• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.246-246
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• 1996

The glucuronide conjugates of morphine have been claimed to exert significant neuropharmacological effects. Morphine-6-glucuronide (M6G) may be a potent opioid agonist in vivo, and morphine-3-glucuronide (M3G) may act as a weak opioid antagonist. The present study addressed the permeability of the blood-brain barrier (BBB) for these metabolites compared to morphine. Tracers were prepared by enzymatic glucuronidation of U-methyl-$^3$H]-morphine. Brain uptake in rats was measured by the internal carotid artery perfusion technique and after i.v. bolus injections. In the perfusion experiments morphine showed a permeability-surface area product (PS) of 3.52${\pm}$0.61 ${\mu}$L min$\^$-1/ g$\^$-1/ Uptake seems to be mediated by passive diffusion and was not saturable by 100 ${\mu}$M morphine in the perfusate. The BBB permeability of [$^3$H]-M3G and [$^3$H]-M6G was too low to be quantified after 5 min of perfusion. Brain uptake of [$^3$H]-M3G and [$^3$H]-M6G 60 min after i.v. bolus injection reached 0.0060${\pm}$0.0003 and 0.0030${\pm}$0.0005% injected dose per g, respectively. From these brain concentrations and from the corresponding plasma concentration - time curves, BBB PS values of 0.14${\pm}$ 0.02 ${\mu}$L min$\^$-1/g$\^$-1/ and 0.11 ${\pm}$ 0.01 ${\mu}$L min$\^$-1/g$\^$-1/, respectively, were calculated. The ratio of BBB PS values is complementary to the analgesic potencies of morphine and M6G after different routes of administration. The low PS of MSG explains, why it is approximate]y equipotent to morphine after systemic injection, although it is about 2 orders of magnitude more potent than morphine after administration directly into the central nervous system.

• The Korean Journal of Pain
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• 제22권1호
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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.

• Journal of Oral Medicine and Pain
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• 제38권4호
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• pp.339-356
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• 2013

이 연구에서는 말초 opioid 수용체를 이용한 저작근 통증 조절 시 성별 효과의 차이를 확인하고자 RDC/TMD로 진단된 지원자 남성 20명, 여성 20명을 saline 주사군, lidocaine 주사군, morphine 1.5 mg 주사군, morphine 3 mg 주사군 각각 5명씩 배정하였다. 통증부위에 주사 전, 주사 후 1시간, 24시간, 48시간에 각각 주관적인 통증 평가인 시각유추척도평가, 맥길통증설문지 평가, 통증부위표시평가 그리고 객관적인 통증 평가인 압력통증역치평가와 압력통증한계평가를 실시하였다. 검사 후 평가된 자료를 통계 처리하여 다음과 같은 결과를 얻었다. 1. 시각유추척도평가에서는 남녀 모두가 morphine 3 mg군에서 통계학적으로 유의성 있는 효과가 있었다. (male: p<0.05, female: p<0.05) 2. 맥길통증설문지 평가에서는 남녀 모두가 morphine 1.5 mg군 보다 morphine 3 mg군에서 더 통계학적으로 유의성 있는 효과가 있었다. (male: p<0.001, female: p<0.01) 3. 통증부위표시평가와 압력통증역치평가에서는 남성이 morphine 3 mg군에서 통계학적으로 유의성 있는 효과가 있었다. (PD: p<0.001, PPT: p<0.05) 이상의 연구 결과로 저작근 통증을 조절하기 위해서 morphine 3 mg을 통증부위에 주사한 경우 객관적인 통증 평가에서 여성 환자보다 남성 환자에게 더 효과가 있다는 것을 알 수 있었으며, 앞으로 시간에 따른 그리고 용량에 따른 남녀 치료효과의 차이에 관한 연구가 더 필요 할 것으로 생각된다.

