• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.193-201
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• 1999

This study was designed to evaluate the effects of opioid receptor agonists on the spontaneous alternation behaviour in an animal model of obsessivecompulsive disorder in rats. According to the theory that dopamine is related to the biological etiology of obsessive-compulsive disorder, the effect of the nalbuphine(opioid kappa agonist) and the tramadol(opioid mu agonist), which act as manipulating agents on the inhibition or stimulation of dopamine release, in the spontaneous alternation behaviour were evaluated. 24 hours prior to the experiment, rats were food-deprived. These rats were put into the T-maze, in which white and black goal boxes were baited with small amounts of chocolate milk. Each rat was given 2 set of 7 trials during which it was placed in the start box and allowed to choose the one of the goal boxes for each time. After identifying the stable baseline of spontaneous alternation behaviour, nonselective 5-HT agonist 5-MeODMT(1.25mg/kg/IP) disrupted spontaneous alternation. Rats were stratified into fluoxetine(10mg/kg/IP), nalbuphine(10mg/kg/IP), tramadol(46.4mg/kg/IP), and saline(0.5cc/IP) injection group with experimental drug treatment for 21 days. The effects on the 5-MeODMT(1.25mg/kg/IP) induced disruption of spontaneous alternation behaviour were checked at the next day of discontinuation of drug treatment. The results were as follows ; 1) At the day after 21 days of the drug treatment, the nalbuphine treated group and the fluoxetine treated group showed significant difference from the tramadol treated group and the saline treated group in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. 2) Within each drug treatment group, the fluoxetine treated group showed significant difference between before and after the treatment of fluoxetine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. And also, the nalbuphine treated group showed significant difference between before and after the treatment of nalbuphine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. There was no difference between the baseline and after the treatment of nalbuphine in the 5-MeODMT(1.25mg/kg/IP) induced suppression of spontaneous alternation behaviour. We indentified that the opioid kappa agonist that act as dopamine release inhibitor affect the spontaneous alternation behaviour which is an animal model of obsessive-compulsive disorder in rat.

• The Korean Journal of Pharmacology
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• v.30 no.1
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• pp.1-9
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• 1994

It has been shown that there are several subtypes of ${\kappa}$ opioid receptor. We examined ligand binding profiles and the effects of various opioid agonists on high potassium-stimulated release of $[^3H]$ histamine. We have evaluated the properties of $non-{\mu},\;non-{\delta},$ binding of $[^3H]\;DIP\;([^3H]\;diprenorphine),$ anonselective opioid antagonist, in rat cortex membranes. Binding $to\;{\mu}\;and\;{\delta}$ sites was inhibited by the use of an excess of competing selective agonists (DAMGO, DPDPE) for these sites. (-) Ethylketocyclazocine (EKC), DIP and bremazocine inhibited $[^3H]$ DIP binding. However, arylacetamides (U69593 and U50488H) gave little inhibition Replacement of sodium by NMDG and the addition of guanine nucleotide influenced the inhibitory potency of (-) EKC, an agonist for {\kappa}_1-and-{\kappa}_2-binding site, but not of bremazocine. This result suggests that bremazocine can be an antagonist at this binding site. Also, we have examined the opioid modulation of $K^+(30mM)-induced\;[^3H]\;histamine$ release in rat frontal cortex slices labeled with $1-[^3H]\;histidine$. The $[^3H]\; histamine$ release from cortex slices was inhibited by EKC in a concentration-dependent manner. However, the ${\delta}$ receptor selective agonists, DPDPE and deltorphine II, ${\mu}$ receptor agonists, DAMGO and TAPS, ${\kappa}_1-agonists$, U69593 and U50488H, and ${\varepsilon}-agonist,\;{\beta}-endorphin,$ did not. The concentration-response curve of EKC was shifted to right in the presence of naloxone, nor-binaltorphimine and bremazocine, respectively. These results suggest that ${\kappa}_2$ opioid receptor regulates histamine release in the fromtal cortex of the rat.

• Korean Journal of Pharmacognosy
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• v.50 no.4
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• pp.272-276
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• 2019

Corylopsis gotoana has been widely used as a traditional medicine for the treatment of lots of disease including cold, edema and vomiting. However pharmacological and phytochemical studies on the C. gotoana are extremely limited. Here in this study, the author investigated the anti-nociceptive effects of the methanolic extract of Corylopsis gotoana (MCG) using various pain models. In the present study, MCG exhibited strong and dose-dependent anti-nociceptive activities on various experimental pain models including thermal nociception and chemical nociception, compared to positive control such as tramadol and indomethacin. In addition, the result from combination test using naloxone, analgesic activity of MCG was slightly reduced, indicating that MCG acts as a partial opioid receptor agonist. These results demonstrated that MCG has potent analgesic potential and thus it may be possibly used as a valuable anti-nociceptive agent.

• Journal of Ginseng Research
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• v.17 no.2
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• pp.109-113
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• 1993

The effects of ginseng total saponins (GTS) on the action of U-50,488H, a $textsc{k}$-opioid receptor agonist, on the electrically induced twitch responses of mouse vats deferens were studied. U-50,488H ($10^9$~$10^{-5}$M) inhibited the twitch contractions in a dose-dependent manner, which were caused by adenosine 5'-triphosphate (ATP) released from the stimulated sympathetic nerve, and this effect was antagonized by naloxone ($10^6$ M). GTS, which itself induced the inhibition of the twitch contractions, acted additively to U-50,488H, GTS and U-50,488H had no effect on the tension of the unstimulated organs. The contractions elicited by ATP were not affected by U-50,488H, but inhibited by GTS. These results suggest that U-50,488H suppressed the twitch contractions by the inhibition of neurotransmitter release from presynaptic nerve terminals via action on opioid receptor, but G75, by inhibiting the action of the neurotransmitter on the smooth muscle.

