• The Korean Journal of Physiology and Pharmacology
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• v.19 no.2
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• pp.125-130
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• 2015

Cholecystokinin is known to be involved in the modulation of nociception and to reduce the efficacy of morphine analgesia. This study investigated the effects of intrathecal administration of morphine and the cholecystokinin type B antagonist CI-988 on below-level neuropathic pain after spinal cord injury in rats. We also examined the interaction of morphine and CI-988 in the antinociceptive effect. Both morphine and CI-988 given individually increased the paw withdrawal threshold to mechanical stimulation in a dose-dependent manner. The combination of ineffective doses of intrathecally administered CI-988 and morphine produced significant analgesic effects and the combination of effective doses resulted in analgesic effects that were greater than the sum of the individual effects of each drug. Thus, morphine showed a synergistic interaction with CI-988 for analgesia of central neuropathic pain.

• 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.30 no.4
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• pp.272-280
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• 2017

Background: The high cost of intrathecal morphine pump (ITMP) implantation may be the main obstacle to its use. Since July 2014, the Korean national health insurance (NHI) program began paying 50% of the ITMP implantation cost in select refractory chronic pain patients. The aims of this study were to investigate the financial break-even point and patients' satisfaction in patients with ITMP treatment after the initiation of the NHI reimbursement. Methods: We collected data retrospectively or via direct phone calls to patients who underwent ITMP implantation at a single university-based tertiary hospital between July 2014 and May 2016. Pain severity, changes in the morphine equivalent daily dosage (MEDD), any adverse events, and patients' satisfaction were determined. We calculated the financial break-even point of ITMP implantation via investigating the patient's actual medical costs and insurance information. Results: During the studied period, 23 patients received ITMP implantation, and 20 patients were included in our study. Scores on an 11-point numeric rating scale (NRS) for pain were significantly reduced compared to the baseline value (P < 0.001). The MEDD before ITMP implantation was 0.59 [IQR: 0.55-0.82]. The total MEDD increased steadily to 0.77 [IQR: 0.53-1.08] at 1 year, which was 126% of the baseline (P < 0.001). More than a half (60%) responded that the ITMP therapy was somewhat satisfying. The financial break-even point was 28 months for ITMP treatment after the NHI reimbursement policy. Conclusions: ITMP provided effective chronic pain management with improved satisfaction and reasonable financial break-even point of 28 months with 50% financial coverage by NHI program.

• Journal of Ginseng Research
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• v.15 no.1
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• pp.6-12
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• 1991

The analgesic effect of morphine was antagonized in mice pretreated with ginseng total saponin intraperitoneally, intracerebrally and intrathecally. The antagonized effects of morphine analgesia were reversed predominantly by treatment with L-3, 4-dihydroxyphenylalanine in the tail pinch test and 5-hydroxytryptophan in the tail flick test respectively. These indicate that the antagonistic action of ginseng total saponin might be due to their inhibitions of the activation of descending ihibitory systems at the cerebral site as well as spinal. In addition, any appreciable changes of brain biogenic monoamine levels were not observed in mice pretreated with ginseng total saponin at various time intervals. These results obtained suggest that a newly equilibrated state of neurologic function could be found in mice pretreated with ginseng total saponin, and modification of neurologic function in the mechanism for the antagonism of morphine analgesia by ginseng total saponin was more important than the changes of brain biogenic monoamine levels.

• The Korean Journal of Physiology
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• v.29 no.2
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• pp.309-321
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• 1995

