• Title/Summary/Keyword: Opiate receptors

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Analgesic Action Mechanism of DA-5018, a New Capsaicin Derivative : Relationship to Opiate :Receptors and Prostanoids (새로운 캅사이신 유도체 DA-5018의 진통활성 기전연구: Opiate 수용체 및 :Prostanoid와의 상관성)

  • 손미원;손문호;배은주;김순희;김원배;양중의
    • Biomolecules & Therapeutics
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    • v.5 no.1
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    • pp.87-93
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    • 1997
  • DA-5018, a new capsaicin derivative, showed potent analgesic effect comparable to that of morphine in various experimental acute pain models. in this study, whether the analgesic mechanism of DA-5018 is related to opiate receptors or prostanoids was investigated. The affinity of DA-5018 for opiate receptor was determined by receptor binding assay. The Ki values of DA-5018 for nonspecific and specific $\mu$, $textsc{k}$, $\delta$-opiate receptor was 299$\pm$8.88, 735$\pm$215, 2930$\pm$ 163, 1550$\pm$813 nM, respectively and DA-5018 exhibited lower affinity than morphine. DA-5018 (10-"~3$\times$10-′M) inhibited electrically-evoked contractions of the guinea ply ileum and rat vas deferens, and these inhibition was not antagonized by naloxone(10 nM), an opiate receptor antagonist. Antagonism of analgesic effect of 7A-5018 by naloxone was examined by tail pinch test. Analgesic action of DA-5018(0.1 ~2 mg/kg, 5.c.) was not antagonized by naloxone(1 mg/rg, i.p.). These results indicate that pharmacological action of DA-5018 is not related with opiate receptor. Cyclooxygenase and 5-lipoxygenase activities in rat peritoneal neutrophil treated with A23187 and arachidonic acid were measured by radioimmunoassay. DA-5018 stimulated the cyclooxygenase activity and the concentration show-ing the two fold increase of activity was 124$\mu$M. DA-5018 slightly inhibited 5-lipoxygenase activity and these results together indicate that analgesic action of 3A-5018 is not mediated through inhibition of cyclooxy genase or lipoxygenase. These results suggest that the analgesic effect of DA-5018 is not due to blocking opiate receptor or to inhibiting the synthesis of prostanoids in the arachidonic acid metabolism pathway.

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Reevaluation of the Effect of Phenobarbital on the Response to Pain in Rat (백서에서 동통에 미치는 Phenobarbital 효과의 재평가)

  • So, Byoung-Gyoum;Kim, Kee-Won;Ko, Myoung-Kyu;Yang, Won-Mo;Cho, Kyu-Park
    • The Korean Journal of Pharmacology
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    • v.22 no.2
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    • pp.88-95
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    • 1986
  • Clinically, subhypnotic doses of barbiturates have been known to elicit hyperalgesia. In this experiment, effect of acute or chronic phenobarital treatment on the response to pain in rat was reevaluated by hot-plate method. To elucidate its mechanism, changes of ${\beta}-endorphin$ contents and [3H]-morphine binding of the rat midbrain as well as functional opiate receptor in vas deferens were also measured. Intraperitoneal injection of sub anesthetic dose phenobarbital induced initial hyperalgesia followed by successive analgesia, while chronic phenobarbital-treatment decreased reactivity to pain. Naloxone (10mg/kg, i.p.) markedly shortened hot plate latency period, and significantly inhibited the analgesic action of phenobarbital. Single dose of phenobarbital did not affect ${\beta}-endorphin$ contents and [3H]-morphine binding in rat mid brain, but in the chronic phenobarbital-treated groups, ${\beta}-endorphin$ contents was increased, while Bmax of opiate receptor binding was decreased. Moreover, very significant correlations among responses to pain, changes of ${\beta}-endorphin$ contents and opiate receptor binding were observed. However, Kd values of opiate receptor bindings were not changed in all preparations. In the chronic phenobarbital-treated vas deferens preparations, ID50 of morphine was increased witb concomittant decrease of maximum effect. But $pA_2 $, value for naloxone was not changed. From these results, it is suggested that phenobarbital can produce analgesia due to changes of ${\beta}-endorphin$ contents as well as functional opiate receptors by receptor regulation.

