Biomedical subjects
Publications and source records attributed to W Feldberg.
Prostaglandin E(1) (PGE(1)) produces a rise in rectal temperature when injected into the cerebral ventricles of unanaesthetized cats, rabbits and rats. An effect is obtained with as little as 20, and sometimes even with 10 ng.
1. Micro-injections of a few nanograms of prostaglandin E(1) (PGE(1)) into the anterior hypothalamus of unanaesthetized cats produced a rise in rectal temperature, whereas temperature was not affected when micro-injections of even larger doses were made into the posterior hypothalamus. The hyperthermia produced by injections of PGE(1) into the cerebral ventricles is therefore attributed to an action of PGE(1) on the anterior hypothalamus.2. During a pentobarbitone sodium anaesthesia the sensitivity of cats to the hyperthermic effect of PGE(1) injected into the cerebral ventricles was found to be greatly reduced, particularly during the early stage of anaesthesia when body temperature was falling steeply.
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1. In unanaesthetized rabbits 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) were injected into the cisterna magna or into the cannulated left lateral cerebral ventricle while rectal temperature was recorded.2. 5-HTP injected intracisternally in a dose of 1.5-3 mg produced a fall in temperature often followed by a rise beyond the pre-injection level. With 6 mg the main effect was a rise in temperature. The intraventricular injection of 1-2 mg 5-HTP usually produced a fall followed by a rise.3. 5-HT injected intracisternally in a dose of 0.2 mg produced a fall in temperature similar to that produced with this dose injected intraventricularly. Following an intracisternal injection of 1-4 mg 5-HT there was either a fall, or a fall followed by a rise, but in a few experiments the effect consisted mainly of a rise in temperature.4. Additional effects regularly observed with these injections were tachypnoea, ear twitching, rapid movements of the vibrissae, shaking of the head, wiping and scratching movements, ataxia, nodding and sideways movements of the head and long-lasting catalepsy.5. The sites where 5-HTP and 5-HT act when producing the temperature responses and the various behavioural effects are discussed.
1. In cats, the effects of tranylcypromine and pheniprazine, two monoamine oxidase (MAO) inhibitors with strong amphetamine-like actions, of pargyline, an inhibitor without amphetamine-like actions, and of amphetamine itself, were examined on the hypothermia produced by a 2 hr period of halothane inhalation.2. The hypothermia was prevented by intraperitoneal injections of the three MAO inhibitors. Tranylcypromine and pheniprazine acted in doses of a few milligrams, pargyline in doses of over 100 mg.3. The hypothermia was prevented by injections into the cerebral ventricles of tranylcypromine and pheniprazine, in doses which were effective also on intraperitoneal injection; intraperitoneal injections were sometimes more effective. The large doses of pargyline needed to prevent the hypothermia when injected intraperitoneally were not tested by the intraventricular route, as the injections had to be made in a volume of 0.1 ml. In smaller doses intraventricular pargyline was not effective.4. The hypothermia was prevented by an intraperitoneal or intraventricular injection of amphetamine in a dose as little as 1 mg; intraperitoneal injections were sometimes more effective.5. The effects of tranylcypromine and pargyline given intraperitoneally, and of amphetamine given intraventricularly as well, were also examined on the hypothermia produced by an intraventricular injection of 200 mug noradrenaline. The two MAO inhibitors and amphetamine prevented the hypothermia, or greatly reduced it.6. It is concluded (a) that even on intraventricular injection the MAO inhibitors must first be absorbed into the blood stream before they can prevent the hypothermia of a halothane anaesthesia; (b) that their action may not be solely on the anterior hypothalamus; and (c) that they may not act only through MAO inhibition.
