• The Korean Journal of Pain
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• 제35권4호
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• pp.423-432
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• 2022

Background: The decreased expression of mu-opioid receptors (MOR) in the amygdala may be a key molecular in chronic post-surgical pain (CPSP). It is known that miR-339-5p expression in the amygdala of a stressed rat model was increased. Analyzed by RNAhybrid, miR-339-5p could target opioid receptor mu 1 (oprm1) which codes MOR directly. So, the authors hypothesized that miR-339-5p could regulate the expression of MOR via targeting oprm1 and cause the effects to CPSP. Methods: To simulate perioperative short-term stress, a perioperative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception rat model was built. A pmiR-RB-REPORT^TM dual luciferase assay was taken to verify whether miR-339-5p could act on oprm1 as a target. The serum glucocorticoid level of rats was test. Differential expressions of MOR, GFAP, and pERK1/2 in each group of the rats' amygdala were tested, and the expressions of miR-339-5p in each group of rats' amygdalas were also measured. Results: Perioperative stress prolonged the recovery time of incision pain. The expression of MOR was down-regulated in the amygdala of rats in stress + incision (S + IN) group significantly compared with other groups (P < 0.050). miR-339-5p was up-regulated in the amygdala of rats in group S + IN significantly compared with other groups (P < 0.050). miR-339-5p acts on oprm1 3'UTR and take MOR mRNA as a target. Conclusions: Perioperative stress could increase the expression of miR-339-5p, and miR-339-5p could cause the expression of MOR to decrease via targeting oprm1. This regulatory pathway maybe an important molecular mechanism of CPSP.

• 대한한의학회지
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• 제26권3호
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• pp.239-248
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• 2005

Objectives : Electroacupuncture (EA)-induced analgesia has been known to be mediated through the activation of opioid, noradrenergic and serotonergic receptors. However, little study on serotonergic mechanism has been performed in an animal model of chronic pain. The present study was designed to elucidate the type of serotonergic receptors responsible for EA analgesia in the chronic pain model. Methods : In rats with complete Freund's: adjuvant-induced inflammation and spinal nerve injury, spinal wide dynamic range (WDR) cell responses to graded electrical stimulation of afferent C fiber were recorded before and after spinal application of selective 5-hydroxytryptamine (5-HT) receptor antagonists. EA stimulation (2Hz, 0.5msec, 3mA) was applied to the contralateral Zusanli point for 30 min. Results : In both models of chronic pain, WDR cell responses were greatly inhibited after EA stimulation. EA-induced inhibition of WDR celt responses was significantly attenuated by spinal application of non-selective 5-HT receptor antagonist, dihydroergocristine Of 5-HT receptor antagonists tested, 5-HT1A (WAY 100635) and 5-HT2 (LY53857) receptor antagonists strongly reduced an ability of EA stimulation to inhibit WDR cell responses. However, 5-HT1B (GR55562) and 5-HT3 (LY278584) receptor antagonists also had weak but significant blocking action on EA-induced inhibitory effect on chronic pain. Conclusions : Dorsal hem cell responses, afferent C fiber stimulation, chronic pain, electroacupuncture, serotonergic receptors.

• Bulletin of the Korean Chemical Society
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• 제31권4호
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• pp.874-880
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• 2010

A series of 13- and 14-membered cyclic enkephalin analogs based on the moderately $\mu$ selective prototype compound Tyr-C[D-$A_2bu$-Gly-Phe-Leu] 8a were synthesized to investigate the structure-activity relationship. The modifications of sequence were mainly focused on two positions 3 and 5, critical for the selective recognition for $\mu$ and $\delta$ opioid receptors. The substitution of hydrophobic $Leu^5$ with hydrophilic $Asp^5$ derivatives led to Tyr-C[D-$A_2bu$-Gly-Phe-Asp(N-Me)] 7 and Tyr-C[D-Glu-Phe-gPhe-rAsp(O-Me)] 5, the peptides with a large affinity losses at both $\mu$ and $\delta$ receptors. The substitution of $Phe^3$ with $Gly^3$ led to Tyr-C[D-Glu-Gly-gPhe-rLeu] 3 and Tyr-C[D-Glu-Gly-gPhe-D-rLeu] 4, the peptides with large affinity losses at $\mu$ receptors, indicating the critical role of phenyl ring of $Phe^3$ for $\mu$ receptor affinities. One atom reduction of the ring size from 14-membered analogs Tyr-C[D-Glu-Phe-gPhe-(L and D)-rLeu] 6a, 6b to 13-membered analogs Tyr-C[D-Asp-Phe-gPhe-(L and D)-rLeu] 1, 2 reduced the affinity at both $\mu$ and $\delta$ receptors, but increased the potency in the nociceptive assay, indicating the ring constrain is attributed to high nociceptive potency of the analogs. For the influence of D- or L-chirality of $Leu^5$ on the receptor selectivity, regardless of chirality and ring size, all cyclic diastereomers displayed marked $\mu$ selectivity with low potencies at the $\delta$ receptor. The retro-inverso analogs display similar or more active at $\mu$ receptor, but less active at $\delta$ receptor than the parent analogs.

