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Biomedical subjects

K Fujibayashi

Publications and source records attributed to K Fujibayashi.

At least 19 recordsLinked to original sources
PubMed2000

Crucial role of insulin in leptin maintenance: profound decrease in serum leptin by octreotide acetate in insulinoma subjects.

To further clarify the relationship between insulin and leptin, time course changes in plasma glucose, serum insulin and leptin levels were analyzed after subcutaneous administration of 100 microg octreotide acetate in two insulinoma subjects. Octreotide acetate induced a prompt decrease in serum insulin level, accompanied with an increase in plasma glucose in both patients. Following the decrease in serum insulin level, serum leptin concentrations were profoundly decreased by 66% and 44%, 8-12 hrs after octreotide injection; that is, the concentrations decreased from 41.1 to 13.8 ng/ml in patient 1, and from 17.5 to 9.8 ng/ml in patient 2. Daily profiles of plasma glucose, serum insulin and leptin without octreotide administration did not show such alterations in these indexes in patient 1. These data show that circulating leptin may be susceptible to decline dependent on the decrease in serum insulin, suggesting that insulin plays a crucial role in the maintenance of leptin secretion in humans.

Blood Glucose↗
PubMed1999

Serum levels of leptin and changes during the course of recovery from diabetic ketoacidosis.

Secretion of leptin, the obese gene product, is stimulated by insulin and glucocorticoids and reduced by fasting. In subjects with diabetic ketoacidosis (DKA), severe insulinopenia and prolonged fasting might cause a decrease in serum leptin levels, and subsequent insulin therapy would reverse the decrease. Otherwise, some other confounding factors, neither insulin nor fasting, might affect serum leptin levels in patients with DKA. The present study was undertaken to address these issues. Eleven patients with type 1 diabetes mellitus (seven males and four females, aged 44+/-6 years, mean +/- SEM), admitted to Jichi Medical School Hospital presenting DKA, were studied during the therapeutic period. Thirty-five sex-, age- and body mass index-matched healthy subjects served as controls. Serum leptin levels at the hospitalization were significantly greater than those of the matched control subjects (5.5+/-1.0 vs. 3.2+/-0.3 microg/l, P < 0.01). After the start of therapy with a small dose of short-acting insulin and a large volume of fluid infusion, serum leptin concentrations further increased to 10.6+/-3.6 microg/l at 24 h, and thereafter the concentrations gradually decreased and normalized at the discharge (3.3+/-0.7 microg/l, day 24+/-4). The peak levels at 24 h were significantly higher than the levels at the discharge (P < 0.05), and also +77+/-34% higher than those at the hospitalization (P < 0.005). Serum cortisol levels (1830+/-200 nmol/l) were markedly elevated at hospitalization. These results indicate that serum leptin levels are increased even under insulinopenia and fasting in the patients with DKA. Such a finding may be associated with marked hyperglycemia or enhanced secretion of glucocorticoid hormone, although the exact mechanisms remain to be elucidated. We speculate that leptin may serve as a stress peptide in DKA, but further analysis is necessary to explore a physiological role of leptin in DKA.

Adolescent↗
PubMed1999

Pharmacological characterization of capsaicin-induced body movement of neonatal rat.

In neonatal rats, nociceptive responses induced by capsaicin were characterized pharmacologically. Capsaicin, injected subcutaneously (s.c.), induced body movement including scratching and struggling responses, and the responses were quantified by using a device composed of an audio speaker as a detector. The capsaicin-induced body movement was inhibited by a tachykinin NK1-receptor antagonist RP-67580 with an ID50 value of 3.5 mg/kg, s.c. Opioid analgesics, morphine, buprenorphine and pentazocine, also inhibited the body movement with ID50 values of 0.085, 0.0079 and 0.92 (mg/kg, s.c.), respectively. Non-steroidal anti-inflammatory drugs, indomethacin, ibuprofen and acetaminophen, did not exert any effect on the capsaicin-induced body movement. Neither the sedative diazepam nor the sedative chlorpromazine inhibited the body movement. It is concluded that the capsaicin-induced body movement in neonatal rats, which is considered to be nociceptive responses mediated by substance P, is sensitive to centrally acting analgesics with micro-opioid receptor agonist activity.

Animals↗
PubMed1999

Antinociceptive effect and enzymatic degradation of endomorphin-1 in newborn rat spinal cord.

