Biomedical subjects

H Kaneto

Publications and source records attributed to H Kaneto.

At least 91 records · Page 5Linked to original sources

PubMed1994

Amino acids and peptides. XXIV. Preparation and antinociceptive effect of [D-Ala2,(N-Me)Phe4]enkephalin analog-poly(ethylene glycol) hybrids.

Hybrids of amino-poly(ethylene glycol) (aPEG) and [D-Ala2,(N-Me)Phe4] enkephalin analogs, H-Tyr-D-Ala-Gly-(Me)Phe-aPEG, H-Tyr-D-Ala-Gly-(Me)Phe-Leu-aPEG and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-aPEG, were prepared by the solution method and their antinociceptive properties were examined in comparison with those of the peptides. H-Tyr-D-Ala-Gly-(Me)Phe-OH and H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH themselves at intracerebroventricular (i.c.v.) doses of 10-30 nmol/animal produced an antinociceptive effect which was less potent than that of i.c.v. morphine, 3 micrograms/animal, and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-OH did not have any marked effect. However, the antinociceptive effects of H-Tyr-D-Ala-Gly-(Me)Phe-Leu-OH and H-Tyr-D-Ala-Gly-(Me)Phe-D-Leu-OH were remarkably potentiated by hybrid formation with aPEG to levels higher than that of 3 micrograms/mouse of morphine, and the effect lasted at least 120 min. In contrast, the effect of H-Tyr-D-Ala-Gly-(Me)Phe-OH was rather diminished by hybrid formation. In view of the low toxicity and weak immunogenic properties of aPEG, the hybrids could be useful in therapy of patients for relieving chronic and severe pain.

Amino Acid Sequence↗

PubMed1994

Involvement of pain associated anxiety in the development of morphine tolerance in formalin treated mice.

The mechanism underlying the previous findings that the development of antinociceptive tolerance to morphine was significantly delayed in the presence of inflammatory pain induced by formalin was examined. Measurements of the pain threshold at different time intervals have shown that pain lasts around one week in the formalin treated mice. A single dose of indomethacin (10 mg/kg) or aspirin (400 mg/kg), 30 min before formalin injection, and daily 400 mg/kg of aspirin had no effects on the pain threshold or swelling, and it also did not affect the delay of morphine tolerance development. Daily administration of diazepam, 1 mg/kg, 1 hr before morphine injection completely abolished the delay. This effect was antagonized by 2 mg/kg of flumazenil, administered 15 min before diazepam injection. These results suggest that pain-associated anxiety participates in the delay of morphine tolerance development and consequently the benzodiazepine-receptor complex plays a role in the development of morphine tolerance during a painful state.

Animals↗

PubMed1994

Morphine dependence with or without tolerance in formalin-treated mice: further evidence for the dissociation.

Pain associated-anxiety induced by formalin, which resulted in a significant delay in the development of tolerance to morphine antinociception, failed to prevent the development of physical dependence as evidenced by naloxone challenge. Dependence also developed in mice rendered tolerant to morphine. Thus, the development of morphine dependence was observed in the absence and presence of tolerance to morphine antinociception; Our results further confirm the dissociation of opioid tolerance and dependence in the animal model of experimental pain/anxiety.

Analgesia↗

PubMed1994

Trends in physiological role of opioids in psychoneuroendocrine-immune network.

Extensive evidence suggests that opioid influences on the immune response are mediated through opioid receptors on the surface of immune cells. In addition, the binding of opioid agonists to centrally located opioid receptors appears also to alter immune activity through interactions with the neuroendocrine and the nervous systems. Finally, other findings summarized in this review provide evidence consistent with the hypothesis that under stressful stimuli, the immune system is altered through the interrelations among the neuroendocrine system, the sympathetic nervous system and central opioidergic pathways.

Animals↗

PubMed1993

Demonstration of a human urinary trypsin inhibitor (urinastatin)-like substance in the murine brain.

