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S Sakurada

Publications and source records attributed to S Sakurada.

At least 19 recordsLinked to original sources
PubMed2003

Involvement of adenosine A1 receptors in forced walking stress-induced analgesia in mice.

We investigated the involvement of adenosine receptors on forced walking stress-induced analgesia using a formalin-induced paw-licking test in male mice. Exposure to forced walking stress for 6 h showed stress-induced analgesia in the second phase (10-30 min), but not in the first phase (0-10 min). In the second phase, forced walking stress-induced analgesia was blocked by theophylline, a nonselective adenosine-receptor antagonist and DPCPX, an adenosine A1-receptor antagonist, but not ZM 241385, an adenosine A2A-receptor antagonist. These findings suggest that adenosine A1 receptors are involved in the analgesic mechanism activated by the forced walking stress.

Adenosine A1 Receptor Antagonists↗
PubMed2001

Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse.

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Analgesics↗
PubMed2001

Subtype-specific, differential activities of the EDG family receptors for sphingosine-1-phosphate, a novel lysophospholipid mediator.

The lysosphingolipid sphingosine-1-phosphate (S1P) and the structurally related lipid lysophosphatidic acid (LPA) elicit a wide spectrum of biological responses in a variety of cell types, including mitogenesis, cell-shape changes, migration and contraction. Recent studies have unveiled the existence of the G protein-coupled heptahelical receptor subfamily for the biologically active lysophospholipids, which consists of the two receptor subgroups specific for S1P and LPA, respectively. The S1P receptor subgroup comprises four members, i.e. EDG-1, EDG-3, EDG-5/AGR16 and EDG-6, with considerable amino acid similarity among them. The S1P receptor subtypes are coupled to different heterotrimeric G proteins, leading to the activation of a unique set of multiple intracellular signaling pathways. The expression of transcripts of the S1P receptor subtypes is wide-spread, except for EDG-6 which exhibits lymphoid tissue-specific expression. Plasma contains substantial concentrations of S1P as well as LPA. Activated platelets appear to be a major source of S1P and LPA in blood. In addition, accumulating evidence demonstrates that S1P and LPA are released from a variety of cell types in response to various extracellular stimuli. These observations demonstrate the existence of the novel signaling system comprising the lysosphingolipids and their cognate receptors, suggesting physiological and pathological roles.

Animals↗
PubMed2001

Ambient temperatures preferred by humans acclimated to heat given at a fixed daily time.

We investigated preferred ambient temperatures (T(pref)) of heat-acclimated humans to assess their behavioral thermoregulation. Seven male volunteers were exposed to an ambient temperature (T(a)) of 42 degrees C and relative humidity (RH) of 40% for 4 h (14:00-18:00 h)/day for 9-10 consecutive days. Rectal temperature (T(re)) was measured, and T(pref) was determined at two distinct times of day, 09:00-11:00 h (AM test) and 14:00-16:00 h (PM test), in both heat- and nonheat-acclimated (control) conditions. Heat acclimation significantly decreased T(re) only in the PM test. There was no difference in the T(pref) between the two tests in the control condition. However, T(pref) in the PM test was significantly lower than that of the AM test in the heat-acclimated condition. The findings suggest that repeated heat exposure in humans for 4 h at a fixed time daily alters the core temperature level and behavioral thermoregulatory function, particularly during the period when the subjects had previously been exposed to heat.

Acclimatization↗
PubMed2001

Alpha 2-adrenoceptor antagonists: effects on ejaculation, penile erection and pelvic thrusting behavior in dogs.

