C.W. Gowdey

Suppression of food intake and body weight gain by naloxone in rats.

Abstract The effect of acute and chronic administration of naloxone on food acquisition and weight gain in rats was studied in 3 experiments. One injection of a sparingly-soluble salt of naloxone in slow-release vehicle markedly lowered mean food intake over that of control rats injected with the vehicle only. Mean body weight of the naloxone-injected rats was significantly lower than that of the control group for one week. Repeated evening injections (2000 h) of naloxone hydrochloride in saline tended to reduce the night-time feeding below control levels throughout the 10-day period of naloxone administration. Food intake was significantly lower in the 4- and 8-h periods after the first injection of naloxone than that on the preceding saline control night. The initial decreases were offset by increased day-time feeding so that total daily food intake was not significantly altered over the 10 days. When saline was substituted for naloxone, food intake increased. Rats given naloxone following 24 h of fasting consumed significantly less food and gained less weight during 4 h of access to food compared to those receiving saline. After a 48-h fast naloxone-treated rats also gained significantly less body weight than those given saline, but the reduction in food intake was not statistically significant. These results suggest the possibility that endorphins may have a modulating effect on feeding activity.

Hypothalamic injection of morphine: Feeding and temperature responses

Abstract Morphine (2.7, 5.6 and 10.3 nmoles) and norepinephrine (10, 20 and 40 nmoles) were applied to the ventromedial hypothalamus of male rats through cannulae which were implanted stereotaxically. Food intake was enhanced by both drugs as compared with saline. Although intake peaked during the first hour following norepinephrine, it was more gradual following morphine. Both drugs also caused a rise in core temperature, but only with morphine did this persist throughout the 3-hour measurement period. Naloxone (10.6 nmoles) injected into the ventromedial hypothalamus 5 minutes before morphine (5.6 nmoles) caused a short-lived decrease in feeding and temperature when compared with a saline control. The same dose of naloxone given into this site 1 hour after morphine had no apparent effect on either parameter. Naloxone (2 and 10 mg/kg) given subcutaneously suppressed feeding and temperature changes produced by intrahypothalamic morphine. These results indicate that morphine can increase feeding and temperature at a site which is also responsive to norepinephrine, and that naloxone, given intracranially or subcutaneously, can suppress the effects induced by morphine to different degrees.

Disruption of diurnal feeding patterns of rats by heroin

Adult male rats receiving 5 or 20 mg/kg heroin HCl by single injections (08:00 or 20:00 hr) or in 3 equal injections (8 hr intervals) showed a disruption in the normal diurnal pattern of behavior. Initially, heroin abolished feeding for several hr after the injection, reduced the total daily food consumption in a dose-related manner, due primarily to decreased night-time feeding, and prevented or slowed weight gain. Subsequent heroin injections led to a phase of vigorous feeding following the period of depression. Magnitude and duration of the depression decreased, but the stimulatory phase of feeding became more pronounced as tolerance developed. Total daily food intake and body weight returned towards control levels, but the proportion eaten during daylight hr became elevated. Sporadic feeding occurred on the first withdrawal day with abolition of the stimulatory phase which had followed each heroin injection. Subsequently, the normal diurnal pattern of behavior gradually returned. Close measurement of 24 hr food consumption may be a sensitive and valuable measure of the disruptive effects of narcotic analgesics.

A probable role for norepinephrine in feeding after hypothalamic injection of morphine

When morphine is instilled directly into the ventromedial hypothalamus of rats there is a latent period followed by a prolonged bout of feeding. This enhanced activity may be mediated by the release of norepinephrine; for morphine-induced feeding was depressed by the alpha-adrenergic receptor blocker phentolamine. Several neurotransmitter agonists and antagonists failed to duplicate this action: propranolol, serotonin, methysergide, apomorphine and haloperidol were ineffective in modifying ingestion elicited after morphine. Unlike apomorphine, dopamine augmented morphines feeding effect. This difference may exist because dopamine acts as a precursor for norepinephrine formation in local ventromedial hypothalamic neurons.

Tolerance and evidence of physical dependence to daily codeine injections in the rat.

