• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.6.1-6.12
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• 2018

Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a ${\mu}$ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.

• 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 Pain
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• v.31 no.2
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• pp.102-108
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• 2018

Background: Nefopam is a non-opioid, non-steroidal analgesic drug with fewer adverse effects than narcotic analgesics and nonsteroidal anti-inflammatory drugs, and is widely used for postoperative pain control. Because nefopam sometimes causes side effects such as nausea, vomiting, somnolence, hyperhidrosis and injection-related pain, manufacturers are advised to infuse it slowly, over a duration of 15 minutes. Nevertheless, pain at the injection site is very common. Therefore, we investigated the effect of warmed carrier fluid on nefopam injection-induced pain. Methods: A total of 48 patients were randomly selected and allocated to either a control or a warming group. Warming was performed by diluting 40 mg of nefopam in 100 ml of normal saline heated to $31-32^{\circ}C$ using two fluid warmers. The control group was administered 40 mg of nefopam dissolved in 100 ml of normal saline stored at room temperature ($21-22^{\circ}C$) through the fluid warmers, but the fluid warmers were not activated. Results: The pain intensity was lower in the warming group than in the control group (P < 0.001). The pain severity and tolerance measurements also showed statistically significant differences between groups (P < 0.001). In the analysis of vital signs before and after the injection, the mean blood pressure after the injection differed significantly between the groups (P = 0.005), but the heart rate did not. The incidence of hypertension also showed a significant difference between groups (P = 0.017). Conclusions: Use of warmed carrier fluid for nefopam injection decreased injection-induced pain compared to mildly cool carrier fluid.

• Journal of Oral Medicine and Pain
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• v.38 no.4
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• pp.339-356
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• 2013

This study was designed to evaluate the sex differences in the pain control effect by morphine injection to masticatory muscle pain patients. Patients with masticatory muscle pain visited the Department of Oral Medicine, Kyung Hee University Dental Hospital were recruited to this study and diagnosed by RDC/TMD. Experimental group were divided into four group each from male (n=20) and female (n=20); saline injection group (n=5), lidocaine injection group (n=5), morphine 1.5 mg injection group (n=5) and morphine 3 mg injection group (n=5). Evaluation list was the subjective pain evaluation(visual analogue scale, Mc Gill pain questionnaire, pain drawing) and the objective pain evaluation(pressure pain threshold, pressure pain tolerance) and evaluation time was injection before, after 1 hour, 24 hour, 48 hour and then it was analyzed statistically. The results were as follows : 1. The male and female were significantly different statistically morphine 3 mg group in visual analogue scale evaluation. (male: p<0.05, female: p<0.05) 2. The male and female were more significantly different statistically morphine 3 mg group than morphine 1.5 mg group in McGill pain questionnaire evaluation. (male: p<0.001, female: p<0.01) 3. The male were significantly different statistically morphine 3 mg group in pain drawing evaluation and pressure pain threshold evaluation. (PD: p<0.001, PPT: p<0.05) Therefore, it was revealed that the morphine 3 mg injection for masticatory muscle pain was effective to pain control male patients and more effect than female patients in the objective pain evaluation.

• Korean Journal of Biological Psychiatry
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• v.5 no.1
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• pp.34-45
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• 1998

We provide the reader with a brief introduction to the neurobiology of neuropeptides. Several comprehensive reviews of the distribution and neurochemical, neurophysiological, neuropharmacological and behavioral effects of the major neuropeptides have recently appeared. In reviews of the large number of neuropeptides in brain and their occurance in brain regions thought to be involved in the pathogenesis of major psychiatric disorders, investigators have sought to determine whether alternations in neuropeptide systems are associated with schizophrenia, mood disorders, anxiety disorders, alcoholism and neurodegenerative disease. There is no longer any doubt that neuropeptide-containing neurons are altered in several neuropsychiatric disorders. One of the factors that has hindered neuropeptide research to a considerable extent is the lack of pharmacological agents that specifically alter the synaptic availability of neuropeptides. With the exception of naloxone and naltrexone, the opiate-receptor antagonists, there are few available neuropeptide- receptor antagonists. Two independent classes of neuropeptide-receptor antagonists has been expected to be clinically useful. Naltrexone, a potent ${\mu}$-receptor antagonist, has been used successfully to reduce the need for alcohol consumption. And cholecycstokinin antagonists are now in development as a new class of anxiolytics, which would be expected to be free from tolerance and physical dependence and lack of sedation. In this review, we deal with these two kinds of neuropeptide system, the opioid system and cholesystokinins in the brain. The role of opioid systems in the reinforcement after alcohol consumtion and that of cholesystokinins in the pathogenesis of anxiety will be discussed briefly. As we know, the future for neuropeptides in psychiatry remains bright indeed.

