A.M. Naylor

Evidence supporting a role for endogenous vasopressin in fever suppression in the rat.

1. Infusion of human purified interleukin‐1 into a lateral cerebral ventricle of the rat evoked a rise in core temperature which was abolished by heating the interleukin‐1. 2. When the intracerebroventricular infusion of interleukin‐1 was preceded by a bilateral injection of saline into the ventral septal area, the resulting febrile response was not different from that induced by interleukin‐1 alone. However, when the vasopressin V1 antagonist, d(CH2)5Tyr(Me)AVP, was injected into the ventral septal area prior to interleukin‐1, a fever was evoked which was significantly greater in magnitude and duration. This enhancement of fever by the V1 antagonist was dose related. 3. Injection of either saline or the V1 antagonist into the ventral septal area, in the absence of interleukin‐1, did not evoke any consistent alteration in the core temperature of the rats. 4. The vasopressin V2 antagonist, d(CH2)5‐D‐ValVAVP, was injected into the ventral septal area to determine the effect of another vasopressin analogue on the fever evoked by interleukin‐1. The V2 antagonist did not alter the time course of interleukin‐1‐induced fever or alter core temperature in the afebrile rat. 5. These data are consistent with the hypothesis that endogenous vasopressin, released in the ventral septal area, may be involved in limiting fever. In addition, these results indicate that the central receptor mediating the antipyretic action of vasopressin may resemble the V1 subtype of peripheral vasopressin receptor.

Perfusion of vasopressin within the rat brain suppresses prostaglandin E-hyperthermia

These experiments were undertaken to determine whether arginine vasopressin (AVP) could suppress a prostaglandin hyperthermia and to localize sites of these actions in the rat. Prostaglandin E2 (PGE2) sensitive sites were localized in the ventral-septal area by microinjecting 200 ng/0.5 microliter of prostaglandin E2. During perfusion with an artificial CSF, PGE2 injected into the lateral cerebral ventricle evoked a hyperthermia of more than 1 degree C. Perfusion of 6.5 micrograms/ml of AVP markedly attenuated the PGE2-induced hyperthermia. These results suggest that AVP suppresses PGE2-induced hyperthermia in sites in which PGE2 evokes an increase in core temperature.

Perfusion of vasopressin within the ventral septum of the rabbit suppresses endotoxin fever

The antipyretic action of arginine vasopressin (AVP), administered into a lateral cerebral ventricle or directly into the brain tissue via push-pull perfusion, was investigated in conscious New Zealand White rabbits. Administration of AVP into a lateral cerebral ventricle (ICV) was ineffective in reducing an endotoxin-induced fever and did not alter body temperature in the afebrile rabbit. Control push-pull perfusions with the carrier vehicle were without effect on endotoxin fevers or normal body temperature. Perfusion of the vehicle containing AVP provided significant antipyretic activity against both intravenous (IV) and ICV endotoxin without affecting normal body temperature. Both the maximum fever height and the fever index were significantly reduced during AVP perfusion. Tissue sites in which AVP was found to be antipyretic were located in the rostroventral parts of the septal region, at sites similar to those where perfusion of the peptide caused antipyresis in the sheep and rat. These results support the hypothesis that AVP, or a closely related molecule, may modulate fever within the central nervous system.

Stimulation of vasopressin release in the ventral septum of the rat brain suppresses prostaglandin E1 fever.

1. Infusion of prostaglandin E1 (PGE1) into a lateral cerebral ventricle of the rat evoked a rise in core temperature which could be attenuated by electrical stimulation of the bed nucleus of the stria terminalis (BST). Electrical stimulation of the BST in the absence of PGE1 did not alter body temperature in the afebrile rat. 2. When the intracerebroventricular (I.C.V.) infusion of PGE1 was preceded by a bilateral injection of saline or vasopressin V2 antagonist d(CH2)5D‐ValVAVP into the ventral septal area (VSA), electrical stimulation of the BST suppressed the PGE1 hyperthermia. However, when the vasopressin V1 antagonist d(CH2)5Tyr(Me)AVP was injected into the VSA prior to I.C.V. infusion of PGE1, electrical stimulation of the BST did not alter the hyperthermic response to PGE1. 3. These actions were site specific in that the suppression of PGE1 hyperthermia was observed only when the electrode tips were located in the area of the BST. Similarly, the V1 antagonist only blocked the effect of electrical stimulation when injected into the VSA. 4. When the vasopressin V1 antagonist was injected into the VSA, the PGE1 fever was prolonged when compared to the controls with saline. 5. Injection of saline, vasopressin V1 and V2 antagonist into the VSA, without PGE1 or BST stimulation, did not evoke any significant change in the core temperature of the rats. 6. These data are consistent with the hypothesis that vasopressin may function within the brain as an endogenous antipyretic and that vasopressin may act in a BST‐VSA neuronal pathway concerned with endogenous antipyresis.

Thermoregulatory actions of centrally-administered vasopressin in the rat

Dependent upon the route and/or site of administration, arginine vasopressin (AVP) evoked a number of thermoregulatory actions in the conscious rat. Infused into a lateral cerebral ventricle, arginine vasopressin produced short-lasting hypothermia of rapid onset. Injected into the preoptic area, arginine vasopressin caused long-lasting hyperthermia of rapid onset that was antagonized by the prior administration of a V1 receptor antagonist, [d(CH2)5 Tyr(Me)AVP]. Injections of arginine vasopressin into the nucleus accumbens, ventral septal area, substantia innominata and the dorsomedial hypothalamus were without effect on body temperature. Although the antipyretic action of arginine vasopressin within the ventral septal area has been well documented, these findings provide further evidence that this peptide exerts additional thermoregulatory actions that are both neuroanatomically and functionally specific.

