• International Journal of Oral Biology
• /
• 제37권1호
• /
• 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.

• 대한수의학회지
• /
• 제39권1호
• /
• pp.45-54
• /
• 1999

In the present study we have analyzed the characteristics and distribution of the mu-opioid receptor(MOR) by raising anti-peptide antisera to the C-terminal peptide of MOR. The antisera against MOR was produced in New Zealand White rabbit against 15 residue corresponding to amino acids, 384-398 of the cloned rat MOR. The antigenic peptide was synthesized using an Applied Biosystems 432 solid-phase peptide synthesizer. The specificity and identification of the antisera were tested by analysis of transfected cells, epitope mapping and immunohistochemical method. COS-7 cells electroporated with MOR cDNA were used to evaluate the characteristics and subcellular distribution of MOR. MOR immunoreactivity was prodominent in the plasmalemma and subcellular compartments such as endoplasmic reticulum, Golgi apparatus and vesicle like structure. Furthermore, both tissue sections and transfected cell lines could be immunostained with these antisera and the immunoreactivity was abolished when anti-MOR sera were preincubated with the peptide against which they were raised. Based on epitope mapping analysis, all antisera appeared to have a similar epitope, which was determined to be within the last amino acid, 391-398. Moreover, immunohistochemistry showed that MOR immunoreactivity was observed in many brain areas including cerebral cortex, striatum, hippocampus, locus coeruleus and the superficial laminae of the dorsal horn. These stained spinal cord and brain areas showed the mirrored pattern observed in auto radiographic studies of mu-opioid binding as well as a pattern similar to that seen by is situ hybridization for MOR. Thus, several lines of evidence support the conclusion that the antisera produced in the present study most likely recognize mu-opioid receptor. These results suggest that MOR antisera may be utilized as useful tool to analyze the physiological and pharmacological studies for mu-opioid receptor in the future.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
• /
• pp.304.3-305
• /
• 2002

The present study investigated the passive avoidance and spatial learning in the ${\mu}$-opioid receptor gene knockout mice and wild type mice. In the step-through passive avoidance task. the ${\mu}$-opioid receptor knockout mice did not differ from the wild type mice. In Morris water maze. however. the ${\mu}$-opioid receptor knockout mice showed significant memory deficit compared to wild type mice. (omitted)

• The Korean Journal of Pain
• /
• 제31권2호
• /
• pp.73-79
• /
• 2018

All drugs have both favorable therapeutic and untoward adverse effects. Conventional opioid analgesics possess both analgesia and adverse reactions, such as nausea, vomiting, and respiratory depression. The opioid ligand binds to ${\mu}$ opioid receptor and non-selectively activates two intracellular signaling pathways: the G protein pathway induce analgesia, while the ${\beta}$-arrestin pathway is responsible for the opioid-related adverse reactions. An ideal opioid should activate the G protein pathway while deactivating the ${\beta}$-arrestin pathway. Oliceridine (TRV130) has a novel characteristic mechanism on the action of the ${\mu}$ receptor G protein pathway selective (${\mu}$-GPS) modulation. Even though adverse reactions (ADRs) are significantly attenuated, while the analgesic effect is augmented, the some residual ADRs persist. Consequently, a G protein biased ${\mu}$ opioid ligand, oliceridine, improves the therapeutic index owing to increased analgesia with decreased adverse events. This review article provides a brief history, mechanism of action, pharmacokinetics, pharmacodynamics, and ADRs of oliceridine.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 2003년도 춘계학술대회
• /
• pp.21-37
• /
• 2003

1. Stimulation of dopaminergic system by morphine was abolished in ${\mu}$-opioid receptor knockout mice. 2. Dopaminergic stimulation by opioid agonists, morphine, DPDPE, and U50488, acts independently. 3. Loss of ${\mu}$-opioid receptors is more sensitive to the response of NMDA-induced convulsion and increase in the expression of mRNA for NMDA receptors.