• The Korean Journal of Physiology and Pharmacology
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• 제5권3호
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• pp.213-221
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• 2001

The amygdala is known as a site for inducing analgesia, but its action on the trigeminal nucleus has not been known well. Little information is available on the effect of dynorphin on NMDA receptor-mediated electrophysiological events in the trigeminal nucleus. The purpose of this study was to investigate the changes in the single neuron spikes at the trigeminal nucleus caused by the amygdala and the action of dynorphin on the trigeminal nucleus. In the present study, extracellular single unit recordings were made in the dorsal horn of the medulla (trigeminal nucleus caudalis) and the effects of microiontophoretically applied compounds were examined. When [D-Ala2, N-Me-Phe4, Glys5-ol]enkephalin (DAMGO, 10-25 mM), a ${\mu}-opioid$ receptor agonist, was infused into the amygdala, the number of NMDA-evoked spikes at the trigeminal nucleus decreased. However, the application of naloxone into the trigeminal nucleus while DAMGO being infused into the amygdala increased the number of spikes. Low dose (1 mM) of dynorphin in the trigeminal nucleus produced a significant decrease in NMDA-evoked spikes of the trigeminal nucleus but the NMDA-evoked responses were facilitated by a high dose (5 mM) of dynorphin. After the ${\kappa}$ receptors were blocked with naloxone, dynorphin induced hyperalgesia. After the NMDA receptors were blocked with AP5, dynorphin induced analgesia. In conclusion, dynorphin A exerted dose-dependent dual effects (increased & decreased spike activity) on NMDA-evoked spikes in the trigeminal nucleus. The inhibitory effect of the dynorphin at a low concentration was due to the activation of ${\kappa}$ receptors and the excitatory effect at a high concentration was due to activation of NMDA receptors in the trigeminal neurons.

• The Korean Journal of Physiology and Pharmacology
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• 제7권6호
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• pp.369-373
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• 2003

This study was performed to test whether endomorphin-1 has analgesic effect, when locally administrated into inflamed peripheral tissue. Carrageenan suspension (0.5%) was injected intraplantarly into the right paw of Sprague-Dawley male rats, and the rats were subjected to a series of mechanical stimuli with von Frei filaments before and after the injection. Carrageenan-injected rats showed typical inflammatory hyperalgesic signs and decrease of withdrawal threshold, peaked at 3 to 6 hours after the injection and lasted more than 3 days. Endomorphin-1 was intraplantarly injected with carrageenan, simultaneously or 3∼4 hours after carrageenan. Simultaneous injection of endomorphin-1 with carrageenan significantly reduced hyperalgesia and thd analgesic effect was prolonged up to 8 hours. The delivery of endomorphin-1 ($50{\mu}g$) into the inflamed area after 3 to 4 hours of carrageenan injection significantly increased the threshold of hyperalgesic mechanical withdrawal response, but only partially. Intrathecal treatment of endomorphin-1 completely reversed carrageenan-induced hyperalgesia. This report is the first to show that peripherally delivered endomorphin-1 relieved inflammatory hyperalgesia. But a control through peripheral ${\mu}-opioid$ receptors appears to be not sufficient for complete pain treatment.

• The Korean Journal of Physiology and Pharmacology
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• 제22권3호
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• pp.225-234
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• 2018

Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of $K_{ATP}$ channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection.

• The Korean Journal of Physiology and Pharmacology
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• 제25권5호
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• pp.489-494
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• 2021

Oxaliplatin, a third-generation platinum derivative, is the mainstay of current antineoplastic medications for advanced colorectal cancer therapy. However, peripheral neuropathic complications, especially cold allodynia, undermine the life-prolonging outcome of this anti-cancer agent. Rosavin, a phenylpropanoid derived originally from Rhodiola rosea, exhibits a wide range of therapeutic properties. The present study explored whether and how rosavin alleviates oxaliplatin-induced cold hypersensitivity in mice. In the acetone drop test, cold allodynia behavior was observed from days 3 to 5 after a single injection of oxaliplatin (6 mg/kg, i.p.). Cold allodynia was significantly attenuated following rosavin treatment (10 mg/kg, i.p.). Specific endogenous 5-HT depletion by three consecutive pretreatments with parachlorophenylalanine (150 mg/kg/day, i.p.) abolished the analgesic action of rosavin; this effect was not observed following pretreatment with naloxone (opioid receptor antagonist, 10 mg/kg, i.p.). Furthermore, 5-HT_1A receptor antagonist WAY-100635 (0.16 mg/kg, i.p.), but not 5-HT₃ receptor antagonist MDL-72222 (1 mg/kg, i.p.), blocked rosavin-induced analgesia. These results suggest that rosavin may provide a novel approach to alleviate oxaliplatin-induced cold allodynia by recruiting the activity of 5-HT_1A receptors.

