• Biomolecules & Therapeutics
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• v.7 no.3
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• pp.278-284
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• 1999

DK1001 is a thebain derivative, which is newly synthesized as an alkaloid analgesic. This study was designed to study effects of DK1001 on the ligands binding to the opioid receptor subtypes, and general pharmacology of DK1001. DK1001 inhibited the binding of [$^3H$]DAMGO, a selective mu-subtype agonist, to the opioid receptor of rat forebrain in a concentration-dependent manner. $EC_{50}$ of DK1001 was significantly lower than that of morphine. DK1001 inhibited the binding of 〔$^3$H〕DPDPE, a selective delta-subtype agonist concentration-dependently. DK1001(0.5 mg/kg) had no effects on behavior, body temperature, blood pressure. respiratory rate, and intestinal charcoal propulsion of mice. In addition, DK1001 did not affect on the contractilities of isolated muscle strips of aorta, ileum, and trachea of rats. These results suggest that DK1001 might be a potent analgesic without serious side effects.

• The Korean Journal of Pain
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• v.23 no.4
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• pp.236-241
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• 2010

Background: Selective inhibitors of cycloosygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antionociception of selective COX-2 inhibitor. Methods: To examine the antionociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are ${\mu}$, $\delta$, and k opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. Results: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2 Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test, CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1, Conclusions: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The $\delta$ and $\kappa$ opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the ${\mu}$ opioid receptor is related only to facilitated pain.

• The Korean Journal of Pain
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• v.22 no.1
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• pp.21-27
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• 2009

Background: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the ${\alpha}_2$ adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. Methods: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 mg/kg, 3 mg/kg, 5 mg/kg) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 mg/kg) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the ${\alpha}_2$ subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). Results: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the ${\alpha}_{2A}$, ${\alpha}_{2B}$, ${\alpha}_{2C}$ subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. Conclusions: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of ${\alpha}_2$ receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the ${\alpha}_2$ subtype gene expression.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.153-165
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• 1994

In this study, we tested the influences of several ${\kappa}$ opioid ligands on the $[^3H]diprenorphine$ binding in rat and guinea pig cortex membrane preparations. Using paradigm to block ${\mu}\;and\;{\delta}$ opioid receptors with $DAMGO(1{\mu}M)$ and $DPDPE(1{\mu}M)$, $[^3H]diprenorphine$ labeled ${\kappa}$ sites. Competition analysis in both rat and guinea pig cortex has shown a single population of $[^3H]diprenorphine$ binding site with different Kd values, respectively. There is a significant difference in Ki values of (-) WIN44441 and (+)WIN44441 in both rat and guinea pig cortex. Bremazocine, (-)ethylketocyclazocine, (-)cyclazocine, nor-binaltorphimine effectively inhibited the $[^3H]diprenorphine$ binding with different Ki values in rat and guinea pig cortex. U-69,593, U-50,488H and dynorphine-A (1-8) did not inhibit the $[^3H]diprenorphine$ binding in rat but in guinea pig cortex. Nor-binaltorphimine was a ligand discriminate the ${\kappa}_1$, and ${\kappa}_2$ receptor most effectively. We, also, examined the influence of Na ion and $GTP{\gamma}S$, a nonhydrolyzable guanine nucleotide analog, on the inhibition of $[^3H]diprenorphine$ binding by diprenorphine, (-)ethyl-ketocyclazocine, U-69,593 and bremazocine. By the replacement of NaCl with N-methy-D-glucamine or addition of $GTP{\gamma}S$, Ki values of diprenorpnine were not changed and that of ethylketocyclazocine were changed significantly in both rat and guinea pig cortex. The Ki value of bremazocine was decreased by removal of Na ion, and increased by $GTP{\gamma}S$, however, was not changed by any one of either. These results suggest that there are 2 kinds of subtypes of ${\kappa}$ opioid receptor, ${\kappa}_1$, and ${\kappa}_2$, showing different Ki values for various ${\kappa}$ opioid ligands, also, bremazocine possess the antagonistic property at ${\kappa}_2$ site which is dominant subtype of K receptor in rat cortex.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.113-117
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• 2005

Background: Serotonin 3 receptor is involved in the modulation of nociceptive transmission in the spinal cord. The serotonin 3 receptor antagonist has been used for the management of opioid-induced nausea and vomiting. The aim of this study was to examine whether the analgesic effect of morphine is antagonized by serotonin 3 receptor antagonists at the spinal level. Methods: Rats were implanted with lumbar intrathecal catheters. For nociception, a formalin solution (5%, $50{\mu}l$) was injected into the hind paw of male Sprague-Dawley rats. To determine whether the effect of intrathecal morphine was mediated via serotonin 3 receptors, serotonin 3 receptor antagonists were intrathecally administered 10 min prior to the morphine delivery. Following the formalin injection, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. Results: Intrathecal morphine produced a dose-dependent suppression of the flinches in both phases during the formalin test. The analgesic action of morphine was not reversed by serotonin 3 receptor antagonists (LY-278,584, ondansetron), which had little per se effect on the formalin-induced nociception. Conclusions: Spinal serotonin 3 receptors may not be involved in the analgesia of morphine on a nociceptive state evoked by a formalin stimulus.