• The Korean Journal of Pain
• /
• 제32권2호
• /
• pp.87-96
• /
• 2019

Background: This study was performed in order to examine the effect of intrathecal sec-O-glucosylhamaudol (SOG), an extract from the root of the Peucedanum japonicum Thunb., on incisional pain in a rat model. Methods: The intrathecal catheter was inserted in male Sprague-Dawley rats (n = 55). The postoperative pain model was made and paw withdrawal thresholds (PWTs) were evaluated. Rats were randomly treated with a vehicle (70% dimethyl sulfoxide) and SOG ($10{\mu}g$, $30{\mu}g$, $100{\mu}g$, and $300{\mu}g$) intrathecally, and PWT was observed for four hours. Dose-responsiveness and ED50 values were calculated. Naloxone was administered 10 min prior to treatment of SOG $300{\mu}g$ in order to assess the involvement of SOG with an opioid receptor. The protein levels of the ${\delta}$-opioid receptor, ${\kappa}$-opioid receptor, and ${\mu}$-opioid receptor (MOR) were analyzed by Western blotting of the spinal cord. Results: Intrathecal SOG significantly increased PWT in a dose-dependent manner. Maximum effects were achieved at a dose of $300{\mu}g$ at 60 min after SOG administration, and the maximal possible effect was 85.35% at that time. The medial effective dose of intrathecal SOG was $191.3{\mu}g$ (95% confidence interval, 102.3-357.8). The antinociceptive effects of SOG ($300{\mu}g$) were significantly reverted until 60 min by naloxone. The protein levels of MOR were decreased by administration of SOG. Conclusions: Intrathecal SOG showed a significant antinociceptive effect on the postoperative pain model and reverted by naloxone. The expression of MOR were changed by SOG. The effects of SOG seem to involve the MOR.

• 대한한의학회지
• /
• 제24권3호
• /
• pp.108-117
• /
• 2003

Objective : The central opioid mechanism of acupuncture analgesia has been fairly well documented in acute behavioral experiments, but little electrophysiological study has been performed on the peripheral mechanism and subtypes of opioid receptors responsible for acupuncture-induced antinociception in chronic animal models. In the present electrophysiological experiment, we studied the peripheral mechanism and opioid receptor subtypes which Were implicated in electroacupuncture-induced antinociception in the rat with chronic inflammatory and neurogenic pain. Methods : In the rat with complete Freund's adjuvant-induced inflammation and spinal nerve injury, dorsal horn cell responses to afferent C fiber stimulation were recorded before and after electroacupuncture (EA) stimulation applied to the contralateral Zusanli point for 30 minutes. Also studied Were the effects of specific opioid receptor antagonists and naloxone methiodide, which can not cross the blood-brain barrier, on EA-induced inhibitory action. Results : EA-induced inhibitory action was significantly attenuated by naloxone methiodide, suggesting that EA-induced inhibition was mediated through peripheral mechanism. Pretreatment, but not posttreatment of naltrexone and spinal application significantly blocked EA-induced inhibitory actions. In inflammatory and neurogenic pain models, ${\mu}-$ and ${\delta}-opioid$ receptor antagonists (${\beta}-funaltrexamine$ & naltrindole) significantly reduced EA-induced inhibitory action, but ${\kappa}-opioid$ receptor antagonist had weak inhibitory effect on EA-induced antinociception. Conclusion : These results suggest that 2Hz EA-stimulation induced antinoeiceptive action is mediated through peripheral as well as central mechanism, and mainly through ${\mu}-$ and ${\delta}-opioid$ receptors.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
• /
• pp.305-305
• /
• 1994

