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- Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. [JOURNAL ARTICLE]
- Eur J Pain 2014 Apr 22.
Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of 5' adenosine monophosphate-activated protein kinase (AMPK) activator resveratrol and AICAR to inhibit microglial activation and to limit the decrease in antinociceptive effects of morphine.The microglial cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using the hot plate and tail-flick tests.(1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase phosphorylation, nuclear factor-κB translocation and mRNA expression of pro-inflammatory cytokines [including interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α], inducible nitric oxide synthase and Toll-like receptor-4, and these changes are inhibited by resveratrol. (2) Resveratrol activates AMPK to suppress morphine-induced BV-2 cell activation. AICAR, another AMPK activator, can mimic the effects of resveratrol, whereas compound C, an AMPK inhibitor, reverses the inhibitory effects of resveratrol treatment. (3) Systemic or spinal administration of resveratrol with morphine significantly blocks microglial activation in the spinal cord and then attenuates the development of acute and chronic morphine tolerance in both male and female mice.Resveratrol directly suppresses morphine-induced microglial activation through activating AMPK, resulting in significant attenuation of morphine antinociceptive tolerance.
- Changes in trends and pattern of strong opioid prescribing in primary care. [JOURNAL ARTICLE]
- Eur J Pain 2014 Apr 22.
This study evaluated the prescribing trends of four commonly prescribed strong opioids in primary care and explored utilization in non-cancer and cancer users.This cross-sectional study was conducted from 2000 to 2010 using the UK Clinical Practice Research Datalink. Prescriptions of buprenorphine, fentanyl, morphine and oxycodone issued to adult patients were included in this study. Opioid prescriptions issued after patients had cancer medical codes were defined as cancer-related use; otherwise, they were considered non-cancer use. Annual number of prescriptions and patients, defined daily dose (DDD/1000 inhabitants/day) and oral morphine equivalent (OMEQ) dose were measured in repeat cross-sectional estimates.In total, there were 2,672,022 prescriptions (87.8% for non-cancer) of strong opioids for 178,692 users (59.9% female, 83.9% non-cancer, mean age 67.1 ± 17.0 years) during the study period. The mean annual (DDD/1000 inhabitants/day) was higher in the non-cancer group than in the cancer group for all four opioids; morphine (0.73 ± 0.28 vs. 0.12 ± 0.04), fentanyl (0.46 ± 0.29 vs. 0.06 ± 0.24), oxycodone (0.24 ± 0.19 vs. 0.038 ± 0.028) and buprenorphine (0.23 ± 0.15 vs. 0.008 ± 0.006). The highest proportion of patients were prescribed low opioid doses (OMEQ ≤ 50 mg/day) in both non-cancer (50.3%) and cancer (39.9%) groups, followed by the dose ranks of 51-100 mg/day (26.2% vs. 28.7%), 101-200 mg/day (15.1% vs. 19.2%) and >200 mg/day (8.25% vs. 12.1%).There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time.
- Predisposing effects of neonatal visceral pain on abuse-related effects of morphine in adult male Sprague Dawley rats. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Apr 23.
Adverse early life experiences are risk factors for drug abuse and addiction. Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but the impact of these changes on abuse-related effects of morphine are unknown. The NVP procedure used models chronic visceral hyperalgesia persisting across development.Intravenous self-administration, drug discrimination, and locomotor activity were used to compare the abuse-related effects of morphine in NVP and control rats.Rats self-administered 0.3 mg/kg/inj morphine under an FR1 schedule, and dose-effect functions for morphine were then established. Separate rats were trained to discriminate 3.2 mg/kg morphine from saline under an FR20 schedule, and morphine dose-effect functions were then determined in the absence and presence of 0.1 mg/kg naltrexone. A third group of rats was tested with a range of morphine doses in an assay of locomotor activity, then injected daily with 10 mg/kg morphine to assess locomotor sensitization.NVP rats self-administered more morphine than controls at reinforcing doses. Discriminative stimulus effects of morphine were similar between groups, but in the presence of naltrexone, the ED50 for morphine was more than 12× greater in control rats than in NVP animals. Morphine did not stimulate locomotor activity at any tested dose in NVP rats, although significant effects were observed in controls. Finally, significant locomotor sensitization was observed only in NVP rats.NVP-induced changes in brain opioid systems have persistent pharmacological consequences into adulthood and may increase sensitivity to abuse-related effects of opioids across development.
- An Ethnographic Study of Barriers to Cancer Pain Management and Opioid Availability in India. [JOURNAL ARTICLE]
- Oncologist 2014 Apr 22.