The role of vasopressin as an antipyretic in the ventral septal area and its possible involvement in convulsive disorders

Perfusion of the peptide, arginine vasopressin (AVP), within the ventral septal area (VSA) of the brain of a number of species reduces fever but not normal body temperature. This antipyretic response appears to be mediated by AVP receptors of the V1 subtype. Lesions of the VSA with kainic acid are associated with prolonged and enhanced fevers in rats. A role for endogenous AVP in fever suppression within the VSA comes from several types of experiments: (1) AVP release within the VSA is inversely correlated to fever height; (2) AVP antagonists or antiserum injected into the VSA prolong fever; (3) animals lacking endogenous AVP in the VSA (Brattleboro rat, long-term castrated rat) develop enhanced fevers. Electrical stimulation of the AVP-containing cell bodies of the bed nucleus of the stria terminalis (BST) orthodromically inhibits VSA neurons and also suppresses fever; the latter effect can be abolished with application of a V1 antagonist to the VSA. Iontophoretic studies indicate that AVP inhibits glutamate-stimulated activity of thermoresponsive and other VSA neurons. AVP can also act in the VSA to cause severe motor disturbances; this action is receptor mediated and increases in severity upon sequential exposure to AVP. Because sites of action of the antipyretic and convulsive action of AVP are similar, and because animals lacking brain AVP display reduced convulsive activity, it is possible that AVP, released during fever, could be involved in the genesis of convulsive activity.

Antipyretic action of centrally administered arginine vasopressin but not oxytocin in the cat.

The antipyretic action of central arginine vasopressin (AVP) was investigated in mongrel cats. Control push-pull perfusions in the ventral septal area (VSA), with the carrier vehicle alone, did not affect the febrile response to Salmonella typhosa administered intracerebroventricularly. When AVP was perfused similarly, the fever was suppressed in a dose-related manner. The lower dose of AVP delayed the onset of fever, whereas the higher concentration of AVP suppressed consistently the fever throughout the period of administration. Another neurohypophyseal peptide, oxytocin, was ineffective in altering the febrile response at the dose tested. The regions of greatest sensitivity to the antipyretic action of AVP are located ventral to the septum, bounded by the diagonal bands of Broca, extending into the posterior septal nucleus. Sites at which AVP was ineffective in producing antipyresis were found more dorsal and lateral to these. Thus, AVP suppresses fever in the cat via an action in the VSA that is dose related, and site specific and peptide specific. These data provide further evidence that AVP may be involved in the central mechanisms which control core temperature.

Central effects of vasopressin and 1-desamino-8-d-arginine vasopressin (DDAVP) on interleukin-1 fever in the rat

The intracerebroventricular administration of arginine vasopressin suppressed significantly the fever evoked by interleukin-1. This antipyretic action of arginine vasopressin was blocked completely by the antivasopressor analog d(CH2)5Tyr(Me)arginine vasopressin, an antagonist of the V1 subtype of peripheral vasopressin receptor. However, in contrast to AVP, the V2 receptor agonist, 1-desamino-8-D-arginine vasopressin, did not alter the normal time course or magnitude of interleukin-1 fever. These data suggest that arginine vasopressin induced antipyresis is mediated via central receptors which may resemble the V1 subtype of peripheral vasopressin receptor. The V2 subtype of vasopressin receptor is unlikely to be involved since an agonist of this receptor did not exhibit any antipyretic activity against interleukin-1 fever.

I. Determination of the endogenous and evoked release of catecholamines from the hypothalamus and caudate nucleus of the conscious and unrestrained rat

The action of catecholamines within the CNS is important for the expression of numerous vegetative and behavioral functions. To understand the role these amines play, it is necessary to measure changes in the levels of these transmitter substances by utilizing new developments and methodology in the behaving animal. Utilizing new developments in methodology, it is possible to measure the release of amines into perfusates obtained from specific sites in the brain of the rat under basal and evoked conditions without prior purification or concentration. Using the push-pull perfusion technique, perfusates were obtained from the hypothalamus and caudate nucleus and analyzed by liquid chromatography with electrochemical detection. It is possible to readily determine basal release of dopamine from the caudate nucleus. Detection of both dopamine and noradrenaline is possible under ephedrine stimulated conditions from both the caudate nucleus and the hypothalamus. Although levels of serotonin (5-HT) were detected in brain perfusates, it may not be of neuronal origin. It may be possible to use these techniques to delineate the roles these amines play in various physiological functions.

Characteristics of pyrogen fevers are altered in the aged rabbit

The febrile response to both intravenous and intracerebral administration of pyrogens was investigated in young and old male New Zealand White rabbits. Intravenous bacterial pyrogen evoked biphasic fevers in both groups of animals. However, the fevers in the group of older rabbits were significantly less than in younger animals. In contrast, intravenous injection of endogenous pyrogen produced identical fevers in the two groups. Bacterial and endogenous pyrogens injected into a lateral cerebral ventricle evoked marked febrile responses of long duration in both young and old rabbits. The responses of the old rabbits were significantly less than those of the younger ones. Finally, direct microinjection of prostaglandin E1 into tissue sites within the anterior hypothalamic preoptic area elicited short latency hyperthermic responses which were significantly less in the older rabbits. Analysis of ear skin temperatures during fever demonstrated that some of the differences may, in part, be due to altered vasoconstrictor responses in the peripheral vasculature. Thus, these data indicate that the febrile response is altered with increasing age in the rabbit.