It has been shown that there are several subtypes of $\kappa$ opioid receptor, We have evaluated the properties of non-${\mu}$, non-$\delta$ binding of 〔$^3$H〕DIP, a nonselective 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) inhibited 〔$^3$H〕DIP binding with Ki. of 70 nM. However, arylacetamides (U69593 and U50488H) gave little inhibition. Also, we have examined the opioid modulation of K$\^$+/(30 mM)-induced histamine release in rat frontal cortex slices labeled with 1-〔$^3$H〕histidine. The 〔$^3$H〕histamine release from cortex slices was inhibited by EKC, a $\kappa$$_1$-and $\kappa$$_2$-agonist, in a concentration-dependent manner(10 to 10,000 nM). The IC$\sub$50/ of EKC was 107 ${\pm}$ 6 nM. However, the $\delta$ receptor selective agonists, DPDPE and deltorphine II, ${\mu}$ receptor agonists, DAMGO and TAPS, $\kappa$$_1$-agonists, U69593 and U50488H, and $\varepsilon$-agonist, ${\beta}$-endorphin, did not inhibit histamine release even in micromoiar dose, indicating that ${\mu}$, $\delta$ or $\kappa$$_1$ receptors are not involved. The concentration-response curve of EKC was shifted to right in the presence of naloxone (300 nM), a ${\mu}$ preferential antagonist, norbinaltorphimine(300 nM), a $\kappa$$_1$ preferential antagonist and bremazocine(1 nM), a $\kappa$$_1$-agonist and $\kappa$$_2$-antagonist. These results suggest that $\kappa$$_2$ opioid receptor regulates histamine release in the frontal cortex of the rat.

• Biomolecules & Therapeutics
• /
• 제7권1호
• /
• pp.1-6
• /
• 1999

Effects of Panax ginseng on the morphine toxicity were studied in relation to its effects on the opioid receptor-G protein interactions. Morphine treatments (3 days) reduced the body weight increment rate and the weight of the thymus and spleen. These changes were usually recovered by the concomitant administration of ginseng total saponin (GTS) but occasionally further deteriorated. This discrepancy was studied in relation to the opioid receptor coupling to G protein, that is, the effects of morphine and GTS on the opioid receptors were studied using the antagonist-agonist competitive binding studies. When GTS recovered the morphine toxicity, morphine shifted the striatal $\delta$ receptors to slightly higher affinity state, and this was partly recovered by the GTS treatment. However, morphine did not have any effect on the affinity state of $\delta$ receptor from NG108-15 cells, suggesting that additional factors were needed for the modulation of the affinity states of $\delta$ receptor. Effects of morphine and GTS on $\mu$ receptor were complicate and variable, and we could not reach a clear conclusion. The morphine toxicity might accompany complicate biological involvements, and the modulation of the affinity states of the opioid receptors might explain a part of the effects of GTS on the morphine toxicity.

• The Korean Journal of Pain
• /
• 제35권4호
• /
• pp.413-422
• /
• 2022

Background: The neocortex, including the medial prefrontal cortex (mPFC), contains many neurons expressing nitric oxide synthase (NOS). In addition, increasing evidence shows that the nitric oxide (NO) and opioid systems interact in the brain. However, there have been no studies on the interaction of the opioid and NO systems in the mPFC. The objective of this study was to investigate the effects of administrating L-arginine (L-Arg, a precursor of NO) and N(gamma)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NOS) into the mPFC for neuropathic pain in rats. Also, we used selective opioid receptor antagonists to clarify the possible participation of the opioid mechanism. Methods: Complete transection of the peroneal and tibial branches of the sciatic nerve was applied to induce neuropathic pain, and seven days later, the mPFC was cannulated bilaterally. The paw withdrawal threshold fifty percent (50% PWT) was recorded on the 14th day. Results: Microinjection of L-Arg (2.87, 11.5 and 45.92 nmol per 0.25 µL) increased 50% PWT. L-NAME (17.15 nmol per 0.25 µL) and naloxonazine (an antagonist of mu opioid receptors, 1.54 nmol per 0.25 µL) inhibited anti-allodynia induced by L-Arg (45.92 nmol per 0.25 µL). Naltrindole (a delta opioid receptor antagonist, 2.45 nmol per 0.25 µL) and nor-binaltorphimine (a kappa opioid receptor antagonist, 1.36 nmol per 0.25 µL) were unable to prevent L-Arg (45.92 nmol per 0.25 µL)-induced antiallodynia. Conclusions: Our results indicate that the NO system in the mPFC regulates neuropathic pain. Mu opioid receptors of this area might participate in pain relief caused by L-Arg.