• Journal of Oral Medicine and Pain
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• v.38 no.2
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• pp.161-174
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• 2013

This study was designed to evaluate the pain control effect by morphine injection to masticatory muscle pain patients. Patients with masticatory muscle pain visited the Department of Oral Medicine, Kyung Hee University Dental Hospital were recruited to this study and diagnosed by RDC/TMD. Experimental group were divided into four group; saline injection group (n=10), lidocaine injection group (n=10), morphine 1.5 mg injection group (n=10) and morphine 3 mg injection group (n=10). Evaluation list was the subjective pain evaluation(visual analogue scale, Mc Gill pain questionnaire, pain drawing) and the objective pain evaluation(pressure pain threshold, pressure pain tolerance) and evaluation time was injection before, after 1 hour, 24 hour, 48 hour and then it was analyzed statistically. The results were as follows : 1. The subjective pain evaluation were significantly different statistically in morphine 3 mg group after 48 hour. (VAS: p<0.01, MGQ: p<0.001, PD: p<0.05) 2. The objective pain evaluation were significantly different statistically in morphine 1.5 mg group after 1 hour. (PPT: p<0.01, PPTol: p<0.05) 3. The morphine 3 mg group were more significantly different than lidocaine group and morphine 1.5 mg group statistically in the McGill pain questionnaire evaluation. (1h: p<0.01, 24h: p<0.01, 48h: p<0.001) Therefore, it was revealed that the morphine 3 mg injection was effective to pain control for masticatory muscle pain patients within 48 hours and more effect than lidocaine injection.

• Proceedings of the PSK Conference
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• 2000.04a
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• pp.70-81
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• 2000

DA-5018 is a synthetic capsaicin derivative under development as a non-narcotic a analgesic ag$\varepsilon$nt. DA-50 18 showed a potent analgesic activity against acute and chronic pain m model(Tablel, 2.), but it had a narrow margin of safety. DA-5018 did not bind to opioid(${\kappa}, {\delta}, {\mu}$), NKl, CGRP receptors in vitro and its analgesic effect was not antagonized by naloxone, a and it did not develop analgesic tolerance. In addition DA-5018 had no inhibitory effects against c cyclooxygenase and 5-lipooxygenase activities. DA-5018 significantly increased the relcase of substance P from the slices of the rat spinal cord. These results suggest that DA-50 18 is not a narcotic nor aspirin-like analgesic and the release of substance P is one of analgesic mechanism of action of DA-5018. We found that DA-5018 was almost ten times more potent and was at l least IOO-times less irritable compared to capsaicin. Accordingly development of topical formula was adopted. Topical formula was desiged and screened by flux test of DA-5018 using hairless mouse skin and several formulas were selected. With these topical formulas we a assessed the analgesic efficacy and carried out the toxicity, skin irritation and pharmacokinetic studies. In streptozotocin-induced hyperalgesic rat and 50 % galactose-fed hyperalgesic rat as diabetic pain models, DA-5018 cream increased the pain thresh이ds up to 77.0% and 24.4% respectively, while Zostrix-HP(capsaicin cream) incr$\varepsilon$as cd by 65.9% and 21.0%. DA-5018 c cream showed a good analgesic effect as welI in FCA-induced arthritic rat. DA-5018 cream did not show any toxicological signs in acute and chronic toxicity test and had little skin irritation in car swclIing and scratching t$\varepsilon$st. Pharmacokinetics of DA-50 18 were studied after topical application of ${14}^C$-Iabelled or unlabelIed DA-5018 cream. Plasma and skin concentrations c except applied skin wcre below the dctection limit and after 7-day cummulative application, plasma concentrations were also below detection limit DA-50 18 may have an advantag$\varepsilon$ ov$\varepsilon$r c capsaicin and is now being developed as a topical agent for the treatment of pains. DA-50 18 cream was approved for Korean IND and is now under a Phase II clinical study for arthritic pain a after finising Phase I study. DA-50 18 was also liscensed out to Stiefel Company in America in