Nociceptive reactions were determined using the hot plate technique (55°C) in sham-operated and hypophysectomized rats. No significant differences were noticed in the latencies to lick, jump, or escape between the two groups. These experiments indicate that pituitary endorphins are not the sole endogenous substances involved in the regulation of thermonociception. In hypophysectomized rats rendered acutely dependent on morphine, following naloxone, some signs of precipitated abstinence (chewing and teeth chattering) were significantly diminished, some others (abnormal posture, body tremor and pilo-erection) were significantly enhanced, and many others (urination, paw shakes, body shakes, diarrhoea, jump, rearing, eye blinking, head shakes and grooming) were not modified. These observations indicate that the pituitary has a complex role in the expression of signs of abstinence. However, concomitant lesions of the adjascent areas such as the hypothalamus might have also contributed to the observed modifications of the abstinence signs. Hence, it may be advisable always to interpret the results obtained with hypophysectomized rats with some caution.

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Effects of carbachol on the Ca²⁺-dependent action potentials were investigated in the canine ventricular muscle which was depolarized and made inexcitable by elevation of the extracellular concentration of K⁺ ([K⁺].) to 30 mM. Regenerative action potentials (“the slow response”) were induced by electrical stimulation at low frequency with high intensity (0.1 Hz, 5 msec duration and 5 mA). The amplitude of the slow response varied 31 mV for a tenfold change in [Ca²⁺]o. The amplitude and duration of the slow response were increased by isoproterenol (10^-7 M) and were decreased by carbachol (3×10^-6 M). The actions of carbachol on the slow response were antagonized by atropine (10^-6 M). Propranolol (3×10^-7 M) decreased the amplitude and duration of the slow response. In the presence of propranolol, carbachol (3×10^-6 M) produced a further decrease in the amplitude and duration of the slow response. These results suggest that electrical stimulation induces the slow response which is augmented by catecholamines released from the adrenergic nerve endings in response to the stimulation and/or K⁺-depolarization. Carbachol depresses the slow response by its muscarinic action which may involve both, “indirect” and “direct” effects, the former being the effect caused by counteracting the catecholamine-induced augmentation of the slow response and the latter, the effect irrespective of catecholamines.

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Effects of 7-ethoxycarbonyl-6, 8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG626) on the spinal trigeminal nucleus (STN), ventral posteromedial nucleus (VPM), and sensory cortex were examined in cats anesthetized with alpha-chloralose in comparison with the effects of morphine. EG626 produced a dose-dependent inhibition of the polysynaptic components of the cortical field potentials upon VPM stimulation and either facilitatory or inhibitory effects on the polysynaptic components of the VPM field potential upon stimulation of the medial lemniscus, while the drug failed to affect the STN field potential with trigeminal nerve stimulation. Morphine inhibited the postsynaptic components of the STN field potentials and to a lesser extent, the polysynaptic components of the cortical field potential; and the effects of morphine on the VPM field potential were similar to those seen with EG626. Pretreatment of the animal with naloxone antagonized the facilitatory effect on the VPM field potentials produced by morphine, but not those by EG626. Morphine and EG626 induced either a prolonged increase in the blood flow or transient increase followed by a decrease in the blood flow in the VPM. These results suggest that EG626 may impair the polysynaptic transmission and/or neuron excitability in the sensory cortex and the VPM at least partly due to the change in blood flow there as does morphine. Unlike morphine, however, EG626 did not produce any obvious effect on the STN.

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The effect of pyrithiamin on thiamin deficient mice was studied clinically and pathologically. Thiamin deficiency was produced in the mice fed with a thiamin deficient diet by a single injection of pyrithiamin (10 mg/ kg, s.c.) on day 0 to produce a mild illness and on day 14 to produce a severe disorder. Clinically, the mild illness showed only Wooley-White sign and histologically, it was characterized by edema in the thalamus, mammillary bodies, and pontine tegmentum. The severe illness showed convulsion and multiple hemorrhages in the same area. This pyrithiamin-induced thiamin deficient animal model can also be useful for research on thiamin deficient encephalopathy.

