This report concerns a review of the neuroendocrine effects of narcotic analgesics and endorphins. Acute administration of narcotic analgesics to rats increases the blood levels of ACTH, GH and prolactin, and decreases levels of LH and TSH, however, there is no general consensus regarding changes in serum FSH, ADH and oxytocin as induced by narcotics in rats. In humans, the narcotic analgesic increases in serum prolactin, decreases in serum LH and has no effect on the release of other known pituitary hormones. Endorphins mimick morphine regarding hormonal effects. Effects of naloxone on the basal levels of prolactin, LH or GH were inverse to the effects seen with narcotics and endorphins, therefore endorphins may play a role in regulating the basal levels of these hormones. Narcotic analgesics depress the increased blood levels of prolactin, gonadotropins or TSH elicited by specific measures. While chronic administration of morphine results in tolerance to the stimulant effect of ACTH, and possibly of prolactin secretion, tolerance does not develop to the stimulant effect on GH secretion. The analgesic potency of narcotic analgesics correlates with their suppressive effect on the pituitary-gonadal system and the potency with which endorphins bind to the opiate receptors correlates with their prolactin releasing activity. It is assumed that narcotic analgesics and endorphins exert their hormonal effects by altering the release of neurotransmitters in the CNS. Thus, a release of hypothalamic releasing hormones is involved rather than a direct action on the pituitary. The central neurotransmitter systems involved in the hormonal effects of narcotics are now being intensively investigated by various groups of workers.

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In the isolated left atria of the guinea-pig, guanfacine and clonidine (10^-8-3×10^-5g/ml) produced positive inotropic effects, which were inhibited by tripelennamine, metiamide and propranolol. Up to the concentration of 10^-6g/ml of these compounds the effects were also inhibited by phentolamine. In the isolated right atria, guanfacine in concentrations over 3×10^-6g/ml, produced a negative, and clonidine, a positive chronotropic effect. Whereas the effect of clonidine was antagonized by metiamide, the effect of guanfacine was not antagonized by any blocking agents we used. In spontaneously beating right atria, the positive inotropic effects induced by guanfacine (10^-8-10^-5 g/ml) were inhibited by propranolol or tripelennamine, while those of clonidine (10^-8-10^-4 g/ml) were antagonized by metiamide. In canine HLP, both drugs produced a decrease in the coronary flow which was associated with a slight rise in the right atrial pressure. These effects were inhibited by phentolamine. Both drugs produced a slight decrease in the myocardial O₂ consumption and an improvement of the myocardial redox potential.

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Effects of various cathartics on charcoal transport, permeability of blood vessels and biogenic amines (serotonin (5-HT), histamine (His), polyamines) in the small intestine of mice were investigated. Diarrhea was induced in mice by oral administration of magnesium sulfate, mannitol, dioctyl sodium sulfosuccinate(DSS), castor oil and pilocarpine. In diarrhea following ingestion of magnesium sulfate and mannitol, vascular permeability in the intestinal membrane accompanied release of His from the small intestine, but such was not so when diarrhea was induced by DSS and castor oil. In diarrhea induced by various cathartics, 5-HT and His were apparently not related to intestinal motility. Thus, alteration in polyamine metabolism in the small intestine may exert an influence on transport of substances in cases of diarrhea in mice.

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Pyrogen acted on mitochondrial outer membrane or structure to increase the penetration of substrate to mitochondrial MAO. Mitochondrial respiratory activity did not change significantly after acute administration of pyrogen. With chronic administration of pyrogen, the ADP/O ratio of liver mitochondria was increased. These results suggest that the acute administration of pyrogen affects the mitochondrial outer membrane, while the chronic administration affects both the outer and inner membranes.