Recently discovered endomorphin-1 and -2 are the first endogenous agonists selective for the mu-opioid receptor. We examined the antinociceptive effect and enzymatic degradation of endomorphin-1 in the newborn rat spinal cord. Endomorphin-1 inhibited the binding of [3H][D-Ala2, N-Me-Phe4, Gly-ol5] enkephalin (DAMGO) to the membrane fraction of the newborn rat spinal cord as potently as DAMGO and morphine. Endomorphin-1 at 1-1,000 nM reduced the slow ventral root potential, which reflects noxious transmission in the isolated newborn rat spinal cord, concentration-dependently via the mu-opioid receptor. A similar effect was observed with endomorphin-2. The newborn rat spinal cord homogenate degraded endomorphin-1 in a 120-min incubation procedure, while it degraded [Leu5]enkephalin even in a 30-min incubation procedure. The degradation of endomorphin-1 was inhibited by actinonin but not by thiorphan. These results showed that in the newborn rat spinal cord, endomorphins had high affinity for the mu-opioid receptor and exerted mu-opioid-receptor-mediated inhibitory effects on noxious responses. Endomorphin-1 was degraded by peptidases, but slowly compared with [Leu5]enkephalin degradation, and the degrading enzymes were actinonin-sensitive peptidases.

Animals↗
PubMed1999

Immunologically-related or incidental coexistence of diabetes mellitus and Graves' disease; discrimination by anti-GAD antibody measurement.

Coexistence of diabetes mellitus and Graves' disease may be classified into either an immunologically-related or an incidental phenomenon. It has been reported that anti-GAD antibody (GAD-Ab) persists at high levels for longer duration in subjects with type 1 diabetes and Graves' disease, whereas the prevalence of positive GAD-Ab (1.5%) in 131 non-diabetic subjects with Graves' disease was comparable to that in normal subjects (0.3%, P=0.2012). Thus, GAD-Ab might be a marker of the immunologically-related coexistence of the two diseases. To test this hypothesis, we investigated characteristics of Japanese subjects having both diseases according to the presence or absence of GAD-Ab. Sixty-one patients having diabetes mellitus and Graves' disease (24 men, 37 women, aged 53+/-2 years old, mean +/- SE) were consecutively registered between 1993-1997. The patients were divided into two groups of 14 GAD-Ab positive and 47 negative subjects. In the GAD-Ab positive subjects, earlier (32+/-3 years old) and abrupt onset (86%) of diabetes and insulin dependency (64%) were documented, as would be expected from the features of type 1 diabetes. Graves' disease often preceded diabetes (57%), presenting typical manifestations (79%). In contrast, older (45+/-2 years old, P=0.0031) and gradual onset (87%, P<0.0001) of diabetes, non-insulin dependency (74%, P<0.0001), and masked manifestations of Graves' disease (57%, P=0.0214) were common in the negative subjects. Precedence of diabetes dominated in these subjects (43%, P=0.0109). Immunological studies showed less frequent HLA-DR 2 locus (0%, P<0.02) in the GAD-Ab positive subjects. There was also a trend of higher frequency of HLA-DQA1*03 allele and of lower frequency of DQA1*01 allele in these subjects. Allelic frequency of cytotoxic T lymphocyte antigen 4 (CTLA-4) differed between the positive and negative subjects (P=0.0432). There were distinct clinical and immunological differences between the GAD-Ab positive and negative subjects having both diabetes mellitus and Graves' disease. The present results indicate that GAD-Ab measurement could draw a distinction between the immunologically-related and incidental coexistence of the two diseases.

Abatacept↗
PubMed1998

Enhancing effect of dimethyl sulfoxide on nociceptive transmission in isolated spinal cord of newborn rat.