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The mode of action of papaverine on smooth muscle relaxation was examined through analyzing its effects on caffeine-induced contraction of guinea pig taenia coil, which might be due to calcium ion mobilized from intracellular store sites. Caffeine contraction induced in normal solution at 32°C was decreased in the presence of papaverine but increased after the removal of papaverine, and it was also increased when the muscle was preincubated with papaverine and then washed out. These papaverine actions were inhibited at low temperature. Caffeine contraction induced in Ca-free, depolarizing solution was also enhanced by treatment with papaverine during Ca-loading. Cyclic AMP and its dibutyryl derivative produced a similar effect on the caffeine contraction induced in normal or Ca-free, depolarizing solution as those of papaverine. In addition, a good correlation was observed between the papaverine-induced increases in caffeine response and in tissue cyclic AMP level. From these results, it is considered that papaverine increases cyclic AMP of the taenia coil, and this increased cyclic AMP stimulates accumulation of calcium ion into its storage sites from where calcium ion was released by caffeine, finally leading to smooth muscle relaxation.

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The response of the phrenic nerve activities during the cough reflex was investigated in anesthetized dogs. The phrenic nerve activities were recorded from the central cut end of the nerve. Changes in phrenic nerve activities were evaluated by means of computer analysis using the programs for power spectrum, amplitude histogram, pulse density variation, and autocorrelation. The cough reflex was induced by mechanical stimulation of the tracheal mucosa. The cough reflex evoked was accompanied by an increase in the number of spike potentials and shortening of the respiratory burst period of the phrenic nerve activities. There was a significant correlation between the intensity of expiration and the multiplication product of the mean amplitude of spike potentials and spike numbers of the phrenic nerve activities during the cough reflex. Total activity of the discharge, amplitude of spike potentials, and pulse density of the phrenic nerve activities also increased during the cough reflex, while the autocorrelation coefficient decreased. These changes were inhibited by codeine. The responses of the phrenic nerve activity during the cough reflex were also observed under artificial respiration as well as under spontaneous respiration. These findings indicate that the phrenic nerve activity can be an indicator of the cough reflex, and it is useful for the indicator to investigate the central mechanisms of the cough reflex.

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This paper describes the distribution of aromatic L-amino acid decarboxylase (AADC) activities in fourteen tissues (eight peripheral tissues and six brain regions) of semicarbazide (SC)-treated rats, using both LDOPA and L-5-hydroxytryptophan (L-5-HTP) as substrates. The distribution of pyridoxal phosphate (PLP) was also measured in control and SC-treated rats. SC-treatment decreased the PLP concentration in all tissues (about 50-60% of control). AADC activities towards L-DOPA and L-5-HTP as substrates were also decreased significantly in almost all tissues of SC-treated rats. After the addition of exogenous PLP in vitro, AADC activities were recovered only partially in most tissues, but the recovery patterns were not parallel between L-DOPA and L-5-HTP as substrates. L-DOPA decarboxylase activity was more sensitive to PLP-deficiency than L-5-HTP decarboxylase activity in the same tissues. Serum AADC activities were decreased drastically using both L-DOPA and L-5-HTP as substrates. No serum AADC activity was detected in SC-treated rats using L-DOPA as substrate, but low activity was detected in the same sample using L-5-HTP as the substrate; both activities recovered completely after in vitro addition of 10μM PLP in the incubation mixtures.

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Effect of the aqueous extract of Cinnamomum Cassia (CCAq) on experimental allergic reaction was investigated. IgE mediated reactions, homologous passive cutaneous anaphylaxis (PCA), degranulation of mast cells, and the release of histamine from sensitized lung tissues classified as the type I reaction by Coombs and Gell were not affected by CCAq. Complement dependent reactions including reversed cutaneous anaphylaxis (RCA), Forssman cutaneous vasculitis (FCV), and nephrotoxic serum (NTS) nephritis classified as type II and the Arthus reaction classified as type III were clearly inhibited by CCAq. However, CCAq did not affect the nephritis caused by the F(ab')₂ portion of the nephrotoxic IgG antibody. CCAq in a high concentration inhibited the immunological hemolysis, chemotactic migration of neutrophils in response to complement activated serum, and the generation of chemotactic factors. The type IV reaction, contact dermatitis, was not affected by CCAq. The production of hemolytic plaque forming cells was slightly inhibited by CCAq. These results suggest that CCAq has an anticomplement action and inhibits the complement dependent allergic reaction.