We previously reported that systemic administration of yohimbine, an alpha2-adrenoceptor antagonist, exerts a biphasic effect (stimulating and suppressing) on ejaculation in dogs, when this function is analyzed using the amount of ejaculated semen in response to genital stimulation. To clarify the effect of alpha2-adrenoceptor blockade on male sexual function, we investigated the effects of four selective alpha2-adrenoceptor antagonists, rauwolscine, idazoxan, RX821002 and mydaglizole, on sexual responses (ejaculation, penile erection and pelvic thrusting behavior) elicited by manual penile stimulation in dogs. Rauwolscine (intraperitoneal, 30 min before the testing) caused a biphasic effect on ejaculation; the amount of ejaculated semen produced by the stimulation was significantly increased by the lower doses (0.1 and 0.3 mg/kg), whereas it was decreased by the higher doses (1.0 and 2.0 mg/kg). The higher doses of rauwolscine also markedly inhibited both penile erection and pelvic thrusting behavior. Idazoxan and RX821002, at doses of 0.1 and 0.3 mg/kg, caused a significant increase in the amount of ejaculated semen without affecting other sexual functions. RX821002 (2.0 mg/kg), but not idazoxan (2.0 mg/kg), moderately inhibited both penile erection and pelvic thrusting behavior. Mydaglizole, a peripherally acting alpha2-adrenoceptor antagonist, did not affect the sexual responses at any doses (0.1-4.0 mg/kg). In the ejaculatory declining test, all alpha2-adrenoceptor antagonists (0.1 mg/kg), except for mydaglizole, completely prevented the decrease in ejaculatory capacity produced by antecedent ejaculation. These results indicate that, though the range of the effective dose is narrow, the alpha2-adrenoceptor antagonists that can block the central alpha2-adrenoceptors have the stimulatory effects on ejaculatory function. The difference of the sexual effects may be based on the action except for the alpha2-adrenoceptor blockade.

Adrenergic Antagonists↗
PubMed2001

Antinociceptive effect of spinally injected L-NAME on the acute nociceptive response induced by low concentrations of formalin.

The formalin test has been proposed as an animal model of pain produced by tissue injury. Although biphasic nociceptive responses to formalin injection have been well documented, low concentrations (0.125 and 0.5%) of formalin injected into the mouse hindpaw produced only the phasic (acute) paw-licking response, lasting the first 5 min after the formalin injection. To explore the involvement of nitric oxide (NO) in the spinal cord and peripheral system during the acute phase of the formalin test, we examined the effect of intrathecal (i.t.) or intraplantar (i.pl.) injection of L-N(G)-nitro arginine methyl ester (L-NAME), a NO synthase inhibitor in mice. Pretreatment with L-NAME (160 nmol), injected i.t., resulted in a significant inhibition of the paw-licking response induced by 0.125 and 0.5% of formalin. L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the antinociceptive effect of L-NAME on the acute nociceptive response induced by low concentrations of formalin. The i.pl. injection of L-NAME (160 nmol) produced a significant decrease of the late (tonic) phase response evoked by 2.0% formalin without affecting the early (acute) phase response. Similar results have been reported in the case of i.t. injected L-NAME as assayed by the 2.0% formalin test. L-NAME (160 nmol), injected into the plantar paw, gave no significant effect on the acute nociceptive response induced by a low concentration of formalin (0.125%). These results suggest that NO in the spinal cord may be involved in not only the late phase response of the formalin (2.0%)-induced paw-licking, but also at least the acute phase response induced by low concentrations (0.125 and 0.5%) of formalin, while peripheral NO has little effect on the early (acute) phase nociceptive response evoked by formalin (0.125--2.0%) injection.

Analgesics↗
PubMed2001

Enzymatic determination of acetylcarnitine for diagnostic applications.

An enzymatic method was proposed for determination of acetylcarnitine (AcCar), even when carnitine (Car), non-acetylated form, co-exists. The method is consisted of four enzymatic reactions: First, AcCar is hydrolysed by acylcarnitine hydrolase to yield acetate; followed by the other three reactions coupled with three enzymes, respectively, acetate kinase, pyruvate kinase and lactate dehydrogenase; finally, the acetate formation causes a decrease in NADH. The amount of AcCar is then evaluated as the change in absorbance at 340 nm. The reagent composition of the reaction mixture was determined, and the characteristics of the method were investigated. The dilution test showed a good linearity over a wide range. The precision and accuracy tests produced satisfactory results. The co-existence of Car gave no effect on the measurement. The present method was found to be used easily, simply and rapidly for the selective determination of AcCar.

Acetylcarnitine↗
PubMed2001

Structure-antinociceptive activity studies of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis.

