Effects of massive doses of α-MSH on thermoregulation in the rabbit

α-MSH-related compounds may prove to be clinically useful antipyretics since the parent peptide is extremely potent in reducing fever, it is effective when given orally, and it neither stimulates corticosteroid activity nor has marked melanotropic effects in man. To determine whether or in what doses α-MSH might cause harmful side-effects, we injected doses greatly exceeding those required to reduce fever into a lateral cerebral ventricle of afebrile rabbits. One hundred to seven hundred and fifty μg α-MSH caused large and prolonged reductions in body temperature and the dose-response relation was bell-shaped for both magnitude and duration. These doses caused no apparent injury to the animals. One mg α-MSH elicited hyperthermic responses that were variable in magnitude and duration. Animals that had previously received large doses of α-MSH ( 100 μg) did not develop hyperthermia, even when given 2 mg, indicating an acquired tolerance to this hyperthermic action of α-MSH. All animals, tolerant or previously uninjected, showed symptoms with doses 1 mg α-MSH that included: increased salivation, agitation, ataxia, respiratory distress, and death (in 30% of the animals); those that recovered from these large doses resumed outwardly healthy appearance and behavior. Although α-MSH is toxic when given centrally in large doses, the 5000-fold difference between antipyretic and toxic doses indicates a wide safety margin should this peptide be used clinically as an antipyretic drug.     

Effects of thyrotropin releasing hormone on hypothalamic thermosensitive neurons of the rat

The actions of thyrotropin releasing hormone (TRH) were tested on the firing rat of temperature-sensitive and temperature-insensitive neurons in the rat preoptic/anterior area of the hypothalamus (POA). Iontophoretic application of TRH resulted in inhibition of the firing rate of temperature-insensitive, warm-sensitive and cold-sensitive neurons. The inhibitory response of cold sensitive neurons in TRH was relatively mild, however, and 2 of 6 of these neurons inhibited by TRH also displayed rebound increases in discharge rate following cessation of TRH application. These results parallel the hyperthermic effects of microinjected TRH and lend further support of the hypothesis that TRH acts as a neurotransmitter or neuromodulator in the POA portion of the CNS thermoregulatory network.     

Behavioral and physiological effects of capsaicin in red-winged blackbirds

We injected red-winged blackbirds (Agelaius phoeniceus) subcutaneously with capsaicin, and assessed (a) changes in basal body temperature, (b) ability to discriminate warm from cool drinking water, and (c) sensitivity to oral and topical applications of capsaicin, a trigeminal irritant. As predicted from studies of mammals, the injections seemed to disrupt thermoregulation when the ambient temperature increased, and eliminated discrimination between warm and cool drinking water (Figs. 1 and 2). In contrast to effects on mammals, injections failed to observably diminish oral or topical sensitivity to capsaicin and apparently induced a capsaicin preference in two-bottle drinking tests between capsaicin and its vehicle (Fig. 3). Such preferences were context-dependent, however, since water was reliably preferred to capsaicin or vehicle in three-bottle tests. To our knowledge, the present work is the first to report physiological and behavioral effects of capsaicin on birds, and the first to suggest that the substance may have different behavioral and physiological effects on different classes of animals.     

Central thermal adaptation of lower brain stem units in the guinea-pig

Summary Cold adaptive changes were found in single units responding to thermal skin stimulation. All units were located in the subcoeruleus region of the lower brain stem. In cold-adapted guinea-pigs (five weeks in ambient temperature of 4°C), the maximum activity of cold-responsive neurones was reduced markedly in comparison with that of cold-responsive neurones in animals adapted to room temperature (ca. 21°C). This decrease may be a neuronal correlate to long-term downward shifts of shivering threshold temperature known to occur within adaptation periods of several weeks in man, as well as in animals.     

The effect of ambient temperatures on eating elicited by hypothalamic stimulation

Rats were implanted with electrodes in the perifornical lateral hypothalamic area. The amount of stimulus-bound-eating (SBE) was defined as the number of pellets eaten during ten consecutive trains of 60 sec stimulation, separated by intervals of 30 sec at a previously fixed stimulus intensity. The effect of increased ambient temperature (39°C) was studied in a group of eight animals and the effect of lowered ambient temperatures in a different group of eleven animals. A significant decrease of SBE as compared to the 24°C control condition was found after 30 min of exposure to 39°C and a significant increase after 90 min of exposure to 9°C. These differences were maintained with repetitive alternate exposures of 180 min to the control and experimental temperature conditions. These exposures did not produce any differential effects on colonic temperatures. After termination of the exposure to both elevated and lowered ambient temperature, SBE returned to control levels within short intervals of 10–20 min.     

Is alcohol induced poikilothermia mediated by 5-HT and catecholamine receptors or by ionic set-point mechanism in the brain?