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Effect of the aqueous extract of Cinnamomum Cassia (CCAq) on experimental glomerulonephritis was studied and compared with that of cobra venom factor (CoVF). In rat nephrotoxic serum (NTS) nephritis, CCAq clearly inhibited the excretion of protein into the urine and the increase of peripheral leucocyte counts. The histological score in CCAq administered animals was significantly lower than that in control animals. However, CCAq did not inhibit or lower the serum complement level. Contrary to CCAq, hypocomplementation was observed by the administration of CoVF, and the excretion of protein into urine was inhibited in a high dose group. In immune complex (IC) and autologous IC nephritis in rats, CCAq clearly inhibited the excretion of protein into urine and the elevation of blood urea nitrogen (BUN). The administration of CoVF caused hypocomplementation, but little inhibition of the excretion of urinary protein was observed in both types of immune complex nephritis. The histological score was slightly inhibited by a low dose of CCAq and a high dose of CoVF. In the experiment employing NZB/NZW F₁ mice, the proteinurea, the elevation of BUN level, and the production of antibodies were clearly inhibited by the administration of CCAq. Similar inhibition was observed by CoVF at a high dose. However, the histological changes of the kidney in NZB/NZW F₁ mice were not prevented by the administration of CCAq or CoVF.

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Liver 9, 000×g supernatants from guinea pigs, rabbits, and dogs could catalyze the oxidation of both sulindac sulfide and sulindac, whereas those from mice and rats could catalyze only the oxidation of sulindac sulfide. In guinea pigs, the sulindac sulfide oxidase activity was detected in the 9, 000×g supernatants of kidney and lung as well as liver, whereas the sulindac oxidase activity was detected only in the liver preparation. In addition, the former activity was located in both liver microsomal and cytosolic fractions, whereas the latter activity was located only in the microsomal fraction. Both sulindac sulfide and sulindac oxidase activities of guinea pig liver microsomes were inhibited by SKF 525-A, N-ethylmaleimide, and potassium cyanide. However, carbon monoxide inhibited only the oxidation of sulindac. The microsomal sulindac oxidase activity was enhanced 4-fold by 3-methylcholanthrene treatment.

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The excretory response of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) to acute saline load was compared to that of control Wistar Kyoto rats (WKY) in pre- and early-hypertensive phases. In each of the 3 groups, half of the animals was fed a low salt diet, and the other half a normal diet. At the prehypertensive phase, sodium and water excretion and sodium-potassium ratio in the urine in SHR and SHRSP fed a normal diet were significantly less than those in WKY. The ability of SHR to excrete sodium and water, however, was improved by the elevation of blood pressure that developed between 7 and 10 weeks after their birth. While young SHR fed a normal diet had a reduced ability to excrete sodium, the young SHR fed a sodium-restricted diet did not. Salt restriction significantly delayed the appearance of high blood pressure in both SHR and SHRSP. These results suggest that in both SHR and SHRSP, an elevation of blood pressure is important to compensate for the reduced ability to excrete sodium and water.

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In order to elucidate the role of central monoamines in muricide of the rat, the effects of electrical stimulation of the locus coeruleus (LC) were investigated on two types of muricide induced by olfactory bulbectomy (OB rats) and midbrain raphe lesions (raphe rats). Muricide was inhibited in 71.4% of the OB rats by bilateral LC stimulation and in 26.7% by unilateral stimulation. Even in the rat in which muricide was not inhibited following LC stimulation, muricide was almost invariably suppressed by LC stimulation after pretreatment with pargyline. The antimuricidal effect of LC stimulation was partially blocked by administration of propranolol, but not by phenoxybenzamine. In contrast, muricide was inhibited by bilateral LC stimulation in 44.4% of the raphe rats, but this effect was not potentiated by pretreatment with pargyline. On the other hand, muricide was not significantly inhibited by either dorsal raphe or medial raphe stimulation in any OB rats. These results suggest that noradrenaline plays a more important role in inhibiting muricide in OB rats than in raphe rats.