Incarvillateine (1), a new monoterpene alkaloid carrying a characteristic cyclobutane ring, has been found to show significant antinociceptive activity in a formalin-induced pain model in mice. To investigate the correlation between its structure and antinociceptive activity, and especially to study whether a cyclobutane ring is necessary or not for expression of activity, we evaluated the antinociceptive activity of two constructive units of incarvillateine, such as a monoterpene unit (incarvilline, 3) and a phenylpropanoid unit (ferulic acid, 2) in the formalin test, and compared activity of the units with that of incarvillateine. Furthermore, in order to obtain more information about the structure-activity relationships, monoterpene alkaloid derivatives, such as incarvine C (5, a precursor of incarvillateine), incarvine A (4, an ester compound comprised of two monoterpene alkaloids and a monoterpene) and 3,3'-demethoxy-4,4'-dehydroxyincarvillateine (6, a synthetic new compound), were examined. The antinociceptive effect of 3,3'-demethoxy-4,4'-dehydroxyincarvillateine was equal to that of incarvillateine. Meanwhile, the other compounds exhibited no or weak activity. These results suggested that the cyclobutane moiety of incarvillateine plays an important role in expression of antinociceptive action.

Alkaloids↗
PubMed2001

Effective human herpesvirus 8 infection of human umbilical vein endothelial cells by cell-mediated transmission.

Cell-free transmission of human herpesvirus 8 (HHV-8) to human cells in vitro has been reported to be difficult, if not impossible. The present experiments were conducted with the idea that cell-cell contact may produce much more effective transmission, so-called cell-mediated transmission. Primary human umbilical vein endothelial cells (HUVECs) were cocultured with an HHV-8-infected lymphoma cell line, BCBL-1 cells. When a ratio of 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated BCBL-1 cells to HUVECs of 10:1 was used, more than 20% of HUVECs were found to express the HHV-8 latency-associated nuclear antigen (LANA) 48 h after the start of coculturing; this value increased to more than 30% after 72 h. HHV-8-encoded ORF26, K8, K8.1, K10, K11, ORF59, and ORF65 proteins were not detected in these HHV-8-infected HUVECs until 72 h. The HHV-8 antigens were not observed in HUVECs cocultured with TPA-treated BCBL-1 cells separated by a membrane. Thirty days after removal of the BCBL-1 cells from the cell-mediated transmission experiment, the HUVECs still expressed LANA and the HHV-8 genome was detected by PCR in these cells. Moreover, the ORF59 protein, a DNA replication-associated protein of HHV-8, was expressed in such HUVECs in the presence of TPA stimulation. These results indicated a far more effective transmission mechanism, cell-cell contact, suggesting the possibility that such a mechanism works in vivo.

Cell Communication↗
PubMed2001

Rho activation in excitatory agonist-stimulated vascular smooth muscle.

Small GTPase Rho and its downstream effector, Rho kinase, have been implicated in agonist-stimulated Ca(2+) sensitization of 20-kDa myosin light chain (MLC(20)) phosphorylation and contraction in smooth muscle. In the present study we demonstrated for the first time that excitatory receptor agonists induce increases in amounts of an active GTP-bound form of RhoA, GTP-RhoA, in rabbit aortic smooth muscle. Using a pull-down assay with a recombinant RhoA-binding protein, Rhotekin, we found that a thromboxane A(2) mimetic, U-46619, which induced a sustained contractile response, induced a sustained rise in the amount of GTP-RhoA in a dose-dependent manner with an EC(50) value similar to that for the contractile response. U-46619-induced RhoA activation was thromboxane A(2) receptor-mediated and reversible. Other agonists including norepinephrine, serotonin, histamine, and endothelin-1 (ET-1) also stimulated RhoA, albeit to lesser extents than U-46619. In contrast, ANG II and phorbol 12,13-dibutyrate failed to increase GTP-RhoA. The tyrosine kinase inhibitor genistein substantially inhibited RhoA activation by these agonists, except for ET-1. Thus excitatory agonists induce Rho activation in an agonist-specific manner, which is thought to contribute to stimulation of MLC(20) phosphorylation Ca(2+) sensitivity.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Age-related differences in forced walking stress-induced analgesia in mice.

We investigated the effects of aging on forced walking stress-induced analgesia using a formalin-induced paw licking test in male mice. Exposure to forced walking stress for 6 h showed forced walking stress-induced analgesia in all mice aged 4, 24 and 48 weeks in the second phase (10-30 min), but not in the first phase (0-10 min). In the second phase, the degree of stress-induced analgesia was age-dependent (4 > 24 > 48 weeks). LY-235959, a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, blocked forced walking stress-induced analgesia in mice aged 4 and 24 weeks, but not in those aged 48 weeks. Naloxone did not antagonize forced walking stress-induced analgesia in mice in any of the age groups. The present study suggests that the degree of forced walking stress-induced analgesia depends on the age of mice and confirms previous findings that forced walking stress-induced analgesia is involved in the nonopioid system via NMDA receptors.