• The Korean Journal of Pain
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• 제14권2호
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• pp.225-230
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• 2001

Background: Opioids such as morphine are widely used in the treatment for pain, but chronic treatment with morphine can be complicated by the development of tolerance. The mechnisms of tolerance were still not completely understood, but recently it has been reported that NOS inhibitors can prevent development of morphine tolerance in animals. The present study accessed the possible role of supraspinal NO on antinociceptive effect of morphine in morphine tolerance using a highly specific inhibitor of the neuronal isoform of NOS, 1-(2-trifluoromethylphenyl) imidazole (TRIM). Methods: Thirty two male SD rats (300 g) were prepared with intracerebroventricular (icv) and IV cannulae. We administrated IV morphine, 3 mg/kg, daily for 4 days, resulting in tolerance. On the fifth day, a challenge dose of morphine, 3 mg/kg, was administered following pretreatment with icv TRIM, $10{\mu}g$. We also evaluated the antinociceptive effect of icv TRIM alone and the effect on a single dose of morphine (3 mg/kg) in morphine nave rats. Antinociception from morphine was determined by response to intraplantar injection of 5% formalin $100{\mu}l$ was qualified as the number of flinches in the first 0-10 min (first phase), 10-40 min Phase IIa, and 40-60 min (Phase IIb). Results: Pretreatment with icv TRIM significantly enhanced the antinociceptive effects of systemically administered morphine in morphine tolerant rats. The antinociceptive effect of morphine in opioid nave rats was also significantly increased by pretreatment with icv TRIM. Conclusions: Our results further support the hypothesis that supraspinal NO modulates morphine-sensitive nociceptive process in morphine tolerance due to chronic intravenous administration.

• The Korean Journal of Pain
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• 제12권1호
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• pp.95-100
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• 1999

Background: About 75% of terminal cancer patients have severe pain. For the treatment of these patients, physicians usually use potent opioid analgesics. But many of the cancer patients were not controlled by IV or IM injection of opioids. In spite of the untreatable nature of the patient's illness, they should be hospitalized only for pain control. In that case, epidural opioid injection is one of the most effective methods in pain management. Methods: We retrospectively analyzed 126 terminal cancer patients who were treated with epidural morphine for pain management from 1993-97. In the routine procedure, an epidural catheter was inserted into the epidural space and tunnelled subcutaneously, exiting out from the anterior chest or abdomen. Morphine was used as the main analgesic and Multiday Infusor$^{(R)}$ (Baxter, 0.5 ml/h) as a continuous infusion system. Results: 1. Mean treatment time was 55 days (range; 3~373). 2. Mean daily epidural start mg dose of morphine was 8 mg (range; 2~20). 3. Mean daily dose at termination was 19 mg (range; 4~60) 4. 94 patients were controlled with continuous infusion but 32 patients needed additional bolus doses of morphine. 5. heter-associated subcutaneous infection occurred in 2 patients (1.6%). Conclusion: Terminal cancer pain management administered by a tunnelled epidural catheter is a simple, inexpensive method with a very small rate of infection.

• The Korean Journal of Pain
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• 제18권1호
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• pp.1-9
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• 2005

Background: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. Results: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. Conclusions: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

• 대한약리학회지
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• 제31권1호
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• pp.17-26
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• 1995

8주, 18주, 그리고 32주된 Spontaneously Hypertensive Rats (SHR)과 Wistar-Kyoto Rats(WKY)과의 blood pressure(혈압)를 측정하여본 결과 SHR 그룹이 WKY에 비해 19에서 70 mmHg 차이로 SHR 그룹이 WKY group에 비하여 혈압이 높았다. 18주된 SHR과 WKY에서 제 3 뇌실내 (intraventricular)로 투여된 morphine과 ${\beta}-endorphin$의 진통작용을 검색하여 보았다. WKY group에 비하여 SHR group에서 뇌실내로 투여된 ${\beta}-endorphin$은 진통작용에 있어서 상승작용 (potentiation)을 보임을 발견하였고 뇌실내로 투여된 morphine은 SHR group에서 약간만 상승작용을 보였다. SHR과 WKY group간에 opioid의 진통작용에 있어서 중요한 역할을 하는 Midbrain과 Medulla (pons), 그리고 spinal cord (척수)의 lumbar부위의 $[Met^5]-enkephalin$과 proenkep-halin A mRNA level을 측정하여 보았다. SHR과 WKY group간의 $[Met^5]-enkephalin$과 proenkephalin mRNA의 양은 별로 차이를 보이지 않았다. 이러한 결과로 미루어 볼때 SHR group에서 뇌실내로 투여된 ${\beta}-endorphin$은 그의 진통효과에 있어서 보인 상승작용은 척수상부에 위치하고 있는 opioid deptide의 양이 변해서가 아니라 다른 기전에 의하여 조절되어지고 있음을 시사한다.