In adult male Sprague-Dawley rats, stainless steel guide cannulae were implanted stereotaxically in either the lateral or third cerebral ventricle. Postoperatively, each animal was maintained at an ambient temperature of 22°C. Just prior to the intragastric gavage of 4.0 g/kg ethyl alcohol (20% solution) individual animals were fitted with a colonic thermistor probe. Then, control CSF, a monoaminergic receptor antagonist, or a Ca⁺⁺ ion chelating agent, EGTA, was infused into either the lateral or third ventricle (ICV) in a volume of 10.0 μl. Phentolamine (20.0 μg), butaclamol (10.0 μg), or methysergide (20.0 μg) injected ICV all failed to prevent the thermolytic action of alcohol. The fall of 1.5 to 2.0°C in the rat's colonic temperature, ordinarily caused by alcohol, was the same as that without the antagonists and lasted 3.0 to 4.0 hrs. EGTA infused into the rat's lateral cerebral ventricle also did not interfere with alcohol's poikilothermic action. However, EGTA infused into the third cerebral ventricle completely blocked alcohol's effect in lowering the body temperature of the rat. These results suggest that: (1) alcohol's profound effects on body temperature are not mediated by 5-HT, norepinephrine or dopamine pathways which are thought to underlie the mechanisms in the hypothalamus for thermoregulation; and (2) the temperature set-point mechanism, controlled by the ratio of diencephalic Na⁺ to Ca⁺⁺ ions, is incapacitated by alcohol. Restoration of the ratio in the diencephalon by the direct, local chelation of Ca⁺⁺ ions thus eliminates alcohol's deleterious effects on body temperature.     

The role of associative factors in tolerance to the hypothermic effects of morphine in mice

Associative learning theories of drug tolerance emphasize the importance of stimuli which predict drug administration. One such model holds that drug tolerance is due to the development of a conditional response (CR) which is directionally opposed to the unconditional response (UCR) to the drug. By virtue of their opposing natures, the overlapping occurence of CR and UCR is seen as a diminished response, i.e., tolerance. The present experiments tested the predictions of this model using two doses of morphine, and included truly random controls to examine the role of excitatory and inhibitory conditioning in tolerance. Tolerance was greatest in mice administered morphine in the context of stimuli previously paired with drug administration, intermediate in random controls, and least or absent in mice administered the drug in the presence of cues paired with vehicle injections. No direct evidence of a compensatory CR which could offset morphine's hypothermic effect was obtained in placebo test sessions, nor was evidence for such a response obtained in cross-drug tests with amphetamine and apomorphine.     

Effect of liver temperature increase on food intake

Artificial heating of rat liver decreases food intake, while it significantly increases the purposeless chewing during the experiment. The hypothesis is suggested that hepatic thermoreceptors are stimulated by a physiologic increase in liver temperature, which afferent to feeding integrative centers. Liver thermoreceptors rather than chemoreceptors are perhaps regulators of food intake.     

Oxygen consumption of the chicken embryo: interaction between temperature and oxygenation

We measured the effects of hypoxia and changes in ambient temperature (T) on the oxygen consumption (VO2) of chicken embryos at embryonic days 11, 16 and 20 (E11, E16 and E20, respectively), and post-hatching day 1 (H1). Between 30 and 39 degrees C, at E11 and E16, VO2 changed linearly with T, as in ectothermic animals, with a Q10 of about 2.1. At E20, VO2 did not significantly change with T, indicating the onset of endothermy. At H1, a drop in T increased VO2, a clear thermogenic response. Hypoxia (11% O2 for 30 min) decreased VO2, by an amount that varied with T and age. At H1, hypoxia lowered VO2 especially at low T. At E20, hypoxic hypometabolism was similar at all T. At E11 and E16, hypoxia lowered VO2 only at the higher T. In fact, at E11, with T=39 degrees C even a modest hypoxia (15-18% O2) decreased VO2. Upon return to normoxia after 40 min of 11% O2, VO2 did not rise above the pre-hypoxic level, indicating that the hypometabolism during hypoxia did not generate an O2 debt. At E11, during modest hypoxia (16% O2) at 36 degrees C, the drop in VO2 was lifted by raising the T to 39 degrees C, suggesting that the hypoxic hypometabolism at 36 degrees C was not due to O2-supply limitation. In conclusion, the hypometabolic effects of hypoxia on the chicken embryo's VO2 depend on the development of the thermogenic ability, occurring predominantly at high T during the early (ectothermic phase) and at low T during the late (endothermic) phase. At E11, both low T and low oxygen force VO2 to drop. However, at a near-normal T, modest hypoxia promotes a hypometabolic response with the characteristics of regulated O2 conformism.     

Chemokines and chemokine receptors: New actors in neuroendocrine regulations

Chemokines are small secreted proteins that chemoattract and activate immune and non-immune cells. Their role in the immune system is well-known, and it has recently been suggested that they may also play a role in the central nervous system (CNS). Indeed, they do not only act as immunoinflammatory mediators in the brain but they also act as potential modulators in neurotransmission. Although we are only beginning to be aware of the implication of chemokines in neuroendocrine functions, this review aims at summarizing what is known in that booming field of research. First we describe the expression of chemokines and their receptors in the CNS with a focus on the hypothalamo-pituitary system. Secondly, we present what is known on some chemokines in the regulation of neuroendocrine functions such as cell migration, stress, thermoregulation, drinking and feeding as well as anterior pituitary functions. We suggest that chemokines provide a fine modulatory tuning system of neuroendocrine regulations.