1. In cats anaesthetized with intravenous chloralose, microinjections of tubocurarine, leptazol, strychnine or picrotoxin, in a volume of 1 mul, were made into the grey matter of the cerebral cortex and the electrical activity was recorded from the site of injection with the microinjection cannula which, insulated except at its tip, served as recording electrode.2. Routinely the injections were made into the gyrus splenialis or into the underlying gyrus cinguli close to the mid-line, because the injections would then most likely be in grey and not in white matter. Injected in this way all four drugs set up foci of excitation which gave rise to synchronous firing of a large number of neurones with the result that high voltage negative spikes were recorded from the microinjection cannula.3. On injection into the gyrus splenialis the threshold dose was about 0.04 mug for picrotoxin, about 0.2 mug for tubocurarine, about 5 mug for strychnine and 25 to 50 mug for leptazol. Following the injection of larger doses the spike discharge continued for a few hours after picrotoxin and tubocurarine, for over an hour after strychnine, but for a few minutes only after leptazol. On injection into the gyrus cinguli the threshold doses were slightly greater and with larger doses the spikes occurred at greater frequency but were of lower voltage than in the gyrus splenialis.4. With large doses of picrotoxin injected into the gyrus splenialis the spikes developed an after-positivity and an after-discharge which sometimes passed into a short period of fast activity.5. The foci of excitation set up by the drugs were restricted to the site of injection because on raising or lowering the microinjection cannula the spikes recorded from it quickly decreased in voltage and then disappeared. When the injections were made close to a sulcus and the microinjection cannula, on being lowered, traversed the sulcus, the spikes changed their polarity.6. The spike discharge appears to be a consistent response to the injections of the drugs into grey matter of any part of the cerebral cortex since it was also obtained on their injection into the pyriform cortex, amygdala and area retrolimbica anterior, but not on their injection into white matter or caudate nucleus, thalamus or hypothalamus.
1. Picrotoxin was perfused through different parts of the cerebral ventricles in cats anaesthetized with chloralose, and applied topically to the upper cervical cord in cats anaesthetized with intraperitoneal pentobarbitone sodium. With both methods, picrotoxin produced effects similar to those produced by tubocurarine; but it was active in weaker concentrations.2. Perfused through the third ventricle, picrotoxin caused shivering resulting in a rise of rectal temperature, increased motor excitability, muscle jerks, tachypnoea, mydriasis, and withdrawal of the nictitating membranes. The effects were due to an action on structures in the walls of the ventral half of the ventricle, because they occurred only on perfusion of tubocurarine through this half and not on its perfusion through the dorsal half of the third ventricle. Noradrenaline perfused through the third ventricle abolished the shivering and the rise in temperature, but did not affect the motor hyperexcitability or the muscle jerks, whereas pentobarbitone sodium similarly perfused abolished these effects as well.3. Perfused through the inferior horn of a lateral ventricle, picrotoxin caused excitation of the hippocampus. This resulted in a rhythmic discharge of high voltage negative spikes in the electrocorticogram taken from the occipital cortices. The spikes developed after-positivity with after-discharges and were interrupted from time to time by bursts of fast activity termed episodes. This abnormal discharge was recorded also from the perfusion cannula which was inserted into the inferior horn and acted as a lead from the surface of the hippocampus.4. Perfused through the anterior horn of a lateral ventricle picrotoxin caused a rhythmic discharge of negative spikes which was recorded from the anterior horn cannula and resulted from excitation of the grey matter in the anterior limbic area which forms part of the medial wall of the horn.5. Applied to the surface of the upper cervical cord, picrotoxin produced scratching movements.
1. A method is described for the perfusion of the liquor space from a lateral cerebral ventricle to the cisterna magna in the unanaesthetized cat. Perfusions were carried out for 30-40 min using various physiological salt solutions whilst rectal temperature was recorded.2. When the salt solution used contained calcium in the physiological concentration, rectal temperature remained unchanged, but when it contained no calcium an intense hyperthermia developed during the perfusion. The finding that calcium must be present in the perfusion fluid for preventing temperature from rising may lead to a new understanding of the working of the ;set-point' in the control of body temperature and of the mechanism of action of pyrogens.3. Independent of the nature of the perfusion fluid a long-lasting late rise in temperature developed after a perfusion. This happened regularly when the infusion needle was inserted only into the hub of the ventricular cannula, but rarely when the needle was extended beyond the tip of the cannula shaft and the cannula had been flushed out during the preceding days. It is therefore thought that an unknown pyrogenic factor present in the lumen of the cannula and washed into the ventricle with the perfusion fluid is responsible for this effect.4. The effluent collected from the cisterna contracted the fundus strip of the rat stomach. As the contractions were little affected by BOL, they are attributed mainly to an action of prostaglandin E(1) and not to an action of 5-HT. There was no difference in the biological activity of the effluent whether the perfusion fluid contained calcium or not.
