic system with a 5-HT3 receptor agonist is without effect on body temperature. Furthermore interference with the action of endogenous 5-HT with a specific 5-HT3 receptor antagonist did not interfere with generation of an LPS fever, indicating that endogenous, peripheral 5-HT (at least acting at this receptor) is not likely to be involved to a significant degree in the generation of the febrile response. Our data concerning the possible involvement of endogenous CCK in body temperature regulation and febrile response are more equivocal: whereas CCK administration caused a short-lived hypothermia, interference with the action of endogenous CCK at CCK-A receptors was without effect on IL-1beta - or LPS-induced fever. Although CCK may play a role in body temperature regulation, no evidence was found to suggest that intraperitoneal injection of LPS or IL-1beta induced fever development via the activation of the CCK-A receptor system. Thus our data support the idea that vagal afferents responsive to pyrogenic cytokines may be different from those responsive to CCK or 5-HT3 agonists.

CCK and body temperature. There is good evidence to consider the participation of CCK in the febrile response to pyrogens. Both CCK and LPS administration result in a similar activation of Fos protein or of its mRNA in central autonomic nuclei (11, 25, 28). In particular, there is activation by both CCK and LPS of cells within the nucleus of the solitary tract, the site of vagal afferent termination in the brain, and the paraventricular nucleus, a site implicated in fever (19). Furthermore, CCK can activate both gastric afferents (1, 8) and the hepatic branch of the vagus (7), the branch thought to be the most relevant for mediating the effects of LPS (32), but possibly not IL-1beta (36) effects on body temperature. On the basis of a report describing similar electrophysiological responses of vagal afferents to both CCK and IL-1beta and the reduction in the magnitude of an IL-1beta -induced increase in vagal nerve activity by a CCK-A antagonist (24), we predicted that the CCK antagonist would interfere with the febrile response. To investigate the possible role of endogenous CCK in the febrile response to modest doses of LPS and IL-1beta , we gave a CCK-A antagonist with these pyrogens. Contrary to our expectations, we did not see any effect of the antagonist on the febrile response to either LPS or IL-1beta , even in replicate experiments, despite the fact that the doses we employed were found previously to interfere with the action of both endogenous CCK (6, 26) and exogenously administered CCK (34). Our observations of the lack of involvement of CCK in the febrile response to LPS and IL-1beta are in agreement with previous reports that peripheral CCK receptors are not involved in the anorexic, behavioral (3), or hypothalamic-pituitary-adrenal response (9) to pyrogens. However, further experiments using a broader range of doses of LPS may yet uncover a subtle interaction of peripheral cytokines and CCK.

The potential involvement of CCK in body temperature regulation is still a possibility given that we observed a transient hypothermia after exogenous CCK. This action of CCK has been reported previously (23, 33, 34), but temperature measurements in previous studies had not been extended long enough to rule out a subsequent hyperthermia. Although the intraperitoneal route of administration of CCK in our experiments does not allow us to specify the site of this action, the previous demonstration that this hypothermia-inducing action is capsaicin sensitive (33) makes it likely that it is acting on afferent fibers. The presence of CCK-A receptors on the vagus makes this nerve a likely site for the hypothermic action of CCK, although capsaicin could also interfere with a possible action on spinal afferents. If indeed peripheral CCK plays a role in thermoregulation, one possibility is that it may be involved in the initial hypothermia sometimes seen after a large dose of LPS. In fact, there is some evidence that this hypothermia is a regulated drop in body temperature important in the body's response to LPS (31).

On the basis of our observations of a hypothermic effect of exogenous CCK, one might anticipate that the CCK antagonist would have caused a bigger fever in response to pyrogen. This we did not see, possibly because the doses of pyrogens used in our experiments did not activate endogenous CCK release. However, Kurosawa and colleagues (24) showed, in anesthetized rats, that plasma CCK was elevated after doses similar to those used in our experiments in conscious rats. Thus, although our experiments do not provide evidence for a role of endogenous plasma CCK in fever generation, CCK may participate in some other aspect of the host-defense response. For example, there is evidence that brain CCK may participate in fever, but this is thought to be via a CCK-B receptor (34).

5-HT and body temperature. 5-HT has been known for many years to influence body temperature (20), but this effect is thought to be mediated by 5-HT1 receptors (22). However, as the receptors on vagal afferents are most likely the 5-HT3 subtype (18), we investigated the possible involvement of 5-HT3 receptors in body temperature regulation using a 5-HT3 agonist. It was without effect on body temperature, indicating that 5-HT-sensitive vagal afferents do not influence normal body temperature. It was interesting to note that, although both 5-HT3 and CCK receptors have been described on vagal afferents, their activation resulted in different responses in body temperature. This possibly reflects the fact that 5-HT3 agonist and CCK are thought to activate different populations of vagal afferents (17).

In keeping with a lack of effect of 5-HT3 activation on body temperature, the 5-HT3 antagonist ondansetron was also without effect on fever. Nonetheless, the possibility that LPS could activate some population of vagal afferents via a serotoninergic mechanism remains, given that gut mast cells, a source of 5-HT (35), are innervated by vagal afferents (38). Furthermore, these cells also contain CD14 receptors that are responsive to LPS (13).

Perspectives

Although our findings are not supportive of a role for either endogenous CCK or 5-HT in fever, it is important to note that the conditions under which the participation of the vagus in fever has been implicated are critical and have been the subject of considerable controversy and experimentation. For example, vagotomy is effective in reducing or abolishing LPS or IL-1beta fever only when the doses of these compounds used are low. When more pronounced fevers were seen, vagotomy was not effective in interfering with fever development (16, 30). Compared with values reported in the literature, our intraperitoneal dose of LPS would be considered fairly low. Nonetheless, under the appropriate conditions, it is still possible that either CCK or 5-HT could contribute to the body's responses to pyrogen.

Of perhaps most interest is the fact that there may be a specific subset of vagal afferents that are sensitive to cytokines, but not to either CCK or 5-HT. To the best of our knowledge, the physiological function of this class of afferents has not been determined. It is also interesting that lack of responses to intraperitoneal CCK is often used as a test for completeness of vagotomy in studies investigating the role of the vagus in communicating peripheral immune responses to the brain. The findings that vagal afferents responsive to CCK are apparently not involved in immune responses relevant for fever or food-motivated behavior (4) suggest that this may not be entirely appropriate.


    ACKNOWLEDGEMENTS

This work was supported by the Medical Research Council (MRC) and Mt. Saint Vincent University.


    FOOTNOTES

Thanks to Dr. Joe Davison for discussions. X. Chen was an MRC Fellow, B. Wilson a Heart and Stroke Foundation Fellow, Q. J. Pittman an Alberta Heritage Foundation for Medical Research and MRC Senior Scientist and Neuroscience Canada Foundation Alberta Scholar. We thank Immunex for the gift of recombinant human IL-1beta .

Address for reprint requests and other correspondence: Q. J. Pittman, Neuroscience Research Group, Dept. of Physiology and Biophysics, 3330 Hospital Dr. NW, Univ. of Calgary, Calgary, Alberta, Canada T2N 4N1 (E-mail: pittman{at}ucalgary.ca).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Received 7 January 2000; accepted in final form 7 April 2000.


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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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