Aging↗
PubMed2000

Characterization of p-chloroamphetamine-induced penile erection and ejaculation in anesthetized rats.

Methodological shortcomings present in elicitation of male sexual reflexes in anesthetized animals. The present study has demonstrated, however, that intraperitoneal (i.p.) injection of p-chloroamphetamine (PCA), an indirect serotonin (5-HT) agonist, elicited simultaneously both penile erection and ejaculation in anesthetized rats. PCA (2.5-10.0 mg/kg, i.p.) caused an intermittent cluster of genital responses consisting of penile erection, glans erections, and penile cups, which closely resembles the response observed during the ex copula tests in unanesthetized rats. Measurements of intracavernous penile pressure showed that rhythmic changes in penile pressure were produced by PCA, together with glans erections and penile cups. PCA also caused a frequent ejaculations and the weighing of ejaculate accumulated over 0.5 hr was increased in a bell-shaped pattern, and the maximum effect was observed at 5.0 mg/kg. Pretreatment with p-chlorophenylalanine, a serotonin (5-HT)-synthesis inhibitor, significantly inhibited the expression of PCA-induced penile erection and ejaculation, while acute spinal transection at thoracic level did not affect the sexual responses. These results indicate that PCA-induced penile erection and ejaculation in anesthetized rats are mainly produced by the release of 5-HT, which is limited to the lower spinal cord and/or the peripheral sites. Furthermore, the sexual responses can be easily and reliably elicited by administration of PCA, which may be useful for the study of the mechanisms underlying male sexual functions.

Animals↗
PubMed2000

Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone.

To determine the role of spinal mu-opioid receptor subtypes in antinociception induced by intrathecal (i.t.) injection of endomorphin-1 and -2, we assessed the effects of beta-funaltrexamine (a selective mu-opioid receptor antagonist) naloxonazine (a selective antagonist at the mu(1)-opioid receptor) and a novel receptor antagonist (3-methoxynaltrexone) using the paw-withdrawal test. Antinociception of i.t. endomorphins and [D-Ala(2), MePhe(4), Gly(ol)(5)]enkephalin (DAMGO) was completely reversed by pretreatment with beta-funaltrexamine (40 mg/kg s.c.). Pretreatment with a variety of doses of i.t. or s.c. naloxonazine 24 h before testing antagonized the antinociception of endomorphin-1, -2 and DAMGO. Judging from the ID(50) values of naloxonazine, the antinociceptive effect of endomorphin-2 was more sensitive to naloxonazine than that of endomorphin-1 or DAMGO. The selective morphine-6beta-glucuronide antagonist, 3-methoxynaltrexone, which blocked endomorphin-2-induced antinociception at each dose (0.25 mg/kg s.c. or 2.5 ng i.t.) that was inactive against DAMGO, did not affect endomorphin-1-induced antinociception but shifted the dose-response curve of endomorphin-2 3-fold to the right. These findings may be interpreted as indicative of the existence of a novel mu-opioid receptor subtype in spinal sites, where antinociception of morphine-6beta-glucuronide and endomorphin-2 are antagonized by 3-methoxynaltrexone. The present results suggest that endomorphin-1 and endomorphin-2 may produce antinociception through different subtypes of mu-opioid receptor.

Analgesics, Opioid↗
PubMed2000

Autonomic and behavioural thermoregulation in starved rats.

1. We investigated the mechanism of starvation-induced hypothermia in rats. 2. Threshold core temperatures (Tcor) for tail skin vasodilatation and cold-induced thermogenesis were determined after a 3 day starvation using a chronically implanted intravenous thermode. Food deprivation significantly lowered the threshold Tcor for heat production, but did not affect the heat loss threshold. 3. Thermogenic response to a fall in Tcor below its threshold was enhanced by starvation. 4. Preferred ambient temperatures (Tpref) and Tcor were measured before and during a 3 day starvation in a thermal gradient. The 3 day starvation significantly lowered Tcor only in the light phase of the day. The level of hypothermia was the same throughout the fasting period, while Tpref gradually increased during the 3 days of starvation. 5. When rats were starved at a constant ambient temperature of 25 C (no thermal gradient), their Tcor levels were comparable with those of the rats kept in the thermal gradient. 6. The results suggest that, in rats, hypothermia caused by starvation was not due to a decrement in thermogenic capability, but was due to a decrease in the threshold for the activation of thermogenesis.