1. In cats anaesthetized with intravenous chloralose, tubocurarine was either perfused through the inferior horn of a lateral ventricle or applied by micro-injection into the hippocampus, and the electrical activity was recorded from the surfaces of the occipital cortices and from the cannulae used for the perfusion or injection which, insulated except at their tips, served as recording electrodes as well.2. With both methods, the hippocampus became activated by tubocurarine acting directly on the hippocampus. The activation resulted in an abnormal spike discharge interrupted from time to time by short bursts of fast activity, termed episodes, followed by periods of electrical silence during which no abnormal activity was recorded. This abnormal discharge was recorded in all leads. The spikes were negative when recorded from the surface of the hippocampus, but changed polarity when the electrode was lowered and penetrated the pyramidal cell layer, and on further lowering the electrode the positive spikes increased in voltage up to 15 mV and then decreased.3. With both methods, signs of indirect activation of the hippocampus were observed when the tubocurarine set up foci of excitation in one of the following three areas of cerebral cortex which lie ventral to the hippocampus, the Area entorhinica, the Area perirhinica and the Area post-splenialis. The foci of excitation resulted in a continuous discharge of negative spikes which were recorded in the leads from these areas only. A characteristic feature of the indirect hippocampal activation arising from the continuous discharge set up in the Area post-splenialis was the periodicity. Activation lasting 20-60 sec occurred every few minutes or at shorter intervals, often leading to an episode.
1. In unanaesthetized rabbits the cerebral ventricles were perfused for 30-75 min from left lateral ventricle to cisterna magna with solutions of different composition, whilst rectal temperature was continuously recorded.2. Temperature did not rise during the perfusion when the perfusing fluid consisted of artificial c.s.f.; it did rise, however, when the perfusing fluid consisted merely of a 0.9% sodium chloride solution.3. Temperature fell, though not in all rabbits, during the perfusion when the calcium in the perfusing fluid was increased from 1.25 mM, the concentration in c.s.f. to 5 mM.4. Magnesium chloride had only a weak action, in comparison to calcium, in preventing the rise produced during perfusion with 0.9% sodium chloride solution. In a concentration of 1.25 mM it had no effect, but in a concentration of 5 mM it delayed and greatly reduced the rise.5. Temperature did not rise during perfusion with an isotonic sucrose solution.6. The rise in temperature produced by an intravenous injection of leucocyte pyrogen was not prevented when the injection was made during a perfusion with artificial c.s.f., but it was prevented when the calcium concentration in the perfusing fluid was raised to 5 mM or when the perfusing fluid consisted of isotonic sucrose solution. Again, magnesium had only a weak action in comparison to calcium.7. These results support the theory put forward recently (Feldberg, Myers & Veale, 1970) that the constancy of temperature depends upon the physiological balance of sodium and calcium ions in the anterior hypothalamus, that the calcium ions act as a kind of ;brake' preventing the sodium ions from exerting their temperature raising effect, and that pyrogen acts by removing the ;calcium brake', the pyrogen fever thus being a sodium fever.
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1. In unanaesthetized cats the effect on rectal temperature was examined of 5-HT injected through a Collison cannula chronically implanted into the left lateral ventricle. The response depended on the amount of 5-HT injected and on the solvent employed.2. An intraventricular injection of 200 mug 5-HT creatinine sulphate dissolved in 0.9% NaCl solution resulted in a long-lasting rise often interrupted initially by a transient fall in temperature.3. This fall became more prominent with larger doses of 5-HT; even more when the 5-HT was dissolved in distilled water, and then the hyperthermic effect was attenuated.4. It is concluded that intraventricular 5-HT raises rectal temperature in cats when the amount is not too large, and that a hypothermic effect when it occurs results from paralysis of cells in the anterior hypothalamus which are excited by small doses. This would be similar to the actions of acetylcholine in the perfused superior cervical ganglion of the cat, where small doses excite but large doses paralyse the ganglion cells.5. An intraventricular injection of distilled water produced a steady rise in temperature which is attributed to release of 5-HT.