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Effect of Opioid on Nicotinic Receptor-Mediated Catecholamine Secretion in the Rat Adrenal Gland (횐쥐 부신에서 Opioid가 니코틴 수용체를 통한 카테콜아민 분비작용에 미치는 영향)

  • Lim, Dong-Yoon;Lee, Jong-Jin;Choi, Cheol-Hee
    • The Korean Journal of Pharmacology
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    • v.28 no.2
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    • pp.181-190
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    • 1992
  • The present study was conducted to investigate the effect of opioids on catecholamine (CA) secretion evoked by a selective cholinergic nicotinic agonist, 1,1-dimethyl-4-phenyl piperazinium (DMPP) and acetylcholine from the retrogradely perfused rat adrenal glands. Methionine-enkephalin $(9.68{\times}10^{-6}\;M)$ caused a significant inhibition of CA secretion evoked by DMPP (100 uM) and $ACh\;(50\;{\mu}g)$, but had no effect on the spontaneous (basal) CA release. Morphine $(1.73{\times}10^{-5}\;M)$ attenuated considerablely the increase in CA release induced by DMPP and ACh. Morphine itself also did not affect the basal CA output. A 20 to 65% reduction of the DMPP- and ACh-evoked increase in CA release was observed after the pretreatment with methionine-enkephalin or morphine. The increase in CA release evoked by DMPP and ACh was reduced markedly by preloading with an opiate antagonist naloxone $(1.22{\times}10^{-7}\;M)$ while basal CA output was not affected by naloxone. These present experimental results suggest that the nicotinic stimulation-evoked CA release from the perfused rat adrenal gland is inhibited by endogenously released opioid peptides through activation of opiate receptors located in the adrenal gland.

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The c-myc Expression on the Opioid Tolerance in Human Neuroblastoma SH-SY5Y Cells (사람 Neuroblastoma SH-SY5Y 세포주에서 Opiate 내성에 의한 c-myc 유전자 표현)

  • Park, Chang-Kyo;Kwon, Gee-Youn;Suh, Sung-Il;Kim, Soo-Kyung
    • The Korean Journal of Physiology and Pharmacology
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    • v.1 no.6
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    • pp.691-697
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    • 1997
  • The mechanisms underlying opiate tolerance and dependence are not fully understood. We used human neuroblastoma SH-SY5Y cells as a model system for studying effects of morphine tolerance and withdrawal on c-myc induction and cAMP levels. It has been reported that regulation of c-fos by acute and chronic morphine withdrawal is mediated through alterations in CREB transcription factor. In this study, we examined the effects of morphine tolerance on c-myc expression and cAMP concentrations. The activation of opiate receptors by an acute morphine administration resulted in an increase in c-myc mRNA and a decrease in cAMP concentrations in a dose-dependent manner $(5,\;10,\;15,\;and\;20\;{\mu}M)$. On the other hand, the chronic treatment of morphine $(10\;{\mu}M\;for\;six\;days)$ did not induce the elevated expression of c-myc mRNA. The c-myc expression was slightly inhibited in comparison with that of the acute morphine response. However, cAMP concentrations were increased with regard to morphine withdrawal response. These results suggest that the alterations in c-myc expression might imply a significant opiate regulation relating to morphine tolerance. This observation differs from increased expression of c-fos via regulation of cAMP pathway.

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Influence of Phenobarbital on the Circadian Rhythm of Opiate Receptor in Rat Brain (백서의 뇌내 Opiate 수용체의 일중 변동에 미치는 Phenobarbital의 영향)

  • Park, Yeoung-Gul;Kim, Kee-Won;Cho, Kyu-Park
    • The Korean Journal of Pharmacology
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    • v.21 no.2
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    • pp.128-141
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    • 1985
  • To investigate the influence of phenobarbital sodium on the action of morphine and on the diurnal rhythms of both opiate receptor binding and ${\beta}-endorphin$ contents, the amount of specifically bound $(^3H)$-morphine and immunoreactive ${\beta}-endorphin$ were measured in the midbrain of phenobarbital-treated rats at 4h intervals in a day. Rats were housed and adapted to a controlled cycle of either 12 h light-12 h dark or 24 h constant dark. After 3 weeks of adaptation, 0.5 ml of physiological saline or phenobarbital sodium (20mg/kg/day, i.p.) were administered twice a day for 2 weeks. Highly significant diurnal rhythms of opiate receptor binding and ${\beta}-endorphin$ were present in rat midbrain. In control group, the peak of maximum $(^3H)$-morphine binding was observed at 22:00 h, whereas the peak of ${\beta}-endorphin$ content was found at 06:00 h. Even in the absence of time cues these diurnal rhythms persisted, but they were highly modified with respect to the wave form as well as differences in the timing of peak and nadir. In the phenobarbital-treated group, these diurnal rhythms were also modified in shape, phase and amplitude, as well as in timing of peak and nadir. In this group, 24 h mean of opiate receptor binding was significantly decreased, while the 24 h mean level of ${\beta}-endorphin$ content was highly increased. However, Kd values in all experimental groups did not change. This indicates that differences in binding were not due to changes in the affinity, but in the number of binding sites. Statistical analysis of regression line indicates that changes of receptor binding were closely correlated with the changes of ${\beta}-endorphin$ content. These results suggest that phenobarbital may influence the action of morphine by changing the number of opiate receptors and that the modification of diurnal rhythm of opiate receptor by the agent is possibly due to changes of ${\beta}-endorphin$ content.