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In spontaneously hypertensive rats, the ¹⁴C-deoxy-D-glucose method was applied to examine the response of glucose utilization rate (GUR), as a measure of the neuronal activity, of 102 cerebral nuclei to the equivalent fall in blood pressure by about 50 mmHg after the treatment with hydralazine, clonidine, and α-methyldopa. All drugs significantly increased GUR in the dorsal medullary nuclei, whereas the drugs decreased it in the n. tegmenti ventralis, substantia reticularis mesencephali, some hypothalamic periventricular nuclei, amygdala nuclei, and n. accumbens septi. Hydralazine (but not other drugs) decreased GUR in the n. parabrachialis ventralis, n. centromedianus, n. reticularis medialis and n. suprachiasmaticus. Clonidine alone increased GUR in medullary reticular nuclei and decreased it in the infundibulum, n. proprius striae terminalis and cortex entorhinalis. aMethyldopa (but not other drugs) increased GUR in the n. reticularis parvocellularis and decreased it in the n. ambiguus, n. ventromedialis, area lateralis and anterior hypothalami, area preoptica medialis and n. medialis septi. Both clonidine and α-methyldopa (but not hydralazine ) increased GUR in the n. reticularis thalami and decreased it in the substantia nigra pars compacta and grisea centralis, n. paramedianus, neuroendocrine hypothalamic nuclei, Forel H, and n. lateralis and intermedium septi. Clonidine and α-methyldopa did not alter GUR in some suprabulbar nuclei responsive to hydralazine. Thus, the non-traumatic deoxyglucose method could be applied successfully to identify cerebral acting sites of clonidine, α-methyldopa and hydralazine in SHR.

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Single neuronal activity has been recorded extra-cellularly from the nucleus amygdaloideus centralis (pars lateralis) (Acl), the nucleus amygdaloideus centralis (pars medialis) (Acm), the nucleus amygdaloideus basalis (pars magnocellularis) (Abm), the nucleus amygdaloideus lateralis (AI), and the nucleus amygdaloideus basalis (pars parvocellularis) (Abp). The majority of the Acl, Acm, and Abm neurons were excited by nociceptive stimulation such as pinching the skin with serrated forceps and/or intraarterial injection of bradykinin. The nociceptive neurons were also driven by non-nociceptive stimulation such as tapping of deep tissues and bending hairs with an air-puff. Their receptive fields were large. After the intravenous administration of morphine, all nociceptive neurons became unresponsive to nociceptive stimuli, although they were driven by nonnociceptive stimuli. Intravenous naloxone antagonized the antinociceptive action of morphine. This suggests that morphine has selective and inhibitory effects on impulse transmission to these nociceptive neurons, and the amygdala, especially the Acl, Acm, and Abm, plays an important role in central nociceptive processing.

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Regulation of the supersensitivity and subsensitivity of the alpha adrenergic (α-Ad) system of rat vas deferens cultured under various experimental conditions was investigated. Muscles cultured for 3 days in normal medium (Eagle's MEM) exhibited marked increase in maximal contraction to noradrenaline (NA) and high K⁺ (154 mM), while muscles cultured with NA (100 μM) were subsensitive to the stimulants. Studies on the binding of ³H-WB4101, an α-Ad antagonist, to the homogenates of normal, supersensitive and subsensitive muscles revealed that the changes in NA-sensitivity were not accompanied by changes in the number or affinity of α-Ad receptors in the muscles. The effect of NA in decreasing NA-sensitivity was depressed by an inhibitor of protein synthesis, puromycin or cycloheximide. These results suggest that NA may be important in regulation of the contraction, at least in part through protein synthesis, without affecting the number or affinity of α-Ad receptors.