Animals↗
PubMed2000

Selective antagonism by naloxonazine of antinociception by Tyr-D-Arg-Phe-beta-Ala, a novel dermorphin analogue with high affinity at mu-opioid receptors.

To examine the role of mu-opioid receptor subtypes, we assessed the antinociceptive effect of H-Tyr-D-Arg-Phe-beta-Ala-OH (TAPA), an analogue of dermorphin N-terminal peptide in mice, using the tail-flick test. Intracerebroventricularly (i.c.v.) or intrathecally (i.t.) injected TAPA produced potent antinociception with tail-flick as a thermal noxious stimulus. The selective mu(1)-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.), or the selective mu-opioid receptor antagonist, beta-funaltrexamine, 24 h before testing antagonized the antinociceptive effect of i.t. or i.c.v. TAPA on the response to noxious stimuli. Pretreatment with beta-funaltrexamine completely antagonized the antinociception by both i.c.v. and i.t. administered TAPA and [D-Ala(2), Me-Phe(4), Gly(ol)(5)]enkephalin (DAMGO). Especially in the tail-flick test, pretreatment with naloxonazine produced a marked rightward displacement of the i.t. TAPA dose-response curve for antinociception. Though DAMGO is a highly selective mu-opioid receptor agonist, pretreatment with naloxonazine partially blocked the antinociceptive response to DAMGO after i.c.v., but not after i. t. injection. These results indicate that TAPA can act as a highly selective mu(1)-opioid receptor agonist (notable naloxonazine-sensitive receptor agonist) at not only the supraspinal level, but also the spinal level. These data also reveal different antinociceptive mechanisms for DAMGO and for TAPA.

Analgesics↗
PubMed2000

Role of histamine H(1) receptor in pain perception: a study of the receptor gene knockout mice.

To study the participation of histamine H(1) receptors in pain perception, histamine H(1) receptor knockout mice were examined for pain threshold by means of three different kinds of nociceptive tasks. These included assays for thermal nociception (hot-plate, tail-flick, paw-withdrawal), mechanical nociception (tail-pressure), and chemical nociception (abdominal constriction, formalin test, capsaicin test) which evoked pain by the activation in nociceptive Adelta and C fibers. The mutant mice lacking histamine H(1) receptors showed significantly fewer nociceptive responses to the hot-plate, tail-flick, tail-pressure, paw-withdrawal, formalin, capsaicin, and abdominal constriction tests. Sensitivity to noxious stimuli in histamine H(1) receptor knockout mice significantly decreased when compared to wild-type mice. This data indicates that histamine plays an important role in both somatic and visceral pain perceptions through histamine H(1) receptors. The difference in the effect of histamine H(1) receptors antagonist, the active (D-) and inactive (L-) isomers of chlorpheniramine on ICR mice further substantiates the evidence of the role of histamine H(1) receptors on pain threshold.

Animals↗
PubMed2000

Evidence that N-terminal fragments of nociceptin modulate nociceptin-induced scratching, biting and licking in mice.

The intrathecal (i.t.) injection of 3.0 fmol nociceptin (orphanin FQ) elicited scratching, biting and licking responses in mice. N-terminal fragments of nociceptin, nociceptin (1-7), nociceptin (1-9) and nociceptin (1-13), induced no characteristic behavioral response. When these N-terminal fragments of nociceptin were injected simultaneously with nociceptin, the behavioral response induced by nociceptin was reduced dose-dependently. Nociceptin (1-13) was much more potent than nociceptin (1-7) and nociceptin (1-9) and antagonized nociceptin-induced response at equimolar doses. No significant effects of the N-terminal fragments were observed against the scratching, biting and licking response elicited by i.t. administration of substance P or N-methyl-D-aspartate. These results suggest that N-terminal fragments formed endogenously in the spinal cord may have an antagonistic effect on nociceptin-induced behavioral responses.

Animals↗