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Regulator of G-Protein Signaling 4 (RGS4) Controls Morphine Reward by Glutamate Receptor Activation in the Nucleus Accumbens of Mouse Brain

  • Kim, Juhwan;Lee, Sueun;Kang, Sohi;Jeon, Tae-Il;Kang, Man-Jong;Lee, Tae-Hoon;Kim, Yong Sik;Kim, Key-Sun;Im, Heh-In;Moon, Changjong
    • Molecules and Cells
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    • v.41 no.5
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    • pp.454-464
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    • 2018
  • Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine-induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knock-down of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration.

Caudal Morphine for Postoperative Pain Control after Abdominal Surgery (천골강내로 주입한 Morphine에 의한 상.하복부 수술후 진통효과)

  • Woo, Nam-Sick;Yoon, Duck-Mi;Oh, Hung-Kun
    • The Korean Journal of Pain
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    • v.1 no.1
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    • pp.74-79
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    • 1988
  • Caudal narcotic analgesia was assesses after the injection of 3mg morphine diluted in 30ml (physiologic) saline into the sacral canal in 15 Patients after upper abdominal surgery, in 20 patients after lower abdominal surgery under general anesthesia, and in 20 patients after perianal surgery under caudal block. Pain relief was evaluated by the subsequent need for systemic analgesics. All eases had considerable relief from pain an4 the morphine was effective for 12 or more hours. There were no significant differances between pain relief of the upper abdominal and lower abdominal surgery group, upper abdominal and perianal surgery group, and lower abdominal and perianal surgery group (p>0.05, p>0.05, p>0.05). It is suggested that the morphine, which was administered into the sacral, cannal, reached the subarachnoid space and produced it's effect by direct action on the specific opiate receptors in the substantia gelatinosa of th.8 posterior horn cell of the spinal cord. Consequently, whether analgesia from epidural narcotics appears to be segmental in distribution or not is still in controversy.

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Influence of Intracerebroventricular Naloxone on the Renal Function of the Rabbit (측뇌실내(側腦室內) Naloxone의 가토현기능(家兎賢機能)에 미치는 영향(影響))

  • Choi, Bong-Kyu;Kook, Young Johng
    • The Korean Journal of Pharmacology
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    • v.16 no.1 s.26
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    • pp.15-24
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    • 1980
  • As it has been reported that opioids such as morphine and methionine-enkephalin induced antidiuresis and antinatriuresis along with decrease in renal hemodynamics when given intracerebroventricularly(ivt), the renal action of ivt naloxone, a pure antagonist of morphine, and its influence upon the morphine action were investigated in this study. Less than $0.3{\mu}M/kg$ naloxone ivt did not change renal funtion. $1{\mu}M/kg$ ivt tended to, increase urine flow rate and induce transient natriuresis. $3{\mu}M/kg$ ivt produced transient: natriuresis. $3{\mu}M/kg$ ivt produced marked diuresis and natriuresis without any changes of renal hemodynamics. $10{\mu}M/kg$ ivt produced significant increases of urine flow rate and excretion of sodium without any changes of renal hemodynamics. Morphine $0.03{\mu}M/kg$ ivt produced marked decrement in renal hemodynamics along with decreases of water and sodium excretion, as previously shown by Kang. These effects of ivt morphine were completely abolished by the pretreatment with $0.3{\mu}M/kg$ naloxone. These observations provide further evidence that opiate receptors and endorphins in the brain might play an important role in the center-mediated regulation of the renal function in the rabbit.