The world's global cancer burden disproportionally affects lower income countries, where 80% of patients present with late-stage disease and have limited access to palliative care and effective pain-relieving medications, such as morphine. Consequently, millions die each year with unrelieved pain.Objective.The objective of this study was to examine barriers to opioid availability and cancer pain management in India, with an emphasis on the experiences of nurses, who are often the front-line providers of palliative care.Methods.Fifty-nine participants were recruited using a purposive, snowball sampling strategy. Ethnographic data collection included in-depth, semistructured interviews (n = 54), 400+ hours of participant observation, and review of documents over 9 months at a government cancer hospital in South India. Systematic qualitative analysis led to identification of key barriers that are exemplified by representative quotes.Results.Morphine is more available at this study site than in most of India, but access is limited to patients seen by the palliative care service, and significant gaps in supply still occur. Systems to measure and improve pain outcomes are largely absent. Key barriers related to pain management include the role of nursing, opioid misperceptions, bureaucratic hurdles, and sociocultural/infrastructure challenges.Implications.Interventions must streamline process details of morphine procurement, work within the existing sociocultural infrastructure to ensure opioids reach patients most in need, target unexpected audiences for symptom management education, and account for role expectations of health care providers.Conclusion.Macro- and micro-level policy and practice changes are needed to improve opioid availability and cancer pain management in India.
- Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats. [JOURNAL ARTICLE]
- Behav Brain Res 2014 Apr 19.
The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5mg/kg, i.p.). Donepezil (0.5, 1, and 3mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1mg/kg, i.p.) were given 20min before morphine during conditioning phase and 20min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1mg/kg) and rivastigmine (0.5mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors.
- Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia. [JOURNAL ARTICLE]
- Int J Clin Pharmacol Ther 2014 Apr 22.
Objective: Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post-operative analgesics on the immune systems of patients undergoing gastric cancer surgery. Methods: 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T-lymphocyte subsets (CD3+, CD4+, and CD8+) and natural killer cells (CD3-CD16+CD56+) were evaluated. Results: No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3+, CD4+, CD4+/CD8+, and CD3-CD16+CD56+ decreased at 2 hours after incision and, except for CD3-CD16+CD56+, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3-CD16+CD56+ at 2 hours after incision and the expression of CD3+, CD4+, CD4+/CD8+, and CD3-CD16+CD56+ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. Conclusion: The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery.
- Dexmedetomidine improves the histological and neurological outcomes 48 hours after transient spinal ischemia in rats. [JOURNAL ARTICLE]
- Brain Res 2014 Apr 19.
Dexmedetomidine, an α2 adrenoceptor agonist, provides neuroprotection against various cerebral ischemia models through its anti-apoptotic effects. Dexmedetomidine also improves paraplegia induced by intrathecal morphine after short-term spinal ischemia. However, there are no reports regarding dexmedetomidine's ability to provide neuroprotection solely against transient spinal ischemia. We investigated whether dexmedetomidine would provide spinal protection following transient spinal ischemia in rats. Adult male Sprague Dawley rats were randomly assigned to one of the following five groups: 1) intravenous infusion of 0.9% NaCl at the rate of 0.5mL/h (control), 2) dexmedetomidine 0.1µg/kg/h, 3) dexmedetomidine 1µg/kg/h, 4) dexmedetomidine 10µg/kg/h, or 5) intravenous infusion of 0.9% NaCl without spinal ischemia (sham). The rats received saline solution or dexmedetomidine from 30min before spinal cord ischemia to 48h after ischemia. Spinal cord ischemia was induced by intraaortic balloon occlusion combined with proximal arterial hypotension for 10min. Ischemic injury was assessed by neurological deficit scores and the number of viable motor nerve cells in the anterior spinal cord at 48h after reperfusion. Neurological deficit scores in the dexmedetomidine-treated rats were significantly lower than the scores in the control group at 24 and 48h after ischemia (P<0.05). The number of viable motor nerve cells was significantly larger in the dexmedetomidine-treated rats than in the control rats (P<0.05), but the number of motor nerve cells in the dexmedetomidine group was significantly smaller than the sham group. Our results indicate that the continuous administration of dexmedetomidine improves neurological and histological outcomes 48h after transient spinal ischemia in rats.
- Cutaneous metastasis of gastric cardia adenocarcinoma in a patient: a case report. [Journal Article]
- Int J Clin Exp Med 2014; 7(3):785-8.