Core temperatures, measured by telemetry, and acquisition of food pellets on a continuous reinforcement schedule were recorded every 30 min in unrestrained male rats given saline for 5 days before and 5 days after 10 daily SC injections of codeine phosphate (200 mg/kg) at 08:00 hr. After the first codeine injection rats were immobile, slightly catatonic, breathed shallowly and had elevated core temperatures, loss of body weight and inhibition of feeding activity. As injections of codeine were repeated, the initial depressant signs decreased and the period of inhibited feeding was replaced by prolonged (greater than 8 hr) post-injection bouts of feeding activity (stimulated feeding) during daylight hours. Core temperatures remained elevated during this phase of drug-induced feeding activity. Mean body weight and 24-hr food intake remained below control levels over the 10-day codeine period as diurnal feeding patterns became reversed. On the first withdrawal day core temperatures declined and feeding patterns changed from those responses on the last codeine day as the rats lost body weight and were hyperirritable. As withdrawal continued core temperature and feeding patterns began to resemble those of the saline control period, body weights increased and hyperirritability subsided. In this study, tolerance and evidence of physical dependence to daily injections of codeine could be demonstrated in rats by continuous monitoring of their diurnal feeding and temperature responses.

Anemia-induced Changes in Cardiac Output in Dogs Treated with Dichloroisoproterenol

The cardiac output of anesthetized dogs was markedly elevated by the production of severe acute anemia by exchanging dextran for blood. Dichloroisoproterenol, in a dose which completely blocked the positive chronotropic effect of epinephrine and several reflexes, usually had minimal effects on the cardiac output. The cardiac responses to acute anemia were not different in the DCI-treated and the control groups. It is concluded that the effect of acute anemia on cardiac output is probably not mediated by the action of adrenergic substances on the heart.

Sympathoadrenal System and Response of Heart to Acute Exchange Anemia

This report deals with a study of the relative roles that the sympathetic nervous system and adrenal medulla play in the cardiac responses to experimental anemia.

Dependence in rats after one injection of heroin-, LAAM- or hydromorphone-zinc tannate.

Complex zinc tannate salts of heroin, hydromorphone and l-alpha-acetylmethadol were synthesized and injected in a slow-release vehicle, into rats. One, 3, 7, 10 and 14 days after the drug was administered rats were injected with naloxone hydrochloride (10 mg/kg) and during the following 4 hours body weights, core temperature and behavioral signs such as diarrhea, writhing, teeth chattering and wet dog shakes were recorded. On every naloxone testing day the narcotic-treated groups presented behavioral signs of abstinence, but weight loss and temperature changes were much less consistent. Reduction of core temperature following naloxone administration seems to be an earlier indicator of physical dependence than weight loss. According to the parameters tested a level of physical dependence can persist for at least two weeks after a single injection of these narcotic salts.