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Imaging Neuroreceptors in the Living Human Brain

  • Wagner Jr Henry N.;Dannals Robert F.;Frost J. James;Wong Dean F.;Ravert Hayden T.;Wilson Alan A.;Links Jonathan M.;Burns H. Donald;Kuhar Michael J.;Snyder Solomon H.
    • The Korean Journal of Nuclear Medicine
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    • v.18 no.2
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    • pp.17-23
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    • 1984
  • For nearly a century it has been known that chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its exact nature. Positron-emitting radioactive tracers have made it possible to study the chemistry of the human mind in health and disease, using chiefly cyclotron-produced radionuclides, carbon-11, fluorine-18 and oxygen-15. It is now well established that measurable increases in regional cerebral blood flow, glucose and oxygen metabolism accompany the mental functions of perception, cognition, emotion and motion. On May 25, 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 methyl spiperone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine receptors than serotonin-2 receptors. Preliminary studies in patients with neuropsychiatric disorders suggests that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits quantitative assay of picomolar quantities of neuro-receptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress. The growth of any scientific field is based on a paradigm or set of ideas that the community of scientists accepts. The unifying principle of nuclear medicine is the tracer principle applied to the study of human disease. Nineteen hundred and sixty-three was a landmark year in which technetium-99m and the Anger camera combined to move the field from its latent stage into a second stage characterized by exponential growth within the framework of the paradigm. The third stage, characterized by gradually declining growth, began in 1973. Faced with competing advances, such as computed tomography and ultrasonography, proponents and participants in the field of nuclear medicine began to search for greener pastures or to pursue narrow sub-specialties. Research became characterized by refinements of existing techniques. In 1983 nuclear medicine experienced what could be a profound change. A new paradigm was born when it was demonstrated that, despite their extremely low chemical concentrations, in the picomolar range, it was possible to image and quantify the distribution of receptors in the human body. Thus, nuclear medicine was able to move beyond physiology into biochemistry and pharmacology. Fundamental to the science of pharmacology is the concept that many drugs and endogenous substances, such as neurotransmitters, react with specific macromolecules that mediate their pharmacologic actions. Such receptors are usually identified in the study of excised tissues, cells or cell membranes, or in autoradiographic studies in animals. The first imaging and quantification of a neuroreceptor in a living human being was performed on May 25, 1983 and reported in the September 23, 1983 issue of SCIENCE. The study involved the development and use of carbon-11 N-methyl spiperone (NMSP), a drug with a high affinity for dopamine receptors. Since then, studies of dopamine and serotonin receptors have been carried out in over 100 normal persons or patients with various neuropsychiatric disorders. Exactly one year later, the first imaging of opitate receptors in a living human being was performed [1].

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CHILDHOOD TRAUMA:PSYCHIATRIC OVERVIEW (아동기 외상의 정신과적 개관)

  • Han, Sung-Hee
    • Journal of the Korean Academy of Child and Adolescent Psychiatry
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    • v.13 no.1
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    • pp.3-14
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    • 2002
  • Childhood psychic trauma appears to be a crucial factor in the development of serious disorders both in childhood and in adulthood. Traumatized children show strong tendency to revisualize or re-feel a traumatic events. Play and behavioral reenactments are frequent manifestations of both the single blow and the long-standing traumas in childhood. Those children who suffer the results of single, intense terror appear to exhibit detailed memory, retrospective reworkings and misperceptions. In long-standing or repetitive trauma, children would show psychic numbing, self-hypnosis, dissociation and rage. Child's brain is undergoing critical and sensitive periods of differentiation. During this time, developing central nervous system is exquisitely sensitive to stress. Stressor-activated neurotransmitters and hormones can play major roles in neurogenesis, migration, synaptogenesis, and neurochemical differentiation. Internal opiate system operates in some trauma and causes the victim to fail to respond, to avoid, to shut off feelings. Evidence is also accumulating in traumatology that dysfuntion of locus coeruleus and ventral tegmental neucleus system leads to catecholamine receptors hypersensitivity. This change result in hypervigilance, increased startle, affective lability, and increased autonomic nervous system hyperreactivity. Another site of action of trauma on the brain is hypothalamic-pituitary-adrenal axis. Individuals with PTSD do not have enough cortisol to halt the alarm reaction. When children are exposed to long-standing extreme events, massive attempts to protect the psyche and to preserve the self are put into gear. These developmental traumas mobilize various kinds of defense mechanisms. Massive denial, dissociation, self anesthesia, identification with aggressor and aggression turned against the self often lead to profound character changes in the youngsters.

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