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Mechanisms involved in the biliary excretion of organic anions were investigated in hemoglobin-free perfused rat liver using iotroxic acid as a test substance. The process of biliary excretion in this system can be separated into three elemental processes, i.e. 1) diffusion into hepatocytes, 2) protein-binding with intracellular protein (accumulation) and 3) active transport into bile. Elimination of iotroxic acid from the perfusate into the hepatocytes followed first-order kinetics, indicating the process to be that of passive diffusion. Though the biliary excretion occurred rather rapidly, the amount of iotroxic acid in the hepatocytes increased with increases in the initial concentration in the perfusate and approached a maximal amount of ca. 2.8 μmoles/g wet weight of liver. The maximal values observed for the biliary concentration and the rate of biliary transport were 20-24 mM and 38-48 nmoles/min·g liver, respectively. Bromsulphalein inhibited the diffusion of iotroxic acid into the hepatocytes whereas accumulation of iopodic acid in the hepatocytes produced an inhibition of diffusion into the hepatocytes and transport into the bile. Dexamethasone-21-sulfate (DXMS) was transported rapidly into the bile, but in the presence of iotroxic or iopodic acids, excretion of DXMS into the bile was inhibited, while diffusion into the hepatocytes was inhibited only by iopodic acid. The competition observed with those substances demonstrates the presence of a common mechanism for the biliary transport of organic anions in the liver.

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Pharmacokinetical properties of eight triiodobenzene derivatives, X-ray contrast agents, were studied in the hemoglobin-free perfused rat liver with emphasis on the structural relation to biliary transport. With chemical modification of the basic structure, these agents showed different characteristics in the processes of diffusion into hepatocytes, accumulation in the cells and active transport into the bile, and were separated into four groups; [I]: Iotroxic acid (1), Iodipamic acid (2), lodoxamic acid (3), and loglycamic acid (4) which showed faster rates of diffusion into hepatocytes [(1)≥(2)>(3)>(4)] and also of biliary excretion [(1)>(2)>(4)> (3)], [II]: Diatrizoic acid and Metrizamide showed poor diffusion and biliary excretion, [III]: Iopodic acid showed the highest permeability into and accumulation in hepatocytes with little biliary excretion, [IV]: ZK73 215 was slowly transported into the bile, yet, showed little permeation through the cell membrane. Characteristics of (1), (2) and (3) observed in the perfused liver were, in principle, confirmed in the pharmacokinetical profile observed in vivo. However, the fast diffusion of (2) into the hepatocytes appears to be hampered by high binding ability with serum proteins, whereas the relatively poor profile of the biliary excretion of (3) was improved by its low protein-binding in blood in vivo. Superiority of (1) as a cholangiographic agent was demonstrated by the fast biliary excretion in both the case of experimental systems and moderate protein-binding.

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Anti-inflammatory activities of prednisolone 17-valerate 21-acetate(PVA) were studied in rats and guinea pigs and results compared with data on topical steroids, such as betamethasone 17-valerate(BV) and hydrocortisone 17-butylate(HB). PVA given subcutaneously inhibited dose-dependently carrageenin and kaolin-induced edema. These anti-inflammatory activities of PVA were the weakest among the steroids tested. A local administration of PVA into the site of inflammation, however, had the same or more potent activities than BV and HB in carrageenin-induced edema and paper disk granuloma. Topical application of PVA ointment in carrageenin-induced edema exhibited an inhibitory effect which was dependent on the concentrations(0.1-1.0%). The anti-inflammatory activity of 0.3% PVA ointment was equivalent to that of 0.12% BV ointment. For the other experimental models, i. e. exuberant granulation, croton oil-induced ear edema, passive cutaneous anaphylaxis and tuberculin-induced delayed type hypersensitivity, the activity of 0.3% PVA ointment was the same or somewhat more potent than 0.12% BV and 0.1% HB ointments. The thymolytic activity of PVA ointment in the exuberant granulation model was similar to the activity seen with HB ointment and weaker than of BV ointment. Thus, the anti-inflammatory activities of PVA were equivalent to or more potent than those of BV and HB, and with topical application, the systemic effect of PVA was weaker than the other steroids examined.

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Contractions evoked by electrical stimulation of isolated longitudinal muscle preparations of guinea pig ileum were inhibited by the addition of opioids in the order of morphine=methionine enkephalin>pentazocine>pethidine. Incubation of the preparation in the medium containing opioids at 4°C for 22 hr resulted in a tolerance to the inhibitory effect in morphine and pethidine but in the case of pentazocine and met-enkephalin, tolerance did not develop under the conditions employed. The same treatment with morphine, pethidine and pentazocine resulted in the development of dependence as demonstrated by naloxone provoked contracture or increase in the height of contraction. Opiate and enkephalin receptors are known to be unevenly distributed in the ileum and a significant difference was also observed in the distribution patterns of both receptors. Distribution of the receptors did not parallel the effect of opioids, thereby indicating a multiplicity in receptors. However, under the conditions employed in the present experiments, our results reflect the in vivo effects of opioids, such as analgesic effect or tolerance and dependence liability, and the validity of this preparation for the evaluation of opioids was confirmed.