Central effects of five muscle relaxants

SummaryFifteen experiments utilizing cross-circulated healthy dogs were perforated to investigate the purely central action of succinylcholine chloride, decamethonium, d-tubocurarine chloride, gallamine tri-ethiodide, and l,6-hexamethylerne-bis-carbaminoylcholine bromide.The experiments were conducted under conditions of normothermia and controlled oxygenation and perfusion pressure to reduce the variables influencing the central nervous system.All the relaxant drugs used were considered to exhibit central activity, apart from their well-known activity at the myoneural junction. Hexamethylene. carbaminoylcholine, in particular, appeared to exert a marked central action because of its ability to permeate the blood-brain barrier with relative ease.By far the most significant central effect was on the respiratory centre, causing depression and apnoea in the isolated recipient body. The dosage required to produce central respiratory arrest or depression was found to approximate closely that required to produce a peripheral myoneural block in the donor body.Significant tachyphylaxis was observed only with decamethonium, where it was difficult to effect myoneural block and long-lasting central respiratory depression.Vasomotor effects were not noted except with d-tubocurare: increasing doses resulted in increasing hypotension.Cerebral stimulation was elicited in. two of the three decamethonium experiments, one of three curare experiments, and one of four hexamethylene carbaminoylcholine experiments.No cardiac effects attributable to these agents were noted. A hypothesis for the possible action of hexamethylene carbaminoylcholine is suggested in the light of the results obtained in these experiments and from other published clinical reports. Further work in this field is indicated.The increasing significance of altered body economy and the increased scope and extent of surgery in the presence of such conditions suggest to us that the side-effects of muscle relaxants may come to assume a more significant role than previously.Species variation in the effects of myoneural blocking agents undoubtedly occurs, but it is felt that the present study, combined with the clinical appraisals, leads to the belief that central activity can indeed be significant in certain cases.The nebulous blood-brain barrier offers a wide field for further investigation of drug action.RésuméNous avons fait quinze expériences en employant des chiens en bonne santé en circulation croisée, pour étudier exclusivement ľaction centrale du chlorure du succinylcholine, du décaméthonium, du chlorure de d-tubocurarine, du tri-iodure de gallamine et du bromure 1, 6-hexaméthyléne-biscarbaminoyl-cholines.Ces expériences ont été faites en maintenant la température normale mais en contrÔlant ľoxygénation et la pression de perfusion dans le but de diminuer le nombre de facteurs susceptibles ďinfluencer le système nerveux central.Tous les médicaments myorésolutifs nous ont semblé produire une activité centrale en plus de leur action bien connue à la jonction myoneurale. Ľhexa-méthylène carbominoylcholine en particulier a semblé produire une action centrale marquée à cause de sa facilité à traverser la barriàre sang-cerveau.Ľaction, de beaucoup la plus marquée sur le système nerveux central, s’est manifestée sur le centre respiratoire en provoquant une dépression et une apnée sur le récepteur isolé. La dose nécessaire pour provoquer un arrêt respiratoire central ou une dépression semble étre voisine de la dose requise pour produire un blocage myoneural périphérique chez le donneur.Une tachyphylaxie importante a été observée seulement avec le décaméthonium avec lequel il a été difficile de produire un blocage myoneural et une dépression respiratoire centrale ďune certaine durée.Nous n’avons pas observé ďeffets vaso-moteurs si ce n’est avec le d-tubo dont des doses croissantes ont provoqué une hypotension proportionnelle.Une stimulation cérébrale a été manifeste au cours de deux des trois expériences avec le décaméthonium au cours ďune des trois expériences avec le curare, et au cours ďune des quatre expériences avec ľhexaméthyléne carbominoylcholine.Nous n’avons observé aucun effet de ces médicaments sur le cœur. A la suite des travaux publiés sur ce sujet et des renseignements recueillis au cours de ces expériences, nous emettons ľhypothèse ďune action possible sur le cœur de ľhexaméthylène carbominoylcholine. Il s’impose de continuer la recherche dans ce domaine.LĽimportance croissante que prennent les perturbations organiques et ľextension progressive de la chirurgie dans ces circonstances nous portent à croire que les effets secondaires des myorésolutifs peuvent venir à jouer un rô1e plus important qu’ils ne ľont fait antérieurement.Sans doute, il existe des variantes dues à ľespàce dans les effets du blocage myoneural, mais nous avons ľimpression que ľétude actuelle, en plus de ľévaluation clinique, conduit à la conclusion que ľactivité centrale, en certains cas, peut être assez marqueé.Cette vague barrière sang-cerveau ouvre un champ considérable de recherches sur ľaction des médicaments.

Sparingly-soluble narcotic zinc tannates cause protracted analgesia in rats.

Pain thresholds were determined in rats by the titration foot shock technique for 5–8 days after a single injection of zinc tannate salts of heroin (HZT)—41.0 and 81.9 mg/kg as base, LAAM (LZT)—41.0 and 81.9 mg/kg; and hydromorphone (DZT)—39.9 and 79.8 mg/kg. These zinc salts were synthesized, analyzed, suspended in a slow-release vehicle (SRV), and injected subcutaneously. Body weight and pain threshold of each rat were determined at the same time each day. Serum levels of the hydrolyzed metabolites of heroin were measured periodically in rats which had received similar injections of HZT. Analysis of variance showed that all narcotic preparations, except for low dose HZT, led to a significant (α = 0.05) elevation of pain threshold above that of the SRV control at 24 hr. Pain thresholds were significantly elevated for 3 days after low dose LZT, 4 days after both doses of DZT and 5 days after high dose LZT. Hydrolyzed heroin metabolites were present in the serum for 7 days after a single injection; at that time no analgesia was evident. The mean body weight of HZT and SRV rats continued to increase, whereas the LZT and DZT groups initially tost weight. This study shows that a single injection of 3 narcotic zinc tannate preparations can induce long-lasting elevations in pain thresholds, but tolerance to the analgesia is evident within days.