The effect of dimethyl sulfoxide (DMSO) on the slow ventral root potential, which is related to nociceptive transmission, was investigated in the isolated spinal cord of a newborn rat. DMSO at 0.3-1% (v/v) enhanced the slow ventral root potential, but not mono- and polysynaptic reflex discharges. DMSO at 1% also enhanced the depolarization induced by substance P or capsaicin. In the presence of tetrodotoxin (0.3 microM), DMSO at 1% did not influence the substance P-induced depolarization but enhanced the acetylcholine-induced depolarization. Edrophonium at 10 microM also enhanced the slow ventral root potential, and the magnitude of the effect was comparable to that of 1% DMSO. In the presence of atropine (0.3 microM) and hexamethonium (30 microM), the effect of edrophonium disappeared, but half of the effect of DMSO remained. Artificial cerebrospinal fluid containing either 0.87% (w/v) urea or 4.6% (w/v) sucrose, which has the same osmotic pressure as that containing 1% DMSO, did not have the same effect as DMSO on the slow ventral root potential. In the saphenous nerve-dorsal root preparation, the compound action potential was enhanced by 4-aminopyridine (10 microM), but was not affected by DMSO up to 3%. The results suggest that DMSO enhances the slow ventral root potential through mechanisms based on the inhibition of cholinesterase activity and other action(s) involved in increasing transmitter release from nerve endings in nociceptive transmission pathways in the isolated spinal cord of the newborn rat. Neither the blockade of K+ channels nor hyperosmotic effects are likely mechanisms of DMSO action.

Animals↗
PubMed1998

Effects of R-84760, a selective kappa-opioid receptor agonist, on nociceptive reflex in isolated neonatal rat spinal cord.

We tested the effects of (3 R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbony l]-2,3,5,6-tetrahydro-1,4-thiazine hydrochloride (R-84760), a selective kappa-opioid receptor agonist, on the slow ventral root potential in the isolated spinal cord of neonatal rats. R-84760 at 10 nM decreased the slow ventral root potential to 35% of the control, leaving the monosynaptic reflex unaffected. The depressant effect of R-84760 progressed slowly for 60 min to the maximum and recovered slightly after removal of the drug from the perfusing solution. This contrasts with [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAMGO) or [MeTyr1, MeArg7, D-Leu-NHEt8]dynorphin A-(1-8) (E-2078) which attained their maximum depressant effect within 15 min with recovery immediately after washout. Reversibility of the R-84760 effect was observed in vivo in antinociceptive tests in mice. R-84760 reduced the depolarization induced by substance P or L-glutamate in the normal solution, but not in the presence of tetrodotoxin at 0.3 microM. Naloxone inhibited the effect of R-84760 at a higher concentration (1 microM) than that (0.1 microM) needed to antagonize the effect of DAMGO. In contrast, R-84760 was more sensitive to nor-binaltorphimine than was DAMGO. The results show that R-84760 selectively inhibits the nociceptive response presynaptically through kappa-opioid receptors and that the inhibitory effect is characteristic, with long duration, in the neonatal rat spinal cord.

Analgesics↗
PubMed1998

A novel method for detecting the analgesic effect of drugs by quantifying body movement after noxious stimulation in neonatal rat.

We developed a method for quantifying nociceptive struggling in neonatal rats induced by bolus, subcutaneous injection of capsaicin (3-3000 ng). The response was quantified by using an audio speaker and electrical instruments such as an amplifier, a rectifier, and a monostable multivibrator. Using this method, we were able to quantify the nociceptive response which appeared immediately after injection of capsaicin. The response peaked at 0-1 min, and then decayed during next 1-3 min. Furthermore, this method also detected that the magnitude of the response increased dose-dependently up to the maximum dose of 3000 ng. In an experiment testing the suitability of this method for screening analgesics, it was shown that morphine (0.03-0.3 mg/kg, s.c.) inhibited the response dose-dependently with an ID50 value of 0.089 mg/kg and that the analgesic effect of morphine (1 mg/kg, s.c.) was reversed by naloxone (0.03-0.1 mg/kg, s.c.). Thus it can be concluded that this method is useful to quantify the capsaicin-induced nociceptive response and is suitable for screening analgesics.

Analgesics↗
PubMed1995

Profiles of the antinociceptive effect of R-84760, a selective kappa-opioid receptor agonist, in the formalin test in mice.