A large proportion of gastric cardia adenocarcinoma (GCA) present initially in an advanced stage in China. Skin metastasis of primary GCA rarely occurs and the incidence of it is still unclear yet. Here we report one case of skin metastasis from GCA in a 58-year-old male patient who underwent gastric cardia resection in 2002 and did not undergo chemotherapy. However, he was diagnosed with anastomotic stoma adenocarcinoma by gastroscopy and histological biopsy in 2012.4. Then he underwent four cycles of "XELOX" regimen chemotherapy and the evaluation was PR. Upper gastrointestinal bleeding occurred and he was administered hemostatic therapy in 2012.9; meanwhile, he suffered from severe pains all over the body and received slow-release morphine. However, he was found to have dozens of cutaneous metastasizes in the skin of abdominal and back. Then, he underwent best supportive care and died of cachexia in 2013.5. GCA cutaneous metastasis indicates a highly invasive potential of tumors, poor chemo-radiotherapy efficacy and poor prognosis. The patient may survive just for another several months without the treatment of anti-tumor agents. Appropriate treatment may prolong patient survival.
- Signal enhancement of glucuronide conjugates in LC-MS/MS by derivatization with the phosphonium propylamine cation tris(trimethoxyphenyl) phosphonium propylamine, for forensic purposes. [JOURNAL ARTICLE]
- Drug Test Anal 2014 Apr 21.
Although chemical derivatization for signal enhancement in drug testing is most often associated with gas chromatography, it also has the potential to improve the detection of analytes poorly ionized by atmospheric pressure ionization techniques, such as electrospray ionization used in liquid chromatography-mass spectrometry. A number of acidic compounds, namely drug glucuronides (e.g. conjugates of temazepam, oxazepam, lorazepam, morphine, testosterone, epitestosterone, 5-α-dihydrotestosterone, androsterone, p-nitrophenol, and paracetamol) were successfully derivatized with tris(trimethoxyphenyl) phosphoniumpropylamine to introduce a quaternary cation functionality to the analytes. Benzodiazepine glucuronides were more specifically investigated, and following positive mode electrospray ionization mass spectrometry, average improvements to peak areas as a result of derivatization were 67-, 6-, and 7- fold for temazepam, oxazepam, and lorazepam glucuronides. Average improvements to the signal-to-noise ratios for temazepam, oxazepam, and lorazepam glucuronides were 1336-, 371- and 217-fold, respectively. The values obtained for the derivatized conjugate were also typically higher than those for the underivatized parent drug. Urine containing benzodiazepine glucuronides was also successfully derivatized. The data indicates potential for the use of charge derivatization to improve the detection of molecules with acidic functionalities by liquid chromatography-mass spectrometry (LC-MS) techniques in certain scenarios. Copyright © 2014 John Wiley & Sons, Ltd.
- Hepatic microsomal UDP-glucuronosyltransferase (UGT) activities in the microminipig. [JOURNAL ARTICLE]
- Biopharm Drug Dispos 2014 Apr 17.
The microminipig, a small minipig was bred as a novel experimental animal for nonclinical pharmacology/toxicology studies by Fuji Micra Inc. (Shizuoka, Japan). Species differences in drug metabolism between humans and the microminipig need to be elucidated in more detail in order to discuss the results of nonclinical studies. Glucuronidation catalyzed by UDP-glucuronosyltransferase (UGT) is an important pathway in the metabolism of a wide variety of compounds. The aim of the present study was to identify the characteristics of hepatic UGT activity in the microminipig and compare them to those in humans and other experimental animals. In this study, we examined in vitro UGT activities using liver microsomes from microminipigs (8 months old and 1-day-old), humans, mice, rats, dogs, monkeys, and minipigs. The glucuronides of estradiol, imipramine, serotonin, propofol, 3'-Azido-3'-deoxythymidine (AZT) and morphine, selective substrates of human UGT1A1, 1A4, 1A6, 1A9, and 2B7 (AZT and morphine), respectively, were measured using LC-MS/MS. Estradiol-3-glucuronidation activity was higher in the microminipig than in humans and the other animals. High levels of estradiol-3-glucuronidation were observed in the microsomes of 1-day-old microminipigs. Imipramine-N-glucuronidation, a distinctive conjugation by human UGT1A4, was catalyzed by microminipig liver microsomes, but not by dog liver microsomes. Although AZT-glucuronidation activity was low in the microminipig rather than that in humans, morphine-3-glucuronidation activity in the microminipig was higher than that in humans. UGT activities in the microminipig were similar to those in the minipig. The results of the present study have provided useful information to select an appropriate animal model for nonclinical studies. This article is protected by copyright. All rights reserved.