A human urinary trypsin inhibitor (urinastatin)-like immunoreactive substance with trypsin-inhibitory activities was found in the murine brain. Regional levels of this urinastatin (UT)-like substance in the brain were within 5 ng/mg protein and were expressed in a descending order as follows: cerebral cortex not equal to hippocampus > hypothalamus > mesencephalon not equal to corpus striatum >> medulla oblongata > cerebellum. Mechanical lesioning of the cerebral cortex or hippocampus with a needle induced a rapid and intense appearance of a UT-like immunoreactive substance in the neuronal cells of injured sites. Conditioned fear-stress induction incited a reversible increase in the level of UT-like immunoreactive substance in the hippocampus. These results suggest that the UT-like immunoreactive substance is produced by neurons in response to brain injury and fear-stress stimuli.

Brain↗

PubMed1993

Lack of the development of morphine tolerance in experimental amnesia: role of arginine vasopressin.

The development of tolerance to morphine analgesia in amnesic model mice and the role of arginine vasopressin (AVP) in the underlying mechanism was examined. Hypoxia, brain ischemia, scopolamine and electroconvulsive shock (ECS) manipulation caused amnesia in the step-through type passive avoidance learning test performed at 24 h after the training trial. The amnesic state lasted for at least 3 days and recovered to naive control level on the 20th day after each manipulation. In all amnesic groups, radioimmunoassayable AVP content in hypothalamus was decreased, in particular, the reduction was significant in hypoxia and ischemic induced amnesic animals, then recovered to the control level by 20 days after each treatment. Daily morphine, 10 mg/kg, s.c. easily resulted in the development of tolerance to the analgesic effect in control animals; however, such treatment failed to develop tolerance in amnesic model animals, leaving the analgesic effect unchanged to the control levels. Daily pretreatment with i.c.v. AVP, dose-dependently reinstated the development of tolerance in amnesic model mice. When morphine injection was started from 20 days after the amnesia inducing treatment, tolerance developed as in a similar pattern as in control animals. Thus, amnesic model mice are deficient in brain AVP levels, and consequently, a certain level of AVP in the hypothalamus is required for maintaining the normal function such as the development of tolerance to morphine and the recovery from amnesia.

Amnesia↗

PubMed1993

Similar ameliorating effects of benzomorphans and 5-HT2 antagonists on drug-induced impairment of passive avoidance response in mice: comparison with acetylcholinesterase inhibitors.

Mice were trained to avoid electric shocks by means of step-down type passive avoidance learning tasks, and memory retention was measured 24 h after the training session. Memory impairment (amnesia) was produced by administering either p-chloroamphetamine (PCA), a serotonin (5-HT) releaser or scopolamine (SCOP), a muscarinic cholinoceptor antagonist, 30 min prior to the training session. Benzomorphans, 5-HT2 antagonists and acetylcholinesterase (AChE) inhibitors were administered immediately after the training session. PCA- but not SCOP-induced amnesia was attenuated by the post-training administration of two benzomorphans, (+)N-allylnormetazocine ((+)SKF-10,047) and (+/- )pentazocine ((+/- )PTZ). Similarly, PCA-induced amnesia was reversed by the post-training administration of 5-HT2 antagonists, ritanserin (RIT) and mianserin (MIA), but SCOP-induced amnesia was not. However, the AChE inhibitors, tetrahydroaminoacridine (THA) and physostigmine (PHY) attenuated both PCA- and SCOP-induced amnesia when administered immediately after the training session. These results indicated that benzomorphans and 5-HT2 antagonists have antiamnestic effects in mice, as do AChE inhibitors. In addition, it is interesting that the patterns of ameliorating effect of benzomorphans were similar to those of 5-HT2 antagonists, which differ from those of AChE inhibitors.

Acetylcholine↗

PubMed1993

Increased expression of TGF-beta 1 mRNA in the obstructed kidney of rats with unilateral ureteral ligation.