• The Korean Journal of Pain
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• 제26권3호
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• pp.265-269
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• 2013

Background: Transforaminal epidural steroid injections are known to reduce inflammation by inhibiting synthesis of various proinflammatory mediators and have been used increasingly. The anti-inflammatory properties of opioids are not as fully understood but apparently involve antagonism sensory neuron excitability and pro-inflammatory neuropeptide release. To date, no studies have addressed the efficacy of transforaminal epidural morphine in patients with radicular pain, and none have directly compared morphine with a tramadol for this indication. The aim of this study was to compare morphine and tramadol analgesia when administered via epidural injection to patients with lumbar radicular pain. Methods: A total of 59 patients were randomly allocated to 1 of 2 treatment groups and followed for 3 months after procedure. Each patient was subjected to C-arm guided transforaminal epidural injection (TFEI) of an affected nerve root. As assigned, patients received either morphine sulfate (2.5 mg/2.5 ml) or tramadol (25 mg/0.5 ml) in combination with 0.2% ropivacaine (1 ml). Using numeric rating scale was subsequently rates at 2 weeks and 3 months following injection for comparison with baseline. Results: Both groups had significantly lower mean pain scores at 2 weeks and at 3 months after treatment, but outcomes did not differ significantly between groups. Conclusions: TFEI of an opioid plus local anesthetic proved effective in treating radicular pain. Although morphine surpassed tramadol in pain relief scores, the difference was not statistically significant.

• Bulletin of the Korean Chemical Society
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• 제29권3호
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• pp.656-662
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• 2008

Antagonists of the d -opioid receptor are effective in overcoming resistance against analgesic drugs such as morphine. To identify novel antagonists of the d -opioid receptor that display high potency and low resistance, we performed 3D-QSAR analysis using chemical feature-based pharmacophore models. Chemical features for d -opioid receptor antagonists were generated using quantitative (Catalyst/HypoGen) and qualitative (Catalyst/HipHop) approaches. For HypoGen analysis, we collected 16 peptide and 16 non-peptide antagonists as the training set. The best-fit pharmacophore hypotheses of the two antagonist models comprised identical features, including a hydrophobic aromatic (HAR), a hydrophobic (HY), and a positive ionizable (PI) function. The training set of the HipHop model was constructed with three launched opioid drugs. The best hypothesis from HipHop included four features: an HAR, an HY, a hydrogen bond donor (HBD), and a PI function. Based on these results, we confirm that HY, HAR and PI features are essential for effective antagonism of the d -opioid receptor, and determine the appropriate pharmacophore to design such antagonists.

• The Korean Journal of Pain
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• 제11권1호
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• pp.109-112
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• 1998

The sympathetic nervous system has been implicated as an important factor contributing to causalgia. Basis on reports of presence of opioid receptors in sympathetic autonomic ganglia, including human stellate ganglion, we administered morphine in stellate ganglion block for a patient with causalgia. The patient suffering from brachial plexus injury treated with stellate ganglion block in conjunction with physical therapy. Stellate ganglion block was performed in a paratracheal approach by injection of 1% lidocaine, or 0.25% bupivacaine 8 ml, with morpine 1 mg. Patient's symptoms were dramatically improved after 13 stellate ganglion blocks.