• YAKHAK HOEJI
• /
• v.43 no.4
• /
• pp.411-418
• /
• 1999

Intracerebroventricular (ICV) infusion of morphine (MOR) produces strong analgesia in man and animals. The analgesic effect is thought to be mediated by the centrifugal inhibitory control. But neural mechanisms of the analgesic effect of ICV morphine are not well understood. In the present study, we found that ICV MOR had dual actions on the activity of dorsal horn heurons: it produced both inhibition and excitation of dorsal horn neurons. Since MOR exerts its action via three different types of opioid receptors, we further sought to investigate if there are differential effects of opioid receptor agonists on dorsal horn neurons when administered intracerebroventricularly. Effects of ICV MOR were tested in 28 dorsal horn neurons of the spinal cord in the cat. ICV MOR inhibited, excited and did not affect the heat responses of dorsal horn neurons. ICV DAMGO and DADLE, $\mu$- and $\delta$-opioid agonist, respectively, exhibited the excitation of dorsal horn neurons. In contract, U-50488, a k-opioid agonist, exhibited both the inhibition and excitation of dorsal horn neurons. These results suggest that opioid receptors have different actions on activity of dorsal horn neuron and that the inhibitory action of k-opioid agonist may subserve the analgesia often produced by ICV MOR.

• International Journal of Oral Biology
• /
• v.37 no.1
• /
• pp.1-7
• /
• 2012

Opioid receptors have been pharmacologically classified as ${\mu}$, ${\delta}$, ${\kappa}$ and ${\varepsilon}$. We have recently reported that the antinociceptive effect of morphine (a ${\mu}$-opioid receptor agonist), but not that of ${\beta}$-endorphin (a novel ${\mu}/{\varepsilon}$-opioid receptor agonist), is attenuated by whole body irradiation (WBI). It is unclear at present whether WBI has differential effects on the antinociceptive effects of ${\mu}-$, ${\delta}-$, ${\kappa}-$ and ${\varepsilon}$-opioid receptor agonists. In our current experiments, male ICR mice were exposed to WBI (5Gy) from a $^{60}Co$ gamma-source and the antinociceptive effects of opioid receptor agonists were assessed two hours later using the hot water ($52^{\circ}C$) tail-immersion test. Morphine and $D-Ala^2$, $N-Me-Phe^4$, Gly-olenkephalin (DAMGO), [$D-Pen^2-D-Pen^5$] enkephalin (DPDPE), trans-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide (U50,488H), and ${\beta}$-endorphin were tested as agonists for ${\mu}$, ${\delta}$, ${\kappa}$, and ${\varepsilon}$-opioid receptors, respectively. WBI significantly attenuated the antinociceptive effects of morphine and DAMGO, but increased those of ${\beta}$-endorphin. The antinociceptive effects of DPDPE and U50,488H were not affected by WBI. In addition, to more preciously understand the differential effects of WBI on ${\mu}-$ and ${\varepsilon}$-opioid receptor agonists, we assessed pretreatment effects of ${\beta}$-funaltrexamine (${\beta}$-FNA, a ${\mu}$-opioid receptor antagonist) or ${\beta}$-$endorphin_{1-27}$ (${\beta}$-$EP_{1-27}$, an ${\varepsilon}$-opioid receptor antagonist), and found that pretreatment with ${\beta}$-FNA significantly attenuated the antinociceptive effects of morphine and ${\beta}$-endorphin by WBI. ${\beta}$-$EP_{1-27}$ significantly reversed the attenuation of morphine by WBI and significantly attenuated the increased effects of ${\beta}$-endorphin by WBI. The results demonstrate differential sensitivities of opioid receptors to WBI, especially for ${\mu}-$ and ${\varepsilon}$-opioid receptors.