The antinociceptive effect of a selective kappa-opioid receptor agonist R-84760, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride, in the second phase of the formalin test, a model of tonic pain, was examined in mice. R-84760 had a 2700 times more potent antinociceptive effect than morphine. The effect of R-84760 was antagonized by subcutaneously administered nor-binaltorphimine, a kappa-selective opioid receptor antagonist. Both intracerebroventricularly and intrathecally administered nor-binaltorphimine partially antagonized the antinociceptive effect of R-84760. Intrathecally administered phentolamine, an alpha-adrenoceptor antagonist, attenuated and desipramine, a noradrenaline reuptake inhibitor, augmented the antinociceptive effect of R-84760. Intrathecally administered noradrenaline attenuated the nociceptive response in the second phase of the formalin test. Intrathecally administered (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), an N-methyl-D-aspartate (NMDA)-receptor antagonist, reduced and threo-beta-hydroxyaspartate, a reuptake inhibitor of glutamate, augmented the second phase nociceptive response. However, R-84760 did not influence the intrathecally injected NMDA-induced nociceptive response. These results suggest the following: R-84760 produces an extremely potent antinociceptive effect against tonic pain through the kappa-opioid receptors; the sites of action of subcutaneously administered R-84760 are the supraspinal and spinal loci in the central nervous system; and a part of the mechanism of the antinociceptive effect of R-84760 is activation of the descending noradrenergic pathway.

Analgesics↗
PubMed1994

Pharmacological properties of R-84760, a novel kappa-opioid receptor agonist.

The pharmacological properties of a structurally novel kappa-opioid receptor agonist, (3R)-3-(1-pyrrolidinylmethyl)-4-[(1S)-5,6-dichloro-1-indancarbo nyl]- tetrahydro-1,4-thiazine hydrochloride (R-84760), were examined. In an opioid receptor binding assay with a guinea pig brain membrane fraction, R-84760 showed a 5 times higher affinity for the kappa-opioid receptor than CI-977, the most potent reference kappa-opioid receptor agonist, and selectivity of R-84760 for the kappa-opioid receptor was higher than that of U-69593, a highly selective kappa-opioid receptor agonist. R-84760 was functionally 2.5 times more potent than CI-977 as a kappa-opioid receptor agonist in rabbit vas deferens. Subcutaneously administered R-84760 had an antinociceptive effect in the phenylquinone writhing test in mice and its potency was 5-846 times higher than those of CI-977, U-50488, morphine, pentazocine and butorphanol. On oral administration, R-84760 was 20-2077 times more potent than the same reference drugs. The antinociceptive effect of R-84760 was not antagonized by naloxone in a dose at which naloxone antagonized the effect of morphine, but on the other hand nor-binaltorphimine antagonized the effect of R-84760 at a dose which did not affect the effect of morphine. R-84760 and the reference kappa-opioid receptor agonists produced sedative and diuretic effects in mice with the same order of potency as for the antinociceptive effect. Tolerance to the antinociceptive effect of R-84760 barely developed, and naloxone-induced jumping tests for morphine-like physical dependence of R-84760 gave negative results.

Amino Acid Sequence↗
PubMed1988

Effect of flunarizine on experimentally induced facial nerve injury.

The effect of flunarizine, a calcium antagonist, on experimentally induced facial nerve injury in guinea pigs was studied electron microscopically. In flunarizine-untreated animals, intra-axonal accumulation of cell organelles and degradation of myelin sheaths were observed. In flunarizine-treated animals, these changes were not observed, but a knob-like protrusion of myelin sheaths and a structure resembling the myelin sheath in Schwann cell cytoplasm was occasionally observed.

Animals↗
PubMed1983

Comparison of analgesic potencies of mu, delta and kappa agonists locally applied to various CNS regions relevant to analgesia in rats.

Analgesic potencies of relatively selective agonists for mu, delta and kappa subtypes of opioid receptors, morphine, [D-Ala2,D-Leu5]-enkephalin (DADL) and ethylketocyclazocine (EKC), respectively, were examined with the tail-pinch test in the rat, when microinjected into the brain stem regions relevant to analgesia such as the nucleus reticularis paragigantocellularis (NRPG), nucleus raphe magnus (NRM) and periaqueductal gray matter (PAG), and into the lumbar subarachnoid space (LSS). Morphine, DADL and EKC produced dose-dependent analgesic effects at the NRPG, NRM, PAG and LSS. The ED50 values indicated that morphine was more potent than DADL at the NRPG and LSS but less at the NRM and PAG. EKC was the weakest at all the injection sites. Further, naloxone (0.1 mg/kg, s.c.) significantly antagonized the analgesic effect of morphine but not that of DADL or EKC at the NRPG. These findings suggest that mu, delta and kappa subtypes of opioid receptors mediate analgesia, and that the extent of contribution of each subtype to the production of analgesia differs among the CNS sites examined in this study.

Analgesics, Opioid↗