• Korean Journal of Pharmacognosy
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• v.51 no.3
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• pp.186-191
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• 2020

In this study, we evaluated the anti-nociceptive activities of Sorbus alnifolia. To investigate the anti-nociceptive properties of the methanolic extract of Sorbus alnifolia (MSA), we conducted several tests using various experimental mouse pain models. Herein, MSA significantly delayed the latency time and writhing motion in the hotplate test and acetic acid test, respectively. These result indicated that MSA has an ability to manage both peripheral and central nociception. We could further confirm the analgesic effects of MSA by performing formalin test. In combination test using naloxone, a non-selective opioid receptor antagonist, analgesic activity of MSA was partly antagonized by naloxone, but not completely, indicating that the MSA acts as a partial opioid receptor agonist. Out results suggest that the S. alnifolia may be possibly used as valuable anti-nociceptive agent.

• Biomolecules & Therapeutics
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• v.5 no.1
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• pp.53-58
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• 1997

$[Lys^7$]dermorphin, abbreviated K7DA, which has structural features similar to a metabolically stable $\mu$-opioid peptide agonist $[D-Arg^2, Lys^4$]dermorphin analogue (DALDA), but is intrinsically more potent with respect to binding to the $\mu$-opioid peptide receptor. The present studies report on attempts to enhance brain uptake of systemically administered K7DA by conjugation to a complex of streptavidin (SA) and the OX26 murine monoclonal antibody to the rat transferrin receptor, which undergoes receptor-mediated transcytosis through the blood-brain barrier (BBB). SA-OX26 conjugate mediates BBB transport of biotinylated therapeutics. The K7DA is monobiotinylated at the $\varepsilon$-amino group of the $[Lys^7$] residue with cleavable linker using NHS-SS-biotin. The brain uptake of $^{125}I$ labeled biotinylated K7DA ($^{125}I$-bio-SSa-K7DA) was very small and rapidly metabolized after intravenous injection. The brain uptake, expressed as percent of injected dose delivered per gram of brain, of the $^{125}I$-bio-55-K7DA bound to the SA-OX26 conjugate $^{125}I$-bio-SS-K7DA/SA-OX26) was 0.14$\pm$0.01, a level that is 2-fold greater than the brain uptake of morphine. The cleavability of the disulfide linker in vivo in rat plasma and brain was assessed with gel filtration HPLC and intravenous injection of labeled opioid chimeric peptides. The disulfide linker is stable in plasma in vivo but is cleaved in rat brain in vivo. In conclusion, these studies show that delivery of these potential opioid peptides to the brain may be improved by coupling them to vector-mediated BBB drug delivery system.

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

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.373-380
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• 2001

The action of opioid on the hyperpolarization-activated cation current $(I_h)$ in substantia gelatinosa neurons were investigated by using whole-cell voltage-clamp recording in rat spinal brain slices. Hyperpolarizing voltage steps revealed slowly activating currents in a subgroup of neurons. The half-maximal activation and the reversal potential of the current were compatible to neuronal $I_h.$ DAMGO $(1\;{\mu}M),$ a selective- opioid agonist, reduced the amplitude of $I_h$ reversibly. This reduction was dose-dependent and was blocked by CTOP $(2\;{\mu}M),$ a selective ${\mu}-opioid$ antagonist. DAMGO shifted the voltage dependence of activation to more hyperpolarized potential. Cesium (1 mM) or ZD 7288 $(100\;{\mu}M)$ blocked $I_h$ and the currents inhibited by cesium, ZD 7288 and DAMGO shared a similar time and voltage dependence. These results suggest that activation of ${\mu}-opioid$ receptor by DAMGO can inhibit $I_h$ in a subgroup of rat substantia gelatinosa neurons.

• Proceedings of the Ginseng society Conference
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• 1990.06a
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• pp.36-44
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• 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
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• v.35 no.4
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• pp.433-439
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• 2022

Background: Repeated administration of opioid analgesics for pain treatment can produce paradoxical hyperalgesia via peripheral and/or central mechanisms. Thus, this study investigated whether spinally (centrally) administered orexin A attenuates opioid-induced hyperalgesia (OIH). Methods: [D-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin (DAMGO), a selective µ-opioid receptor agonist, was used to induce mechanical hypersensitivity and was administered intradermally (4 times, 1-hour intervals) on the rat hind paw dorsum. To determine whether post- or pretreatments with spinal orexin A, dynorphin A, and anti-dynorphin A were effective in OIH, the drugs were injected through an intrathecal catheter whose tip was positioned dorsally at the L3 segment of the spinal cord (5 ㎍ for all). Mechanical hypersensitivity was assessed using von Frey monofilaments. Results: Repeated intradermal injections of DAMGO resulted in mechanical hypersensitivity in rats, lasting more than 8 days. Although the first intrathecal treatment of orexin A on the 6th day after DAMGO exposure did not show any significant effect on the mechanical threshold, the second (on the 8th day) significantly attenuated the DAMGO-induced mechanical hypersensitivity, which disappeared when the type 1 orexin receptor (OX1R) was blocked. However, intrathecal administration of dynorphin or an anti-dynorphin antibody (dynorphin antagonists) had no effect on DAMGO-induced hypersensitivity. Lastly, pretreatment with orexin A, dynorphin, or anti-dynorphin did not prevent DAMGO-induced mechanical hypersensitivity. Conclusions: Spinal orexin A attenuates mechanical hyperalgesia induced by repetitive intradermal injections of DAMGO through OX1R. These data suggest that OIH can be potentially treated by activating the orexin A-OX1R pathway in the spinal dorsal horn.