• Journal of Ginseng Research
• /
• v.23 no.4
• /
• pp.239-246
• /
• 1999

The analgesic effect of ginsenosides or morphine was determined following intrathecal (i.t.) administration in rat tail-flick test. The effects of intrathecal co-administration of ginsenosides with morphine on the development of opioid tolerance and dependence were also examined using rat tail-flick test and naloxone-pre-cipitated withdrawal, respectively. Administration of ginsenosides (i.t.) produced a weak antinociception in a dose-dependent manner. Administration of morphine (i.t.) also produced antinociception in a dose-dependent manner. The $ED_50$ was $1.20\;{\mu}g\;(1.14\~1.29\;{\mu}g)$. However, the acute co-administration of $200{\mu}g$ ginsenosides with 0.1-1.0${\mu}g$ morphine did not show additive effect on morphine induced analgesia in rat tail-flick test. I.t. co-administration of 200 ${\mu}g$ ginsenosides with 10 ${\mu}g$ morphine for 7 days inhibited development of tolerance induced by 10 ${\mu}g$ morphine in rat tail-flick test, although i.t. co-administration of 50 or 100 ${\mu}g$ ginsenosides with morphine was without effect. I.t. co-administration of 200 ${\mu}g$ ginsenosides for 7 days also partially attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. In conclusion, these results suggest that i.t. administered ginsenosides produce a weak antinociception in rat tail-flick test and also prevent opioid tolerance and attenuate opioid dependence in chronic treatment with morphine at the spinal sites.

• Archives of Pharmacal Research
• /
• v.16 no.2
• /
• pp.83-88
• /
• 1993

opioid pure agonists, morphine, meperidine and methadone, were used to investigate the effect on the opioid receptor of fron sciatic nerve fibers using sucrose gap apparatus. When applied extracellularly by perfusion, morphine, methadone and meperidine significantly depressed the amplitude of the action potential in frog sciatic nerve fibers as a dose-dependent $(10^{-10}\;M-10^{-2}\;M)$ manner. The depression with morphine or methadone was partially antagonized by the simultaueous treatment with a lower $(10^{-10}\;M-10^{-8}\;M)$ concentration of naloxone, but that of meperidine was not blocked. When the three opioid agonists were applied intracellularly by placing it in a compartment with a cut end of the sciatic nerve fibers, all of themn depressed the amplitude of the action potentials by similar potency, and these reductions significantly blocked by pretreatment of lower concentration $(10^{-10}\;M-10^{-8}M)$ of naloxone. These results support the previous findings by other workers that the stereospecific opioid receptors of this preparation are located on or near the intracellular opening of the sodium channels which are sensitive to naloxone.

• Journal of Ginseng Research
• /
• v.19 no.3
• /
• pp.219-224
• /
• 1995

The modulatory effects of total ginseng saponin (TGS) on the 1, 6, and opioid receptor binding in morphine tolerance and dependence were examined in this study. The specific [$^{3}H$]DAGO ([D-$Ala^2$, N-$Mephe^4$, $Glyco^4$] enkephalin) binding was significantly increased in chronic morphine (10 mg/kg, i.p.) treated mouse striatum. The specific [$^{3}H$]DPDPE ([D-$Pen^2$, D-$Pen^5$] enkephalin) binding was ignificantly increased following morphine treatment in the mouse striatum and cortex. Also, an apparent decrease in the affinity of [$^{3}H$]DPN (diprenorphine) was observed after chronic morphine treatment in mouse striatum and cortex. 7GS produced a sleight increase of specific [$^{3}H$]DAGO, [$^{3}H$]DPDPE binding and a significant increase of specific [$^{3}H$]DPN binding in the mouse brain striatum. In cortex, TGS produced an inhibition of specific [$^{3}H$]DAGO and [$^{3}H$]DPDPE binding and increase of the specific [$^{3}H$]DPN binding. The prolonged administration of TGS (25, 50, 100, and 150 mg/kg, i.p., 3 wks) produced an inhibition of increased [$^{3}H$]DAGO specific binding following morphine without significant changes in the agonist binding to and receptors in mouse striatum and cortex. These contracted alterations in $\mu$, $\gamma$ and $\kappa$ opiate receptor binding were dependent in TGS dogs and brain sites.

• Journal of Nutrition and Health
• /
• v.17 no.4
• /
• pp.313-319
• /
• 1984

The effect of morphine on food intake on freely fed Sprague - Dawley rats was examined Opiate receptor binding assay was used to investigate the possibility of the opioid system involved in food intake regulation of normal rats. When rats were treated with 5mg morphine per kg body weight, subcutaneously, the food intake of the rats for the first 2 hours was increased 125% of the control rats. The effect of morphine on food intake of male and female rats were greater when the morphine was injected at 10 : 00 a.m than that in the rats administered the morphine at 4 : 00 p.m. The morphine effect was not significant in older rats and female was more responsive than male rats. In morphine treated rats, opioid receptor density has exhibited 33% reduction as measured by the $^{3}H-naloxone$ binding assay with whole brain homogenate. These results indicate that the increase of food intake by morphine for 2 hours after the injection may be mediated through the opioid system in rat brain.