Renal interstitial fibrosis is a common consequence of chronic ureteral obstruction. While several cytokines may initiate fibrogenesis, TGF-beta is considered to be a major stimulating factor. It has been reported that TGF-beta 1 regulates extracellular matrix (ECM) synthesis, that thromboxane (Tx) stimulates ECM protein synthesis, and that angiotensin II (Ang II) increases expression of TGF-beta 1 mRNA in rat aortic smooth muscle cells. Therefore, we measured TGF-beta 1 mRNA expression by reverse transcription coupled with polymerase chain reaction in renal cortex of rats with unilateral ureteral obstruction (UUO) to determine whether Ang II and/or Tx stimulates increases in TGF-beta 1 mRNA. TGF-beta 1 mRNA levels in contralateral kidneys of rats with UUO did not change significantly during 14 days of obstruction, while in the obstructed kidney TGF-beta 1 mRNA levels were increased significantly after three days as compared to the control (unoperated rats) kidneys. The increase in TGF-beta 1 mRNA expression in the obstructed kidney cortex was found in tubular cells rather than glomeruli. OKY-046, an inhibitor of thromboxane synthase, did not affect the changes in TGF-beta 1 mRNA in the obstructed kidney. Enalapril, an angiotensin I converting enzyme inhibitor, significantly blunted but did not completely abrogate the increase in TGF-beta 1 mRNA. These data suggest that in obstruction TGF-beta 1 is increased at the transcriptional level and thus may play a role in initiating fibrogenesis in obstructive nephropathy. The effect of thromboxane on extracellular matrix synthesis does not appear to be mediated by TGF-beta 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Antinociceptive effect of dihydroetorphine and its tolerance/dependence liability in mice.

The profile of actions of dihydroetorphine (DHE) concerning antinociception, tolerance and dependence was compared with those of morphine in mice. DHE at 1, 5, 10 or 20 micrograms/kg produced an antinociceptive effect in a dose dependent manner and 10 micrograms/kg was nearly equipotent to that of 10 mg/kg of morphine. The antinociceptive effect of both drugs was completely suppressed by 1 mg/kg of naloxone, while neither 10 mg/kg of naltrindole nor 1 mg/kg of nor-binaltorphimine had any suppressive effect. Mice tolerant to morphine antinociception were tolerant to DHE and vice versa. The naloxone-sensitive, locomotor accelerating activity was progressively enhanced by daily administration of DHE and morphine and a cross reverse tolerance developed between these compounds, suggesting that common mechanisms, especially mediating opioid receptors, underlay the activity enhancement. The development of physical dependence as evidenced by naloxone precipitated withdrawal signs, however, was not observed with daily treatment with DHE, 10, 20 and 100 micrograms/kg for 6 d. Thus, we demonstrated that DHE produces the antinociceptive effect mediated through mu opioid receptors without causing development of a physical dependence, suggesting that it is safe to use in the clinical therapy of patients suffering severe pain such as that accompanying cancer.

Analgesics↗

PubMed1993

Modulation of morphine action by lauric acid.

Intraperitoneal administration of lauric acid (C12) at the high doses, 100-1000 mumol/kg, showed weak but dose-dependent antinociceptive effect in mice. Pretreatment of the animals with 0.1 mumol/kg of i.p. C12 tended to suppress the antinociceptive effect of 7 mg/kg of s.c. morphine and daily combination of this dose of C12 with 10 mg/kg of s.c. morphine blocked the development of antinociceptive tolerance to morphine. However, increasing or decreasing of the dose of C12 resulted in the loss of its modulatory effect on morphine. The strict dose-dependency of C12 in its action on morphine suggests that there is a regulatory role for C12, a medium length straight chain fatty acid, in the endogenous pain inhibitory system.

Analgesics↗

PubMed1993

Amino acids and peptides. XIX. Preparation of enkephalin-poly(ethylene glycol) hybrid and evaluation of its analgesic activity.

The poly(ethylene glycol) hybrid of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) was prepared and its analgesic activity was examined. Poly(ethylene glycol) #4000 was converted to amino-poly(ethylene glycol) and coupled with the N alpha-protected pentapeptide, followed by trifluoroacetic acid treatment to give the hybrid. The hybrid was soluble in water or various organic solvents. The analgesic activity of Leu-enkephalin was markedly potentiated by hybrid formation with poly(ethylene glycol).