• The Korean Journal of Physiology and Pharmacology
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• 제5권2호
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• pp.189-197
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• 2001

To investigate propofol's effects on ionic currents induced by ${\gamma}-aminobutyric$ acid (GABA) and glycine as well as on those produced by the nicotinic acetylcholine- and glutamate-responsive channels, rat dorsal raphe neurons were acutely dissociated and the nystatin-perforated patch-clamp technique under voltage-clamp conditions was used to observe their responses to the administration of propofol. Propofol evoked ion currents in a dose-dependent manner, and propofol $(10^{-4}\;M)$ was used to elicit ion currents through the activation of $GABA_A,$ glycine, nicotinic acetylcholine and glutamate receptors. Propofol at a clinically relevant concentration $(10^{-5}\;M)$ potentiated $GABA_A-,$ glycine- and NMDA receptor-mediated currents. The potentiating action of propofol on $GABA_A-,$ glycine- and NMDA receptor-mediated responses involved neither opioid receptors nor G-proteins. Apparently, propofol modulates inhibitory and excitatory neurotransmitter-activated ion channels either by acting directly on the receptors or by potentiating the effects of the neurotransmitters, and this modulation appears to be responsible for the majority of the anaesthetic and/or adverse effects.

• 대한약리학회지
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• 제27권2호
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• pp.99-108
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• 1991

Racemic ketamine을 사용하여 개구리의 좌골신경 및 toe muscle에 대한 작용을 관찰하였다. 실험방법으로는 214 mM sucrose을 사용하여 서로 다른 두 종류의 투여 방법으로 세포막의 활동 전압에 대한 영향을 electric recording으로 관찰하였다. 즉, intracellular 투여는 single sucrose gap technique으로, extracellar 투여는 double sucrose gap technique을 사용하였으며 그 실험 결과는 아래와 같았다. 1. Racemic ketamine은 개구리의 좌골신경 및 toe muscle의 활동전압을 intracellular 및 extracellular 투여시 모두 의의 있게 억제하였다. 2. 개구의 toe muscle에서 $K^+$-수축을 억제하였다. 3. naloxone은 ketamine의 억제작용을 완전히 차단하지는 못하였다.

• Journal of Oral Medicine and Pain
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• 제38권4호
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• pp.313-318
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• 2013

수면은 외부의 자극에 대해 반응하지 않는 상태로 만성통증을 지닌 환자는 수면 장애를 겪고 있으며 수면장애는 통각과 민한 상태를 유발하고 통증인지에 영향을 미친다. 구강작열감 증후군은 구강점막에 화끈거리는 감각을 포함하는 만성 안면통증으로 감각과 통증 역치가 변성되고 신경병증 징후를 보인다. 구강작열감 증후군은 첫 번째로 국소적, 전신적 요인 즉, 흡연, 투약 등 작열감 증상의 원인으로 가능한 요인을 제거하고, 두 번째로는 환자를 안심시키는데 있다. 수면박탈 내인성, 외인성 아편유사제의 진통효과는 수면 계속성 즉, 선택적인 렘수면 박탈은 아편유사제 진통효과를 방해 하고 opioid protein synthesis 억제를 야기하고 ${\mu}$ 와 ${\delta}$ opioid 수용체 친화력을 감소시킨다. enkephalinase-inhibitor와 MAO-B inhibitor 적용으로 나타나는 아편유사제의 진통상승효과는 렘수면 박탈시에 무효화 된다. 렘수면 박탈후에는 5-HT 와 5-hydroxy indole acetic acid 레벨이 유의하게 감소되고, 아편유사체에 활성에 의해 유발되는 통증억제를 지지하는 세로토닌 체계를 가능하지 않게 한다. 구강작열감 증후군은 설말단 신경섬유에서 추삭변성 변화가 있고 특히, 열자극, 냉자극 및 미각 유해수용성 자극의 인지를 포함한 감각변화가 폐경기후 생식스테로이드의 급격한 감소가 신경활성 스테로이드 생성에 변성을 일으켜며, 이것은 말초성 변성와 중추성 변성이 존재함을 제시한다. 구강작열감 증후군은 기본적으로 가능한 요인을 제거하는 것이 중요하므로 구강작열감의 진행을 방지하고, 만정적인 작열감의 경감을 위하여 증상 경과에 영향을 미칠 수 있는 수면에 대하여 고찰하고자 한다.