In the present study, the relationship between the somatosympathetic reflexes and arterial blood pressure responses to electrical stimulation of the peripheral nerve was investigated in cats anesthetized with ${\alpha}-chloralose$. Single sympathetic postganglionic fiber activities were recorded from the hindlimb muscle and skin nerves and also from the cervical and abdominal sympathetic chains. Effects of the morphine on responses of the sympathetic nerve and arterial blood pressure to activation of the peripheral $A{\delta}-$ and C-afferent nerves were analyzed. The following results were obtained. 1) Arterial blood pressure was depressed by peripheral AS-afferent stimulation (A-response) and was elevated during C-afferent activation (C-response). 2) Intravenously administered morphine enhanced the C-response while the A-response decreased insignificantly, Only the C-response was decreased by intrathecal morphine. 3) All the ten recorded cutaneous sympathetic fibers showed periodic discharge pattern similar to respiratory rhythm and five of them also showed cardiac-related rhythm. However, most of the muscular sympathetic fibers had cardiac-related rhythm and only four fibers showed respiratory rhythm. 4) Morphine decreased the sympathetic C-reflex elicited by the peripheral C-afferent activation and the abdominal sympathetic A-reflex was also decreased by morphine. From the above results, it was concluded that supraspinal mechanisms were involved in the enhanced arterial pressor response to peripheral C-afferent activation by intravenous morphine.

• The Korean Journal of Pain
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• v.9 no.1
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• pp.69-74
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• 1996

Background: Efficacy of spinal opioids for the treatment of intractable cancer pain has been reported by several authors. The epidural route seems to be a more reliable and effective method of pain control as compared to the intrathecal route which can lead to opioids by portal system. Methods: Medical records were reviewed of 18 patients who had been treated with epidural morphine via an implanted port-A-Cath from Mar. 1991 to Sep. 1994. Results: Patients were treated for a mean of 92 days. There were wide variation of dose requirements. The minimum daily dose ranged from 2 to 10mg, and maximum daily dose from 3 to 30 mg. Verbal rating scale were below moderate until 100th days after posrtal implantation. When 3 patients suffered from aggravated pain associated with vertebral metastasis. Five of 11 patients who were administered medication longer than 50 days reguired increased doses ranging from 3 mg to 25 mg which were higher as compared to initial doses. These patients also experienced pain due to vertebral metastasis. There were no report of epidural scarring, respiratory depression, epidural infections, meningitis, or catheter blockade. Conclusion: Continuous epidural morphine administration via Port-A-Cath is an effective method with minimal complication.

• The Korean Journal of Pain
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• v.1 no.1
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• pp.91-97
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• 1988

Herein is a review of eigthy six surgical cases from March to August, 1986 which recieved tetracaine hydrochloride spinal anesthesia. In an attempt to relieve postoperative pain, 0.5 mg morphine sulfate was administrated into the lumbar subarachnoid space. Pruritus, a side effect of intraspinal morphine, was explored in detail. The results were as follows : 1) The incidence of pruritus was 67.4%, 65.5% in man and 71.0% in woman. 2) The time of onset of pruritus was between 30 and 120 minutes with an average of 79.1 minutes. 3) Pruritus primary occurred on the face(87.9%), especially on the nasal, perinasal and periocular areas. Other sites included the scalp, neck, chest, abdomen, shoulder, hip, thigh, flank, and whole body. 4) The severity of pruritus was classified as mild and moderate, but 4 cases(6.9%) were regarded as severe and were treated with naloxone. 5) The duration of pruritus was from 15 minutes to 19 hours with an average of 4.7 hours. 6) There was no significant difference in the prevention of pruritus between the group recieving diphenhydramine and the one which received normal saline.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.5
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• pp.281-288
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• 2004

The present study was undertaken to confirm whether melittin, a major constituent of whole bee venom (WBV), had the ability to produce the same nociceptive responses as those induced by WBV. In the behavioral experiment, changes in mechanical threshold, flinching behaviors and paw thickness (edema) were measured after intraplantar (i.pl.) injection of WBV (0.1 mg & 0.3 mg/paw) and melittin (0.05 mg & 0.15 mg/paw), and intrathecal (i.t.) injection of melittin $(6{\mu}g)$. Also studied were the effects of i.p. (2 mg & 4 mg/kg), i.t. $(0.2{\mu}g\;&\;0.4{\mu}g)$ or i.pl. (0.3 mg) administration of morphine on melittin-induced pain responses. I.pl. injection of melittin at half the dosage of WBV strongly reduced mechanical threshold, and increased flinchings and paw thickness to a similar extent as those induced by WBV. Melittin- and WBV-induced flinchings and changes in mechanical threshold were dose- dependent and had a rapid onset. Paw thickness increased maximally about 1 hr after melittin and WBV treatment. Time-courses of nociceptive responses induced by melittin and WBV were very similar. Melittin-induced decreases in mechanical threshold and flinchings were suppressed by i.p., i.t. or i.pl. injection of morphine. I.t. administration of melittin $(6{\mu}g)$ reduced mechanical threshold of peripheral receptive field and induced flinching behaviors, but did not cause any increase in paw thickness. In the electrophysiological study, i.pl. injection of melittin increased discharge rates of dorsal horn neurons only with C fiber inputs from the peripheral receptive field, which were almost completely blocked by topical application of lidocaine to the sciatic nerve. These findings suggest that pain behaviors induced by WBV are mediated by melittin-induced activation of C afferent fiber, that the melittin-induced pain model is a very useful model for the study of pain, and that melittin-induced nociceptive responses are sensitive to the widely used analgesics, morphine.