Amino Acid Sequence↗

PubMed1993

Involvement of serotonergic receptor subtypes in the production of antinociception by psychological stress in mice.

Besides the important role of emotional factors in the production of psychological-stress-induced analgesia (PSY-SIA), recent attention to the participation of serotonergic (5-HTnergic) neurons in the fear- and anxiety-evoking mechanism led us to examine the effects of 5-HTnergic ligands on PSY-SIA. Pretreatment of mice with 2.0 to 10 mg/kg of methysergide, a 5-HT receptor antagonist, or 1.0 to 10 mg/kg of buspirone, a 5-HT1A receptor partial agonist, dose-dependently suppressed the production of PSY-SIA. Ritanserin, a 5-HT2 receptor antagonist, 1.0 to 5.0 mg/kg, or Y-25,130, a 5-HT3 receptor antagonist, 0.03 and 0.1 mg/kg, also inhibited PSY-SIA dose-dependently, while (+/-)pindolol, a 5-HT1A/1B receptor antagonist, was ineffective at doses up to 3.0 mg/kg. Furthermore, the suppressive effect of PSY-stress on the development of antinociceptive tolerance to morphine was also antagonized by methysergide, buspirone, ritanserin and Y-25,130, but not by (+/-)pindolol. These results suggest that 5-HT receptor (5-HT1A, 5-HT2 and 5-HT3 but not 5-HT1B)-mediated mechanisms play an important role in the production of PSY-SIA.

Animals↗

PubMed1993

Development of tolerance to morphine antinociception in mice treated with nociceptive stimulants.

We have examined whether or not the presence of pain can block the development of tolerance to morphine antinociception in mice. A single injection of formalin or Freund complete adjuvant into the dorsal part of one side of the hind paw resulted in a significant swelling of the treated paw which lasted more than 5 days. In formalin-treated animals that received the initial morphine 2 hr after the stimulant, the development of tolerance to morphine was delayed without affecting morphine antinociception when the effect was measured daily by the tail-pinch (TP) method but not by the tail-flick (TF) method. However, the stimulant suppressed tolerance development even in the TF method unless the daily measurement was undertaken. When morphine injection was started from 5 days after the formalin injection, tolerance developed in a pattern similar to that in the control animals. On the other hand, treatment with Freund adjuvant did not affect the development of tolerance measured by both the TP and TF methods, with or without daily measurement of antinociception. When acetic acid was used as a stimulant, daily morphine was administered before or after the acetic acid injection, in the presence or absence of pain, tolerance developed to the same extent as in the control group, regardless of the time of morphine injection. Thus, our results suggest that the development of tolerance to narcotics may be modified by various factors, such as the type and intensity of nociception; and they also suggest that different results may be produced depending on the test method.

Acetates↗

PubMed1993

[Study of a new endogenous inhibitor of enkephalin-degrading enzymes; pharmacological function and metabolism of spinorphin].

Spinorphin, a potent inhibitor of enkephalin degrading enzyme isolated from the bovine spinal cord, produces a dose-related inhibition of electrically evoked contractions of both MVD (mouse vas deferens) and GPI (guinea-pig ileum). Analgesic activity of Spinorphin was evaluated by the tail pinch method. The intraventricularly injected Spinorphin produced antinociceptive effect in a dose-dependent manner, in dose of 50-200 micrograms.mouse-1. Most Spinorphin was degraded when incubated in the spinal cord for 24 hs. However, approximately 86% of the Spinorphin was intact on HPLC when incubated with probestin, which is an inhibitor of aminopeptidase-M. Spinorphin has a high inhibitory activity against enkephalin degrading enzymes when compared to the various hydrolysis products. In conclusion, the most important structure for enkephalin inhibitory activity in Spinorphin. It is suggested that Spinorphin acts as a neuromodulator of enkephalin metabolism in the spinal cord.