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Specific bindings of ³H-TRH to rat pituitary homogenate and apparent affinities of TRH analogs for binding sites were studied. The dissociation constant for ³H-TRH binding to rat pituitary homogenate was 30 nM at 0°C, and the number of the binding sites was 120 fmoles/mg protein. The apparent affinities of TRH analogs for the binding sites, which were estimated from the ability to displace ³H-TRH from those binding sites, were found to correlate well with their TSH releasing activities. These findings support the idea that the TSH releasing activities of TRH analogs depend almost entirely upon their binding abilities to the TRH receptor in the pituitary.

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Effects of divalent cations and solubilization with Lubrol-PX were studied on guanine nucleotide regulation of synaptosomal adenylate cyclase activity of the rat caudate nucleus. In the presence of Mg²⁺, both GTP and Gpp(NH)p exerted biphasic actions on the membrane-bound adenylate cyclase activity. The K_0.5 value for the GTP stimulation of the cyclase was 47 nM, and the value for the GTP inhibition was 4.5 μM. One hundred μM dopamine selectively enhanced the stimulatory phase of the GTP action, whereas 10μM morphine selectively enhanced the inhibitory phase of the GTP action. When Mg²⁺ was replaced by Mn²⁺, the inhibition of the membrane-bound adenylate cyclase by these nucleotides and morphine was completely abolished; but the catalytic activity of adenylate cyclase was not impaired. These results suggest that the inhibitory action of GTP is responsible for the morphine inhibition of synaptosomal adenylate cyclase. Lubrol-solubilized adenylate cyclase prefered Mn²⁺ to Mg²⁺ for its activity. The stimulation of adenylate cyciase by either GTP or Gpp (NH)p was eliminated in the Sepharose 6B-fractionated solubilized preparation in the presence of either Mg²⁺ or Mn²⁺. Ten mM NaF also failed to activate the fractionated adenylate cyclase. In the fractionated solubilized preparation, GTP and Gpp(NH)p failed to inhibit adenylate cyclase. These results indicate that GTP and Gpp(NH)p are unable to inhibit the resolved catalytic unit of the synaptosomal adenylate cyclase.

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The present study deals with the effects of nicotinamide and insulin on glycosylated hemoglobin (HbA₁) and blood glucose in thyroidectomized streptozotocin (STZ)-diabetic male rats. Nicotinamide (500 mg/kg body wt., i.p.) significantly decreased the levels of HbA₁ and blood glucose in both STZ-treated (65 mg/kg body wt., i.v.) intact and STZ-treated thyroidectomized animals. Administration of NPH-insulin recovered hyperglycemia, and the increased HbA₁ in thyroidectomized STZ-diabetic rats to control levels.

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Effects of various anti-inflammatory drugs on triple vaccineinduced pleurisy, a model of delayed hypersensitivity, were examined and compared with those on carrageenin-induced pleurisy in rats. Steroidal drugs depressed markedly the volume of exudate and the number of leucocytes in both types of pleurisy. Gold compounds also depressed both types of pleurisy. Non-steroidal anti-inflammatory drugs were apt to show depressive effects on carrageenin-induced pleurisy, especially on increased exudate volume. BW755C produced a depressive effect on carrageenin-induced pleurisy, but on triple vaccine-induced pleurisy, BW755C produced only a slight depressive effect. Cyproheptadine produced a slight depressive effect on carrageenin-induced pleurisy, but not on triple vaccine-induced pleurisy. Promethazine had a slight depressive effect on both types of pleurisy. D-penicillamine and levamisole did not show any depressive effects on triple vaccine-induced pleurisy. The results show that reported mediators in carrageenin-induced pleurisy (prostaglandin, serotonin, leukotriene B, etc.) are not relevant to triple vaccine-induced pleurisy. Specific lymphokines and/or degradated products of complement may participate in the latter. This triple vaccineinduced pleurisy seems to be a good model for screening non-steroidal antiinflammatory drugs which have steroidal-like activity.

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