• The Korean Journal of Pain
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• v.27 no.3
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• pp.200-209
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• 2014

Background: Spinal opioid administration is an excellent option to separate the desirable analgesic effects of opioids from their expected dose-limiting side effects to improve postoperative analgesia. Therefore, physicians must better identify either specific opioids or adequate doses and routes of administration that result in a mainly spinal site of action rather than a cerebral analgesic one. Methods: The purpose of this topical review is to describe current available clinical evidence to determine what opioids reach high enough concentrations to produce spinally selective analgesia when given by epidural or intrathecal routes and also to make recommendations regarding their rational and safety use for the best management of postoperative pain. To this end, a search of Medline/Embase was conducted to identify all articles published up to December 2013 on this topic. Results: Recent advances in spinal opioid bioavailability, based on both animals and humans trials support the theory that spinal opioid bioavailability is inversely proportional to the drug lipid solubility, which is higher in hydrophilic opioids like morphine, diamorphine and hydromorphone than lipophilic ones like alfentanil, fentanyl and sufentanil. Conclusions: Results obtained from meta-analyses of RTCs is considered to be the 'highest' level and support their use. However, it's a fact that meta-analyses based on studies about treatment of postoperative pain should explore clinical surgery heterogeneity to improve patient's outcome. This observation forces physicians to use of a specific procedure surgical-based practical guideline. A vigilance protocol is also needed to achieve a good postoperative analgesia in terms of efficacy and security.

• The Korean Journal of Pain
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• v.9 no.2
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• pp.311-317
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• 1996

Background: Following peripheral nerve injury, rats will show a tactile allodynia and hyperalgesia. But the mechanism of allodynia is still obscure. Previous studies have shown this allodynia was reversed by intrathecal alpha-2 agonists and NMDA antagonists, but not by morphine. In formalin test, either the pretreatment of NMDA antagonist or morphine prevents the hyperalgesia. The present studies, using rats rendered allodynic by ligation of the left L5 and L6 nerves, aimed to investigate the effects of pretreatment of MK-801 and morphine on the development of tactile allodynia. Methods and Material: Male Sprague-Dawley rats (100~150g) were anesthetized with halothane, the left L5 and L6 spinal nerves were ligated tightly by 6-0 black silk. For sham operation muscle dissection was performed but the spinal nerve was not ligated. For pretreatment of drugs, MK-801 (NMDA antagonist; 0.3 mg/kg). CNQX (non-NMDA) antagonist; 0.3 mg/kg), morphine (1 mg/kg) or saline (placebo) was administered subcutaneously 30 minutes before operation. A second dose was administered subcutaneously 24 hours after operation and further doses were given daily for 2 days further. The volume of injection was 5 ml/kg. To assess the mechanical allodynia, paw withdrawal thresholds of ipsilateral limb were determined using 8 von Frey hairs. Results: Within 2 days saline, CNQX or morphine injected rats developed tactile allodynia (paw withdrawal threshold was about 2g), and persisted for over 2 weeks. Pretreatment of MK-801 delayed the development of tactile allodynia for 3 days comparing to that of saline injected rat. Conclusion: NMDA receptor in the central nerve system plays an important role in the development of tactile allodynia induced by peripheral nerve injury. But the mechanism may be different from hyperalgesia developed in formalin test.