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In dogs and rabbits anesthetized with pentobarbital sodium or urethane, respectively, the gastric mucosal blood flow was measured by the thermoelectrical method after intravenous administration of 3-(3, 4, 5-trimethoxybenzamido)piperidine(KU-54), an antiulcer drug. In the gastric corpus of rabbits, the maximal mucosal blood flow(11.9%) was attained within 1 min after KU-54(5 mg/kg i.v.) dosing and there was a prolonged increase during 8 min. Administration of KU-54 produced a transitory depression of the blood pressure by about 20%, and induced a β-adrenergic-like action, presumably because both the blood pressure depression and the gastric mucosal blood flow increment were simultaneous in rabbits. This phenomenon was however, not abolished by pretreatment with propranolol, a β-adrenergic blocker, therefore KU-54 may not be a β-adrenergic blocking agent. Administration of gefarnate, a standard antiulcer drug, produced a slight increase in gastric mucosal blood flow and response to this drug was less than that seen with KU-54. Sulpiride, a standard antiulcer drug, produced two peaks on the gastric mucosal blood flow increment in rabbits and the pattern of blood flow increment differed from that seen with KU-54. The increment of gastric mucosal blood flow produced by KU-54 (5 mg/kg i.v.) was more successive in the gastric antrum than that in the gastric corpus. In fasting rabbits, the main period of gastric mucosal blood flow increment produced by KU-54 (5 mg/kg i.v.) was more successive than that seen in the non-fasting animals. In dogs, the maximal blood flow (16%) was observed at 7 min after KU-54 (5 mg/kg i.v.) dosing and there was a prolonged increase during 6 min.

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The in vivo effects of prednisolone 17-valerate 21-acetate (PVA), an anti-inflammatory glucocorticoid on several immunological responses in mice were investigated in comparison with hydrocortisone 17-butyrate (HB) and betamethasone 17-valerate (BV), when given subcutaneously. PVA reduced the spleen weight, the number of splenic nucleated cells, the formation of hemolytic plaque forming cells (PFC), delayed type footpad reaction and the responsiveness of splenic lymphocytes to concanavalin A. These suppressive effects were almost the same as those seen with HB and weaker than those of BV. However, the responsiveness of splenic cells to lipopolysaccharide and circulating IgM antibody response to sheep red blood cells were suppressed by a smaller dose of PVA than that of HB. PVA had no effect on the responsiveness to phytohemagglutinin-P, whereas HB and BV enhanced the phytohemagglutinin-P reponsiveness. The suppressive effect of PVA on the host defense to experimental infection with Escherichia coli was weaker than those of HB and BV. From these results, PVA appears to be similar to other glucocorticoids in that it exerts complicated effects on several immunological responses in mice.

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The present study was an attempt to determine whether the circadian rhythm as recorded by Animex and EEG can be used as an indicator of drug dependence in rats, and also to examine the correlation between drug dependence and changes in several monoamines. Repetitive injections of morphine (MP), methamphetamine (MAPT) and cocaine (CC) markedly increased motor activity for about 4 hours post-injection, depending on the number of injections and also remarkably increased the state of wakefulness (AW), but decreased the amount of both slow wave sleep (SWS) and fast wave sleep (FWS) in the EEG sleep-wakefulness cycles during the 7-hour observation period. The injection of MP induced the dissociation between EEG and behavior. SWS increased in phenobarbital (PNB)- and diazepam (DZP)-dependent rats. Abrupt withdrawal of MP resulted in a consistent decrease in motor activity, an increase in AW, and a decrease in SWS and FWS both during the day and at night. The withdrawal of PNB and DZP produced an increase in motor activity and AW, and a decrease in SWS both during the day and at night. The circadian rhythm seen during the course of repetitive injections of MAPT and CC disappeared immediately following the withdrawal. Normal rhythm was recovered with an increase in SWS at night. Repetitive administration and subsequent abrupt withdrawal of the drugs altered the contents and turnover rates of the three monoamines.

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