Animals↗

PubMed1992

Dependency on the brain function of arginine vasopressin system of the development to and recovery from analgesic tolerance to morphine.

Concomitant intracerebroventricular (i.c.v.) injection of anti-arginine vasopressin (AVP) antiserum dose-dependently suppressed the development of analgesic tolerance to daily morphine, 10 mg/kg, s.c., in mice. This suppressive effect of the antiserum was reduced by incubating the antiserum with AVP in vitro, before i.c.v. injection, suggesting that the antiserum inactivates brain AVP to result in the suppression of the development of tolerance in vivo. Similar to the antiserum, both AVP V1 and V2 antagonists given i.c.v., 10 ng and 20 ng/mouse, respectively, suppressed the development of morphine tolerance. Meanwhile, the administration of antiserum dose-dependently recovered morphine analgesia in morphine-tolerant mice and a complete recovery of analgesia was observed at the highest dose of antiserum following the second injection, and the effect of antiserum was maintained for 3 days after its withdrawal. Likewise, 10-100 ng/mouse of AVP V1 receptor antagonist given i.c.v. recovered morphine analgesia partially but significantly in a dose-dependent manner; however, AVP V2 receptor antagonist at the same doses partially recovered analgesic effect but the effect was neither significant nor dose-dependent. These findings suggest that the tolerance developed to morphine can be reversible when disturbing the function of brain AVP, but in addition to the different mechanisms of antiserum, V1 and V2 receptor antagonists, the V1 receptor-mediated mechanism may be more closely concerned in this phenomenon.

Angiotensin Receptor Antagonists↗

PubMed1992

Development of physical dependence on morphine not accompanied with tolerance formation.

The development of tolerance induced by daily repeated administration of 10 mg/kg of s.c. morphine was suppressed by combined injection of adrenergic blockers, 10 mg/kg i.p. phentolamine or propranolol, in mice. However, this treatment could not prevent the development of physical dependence as evidenced by the naloxone precipitated abstinence signs. Thus, we provide a new evidence that morphine analgesia, tolerance and physical dependence is dissociable from each other.

Analgesia↗

PubMed1992

Anti-stress effect of ginseng on the inhibition of the development of morphine tolerance in stressed mice.

We examined how the ginseng extract (GE) acts on the antinociceptive effect induced by footshock (FS)-, psychological (PSY)- and forced swimming (SW)-stress (stress-induced analgesia, SIA), and also on the suppression by FS- and PSY-stress of the development of tolerance to morphine in mice. Neither an acute treatment nor 5 daily pretreatments with GE at 100 mg/kg, p.o. affected each SIA. Pretreatment with GE at 100 mg/kg, p.o. for 5 days followed by the treatment in combination with the exposure to stresses for another 5 days caused no appreciable changes in the development of tolerance to FS- and SW-SIA, but suppressed the development of tolerance to PSY-SIA. When mice were pretreated with GE for 5 days and given GE daily prior to morphine at 10 mg/kg/day, with stress exposure for another 5 days, the inhibitory effect of FS-stress on the development of tolerance to morphine was completely eliminated. The present results suggest that GE, by improving the general metabolism in the body, directs toward normalization of the adaptability which is impaired by stress exposure, while not compromising morphine antinociceptive activity or the SIA, another adaptability produced in confrontation to abnormal environmental stimuli. In addition, the differences in the mechanism underlying the FS- and PSY-stress effect which we have previously demonstrated are also reconfirmed.

Analgesics↗

PubMed1992

Blockade by ginseng extract of the development of reverse tolerance to the ambulation-accelerating effect of methamphetamine in mice.

Daily repeated administration of methamphetamine (MAP) developed reverse tolerance to its ambulation-accelerating effect. After pretreatment of mice daily with ginseng extract (GE) for 5 days, concomitant injections of MAP and GE suppressed the development of reverse tolerance to the effect of MAP, although GE itself did not affect the spontaneous motor activity of the naive mice. These results provide evidence that GE may be useful for prevention and therapy of the adverse action of MAP.

Animals↗