• Proceedings of the Ginseng society Conference
• /
• 1990.06a
• /
• pp.36-44
• /
• 1990

The analgesic effect of morphine was antagonized and the development of tolerance was suppressed by the modification of the neurologic function in the animals treated with ginseng saponins. The activation of the spinal descending inhibitory systems as well as the supraspinal structures by the administration of morphine was inhibited in the animals treated with ginseng saponins intracerebrally or intrathecally The development of morphine tolerance and dependence, and the abrupt expression of naloxone induced abstinence syndrome were also inhibited by ginsenoside Kbl , Rba, Rgl and Re. These results suggest that ginsenoside Kbl, Rba, Rgl and Re are the bioactive components of panax ginseng on the inhibition of the development of morphine tolerance and dependence, and the inhibition of abrupt abstinence syndrome. In addition, further research on the minor components of Panax ginseng should be investigated. A single or daily treatment with ginseng saponins did not induce any appreciable changes in the brain level of monoamines at the various time intervals and at the various day intervals, respectively The inhibitory or facilitated effects of ginseng saponins on electrically evoked contractions in guinea pig ileum (U-receptor) and mouse was definers (5·receptor) were not mediated through opioid receptors. The antagonism of a x receptor agonist, U-, iO.488H was also not mediated through opioid receptors in the animals treated with ginseng saponins, bolt mediated through serotonergic mechanisms. Ginseng saponins inhibited morphine S-dehydrogenase that catalyzed the production of morphine from morphine, and increased hepatic glutathione contents for the detoxification of morphine. This result suggests that the dual action of the above plays an important role in the inhibition of the development of morphine tolerance and dependence.

• The Korean Journal of Pain
• /
• v.2 no.2
• /
• pp.189-193
• /
• 1989

The analgesic effects of epidural morphine were evaluated on various types of cancer-related pain in forty-eight adult patients. Epidural morphine injections were given via an epidural catheter introduced to an epidural level corresponding to the pain area. Pain relief was classified as excellent, fair, or poor by subjective scoring and by the subsequent need for systemic analgesics. Thirty-two patients of all the patients became pain-free. In sixteen patients, pain relief was complete only for one or two of various types of pain with a certain dose of epidural morphine, The best result was obtained when the pain was continuous and originated from deep somatic structures. Based on the results, the ranking order of different types of cancer pain with regard to their susceptibility to epidural morphine was as follows: 1) Continuous somatic pain 2) Continuous visceral pain 3) Intermittent somatic pain 4) Intermittent visceral pain The differential effects of epidural morphine on cancer-related pain may suggest that various types of noxious stimuli involve different kinds of opioid receptors which differ in affinity to morphine, and that there are some pain-mediating systems which function independently of opioid mechanisms.

• International Journal of Oral Biology
• /
• v.35 no.2
• /
• pp.69-74
• /
• 2010

The mu opioid receptor (MOR) has been regarded as the main site of interaction with analgesics in major clinical use, particularly morphine. The repressor element-1 silencing transcription factor (REST) functions as a transcriptional repressor of neuronal genes in non-neuronal cells. However, it is expressed in certain mature neurons, suggesting that it may have complex and novel roles. In addition, the interactions between MOR and REST and their functions remain unclear. In this study, we examined the effects of morphine on the expression of REST mRNA and protein in human neuroblastoma NMB cells to investigate the roles of REST induced by MOR activation in neuronal cells. To determine the effects of morphine on REST expression, we performed RT-PCR, real-time quantitative RT-PCR, western blot analysis and radioligand binding assays in NMB cells. By RTPCR and real-time quantitative RT-PCR, the expression of REST was found to be unchanged by either the MOR agonist morphine or the MOR specific antagonist CTOP. By western blot, morphine was shown to significantly inhibit the expression of REST, but this suppression was completely blocked by treatment with CTOP. In the radioligand binding assay, the overexpression of REST led to an increased opioid ligand binding activity of endogenous MOR in the NMB cells. These results together suggest that morphine inhibits the expression of REST in human neuroblastoma cells through a post-transcriptional regulatory mechanism mediated through MOR.

• Archives of Pharmacal Research
• /
• v.28 no.9
• /
• pp.995-1001
• /
• 2005

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (I-L-receptors) and mouse vas deferens $(\delta-receptors)$ are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine $A_{2A}1\delta-opioid$ receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.