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- Morphine Regulates Expression of MOR-1A, an Intron-retention Carboxyl Terminal Splice Variant of the μ Opioid Receptor (OPRM1) Gene Via miR-103/miR-107. [JOURNAL ARTICLE]
- Mol Pharmacol 2013 Dec 3.
The μ opioid receptor (MOR-1) gene, OPRM1, undergoes extensive alternative splicing, generating an array of splice variants. Of these variants, MOR-1A, an intron-retention carboxyl terminal splice variant identical to MOR-1 except for the terminal intracellular tail encoded by exon 3b, is quite abundant and conserved from rodent to humans. Increasing evidence indicates that miroRNAs (miRNAs) regulate MOR-1 expression and μ agonists such as morphine modulate miRNA expression. However, little is known about miRNA regulation of the OPRM1 splice variants. Using 3' rapid amplification cDNA end (RACE) and Northern blot analyses, the present study identified the complete 3' untranslated region (3'-UTR) for both mouse and human MOR-1A and their conserved polyadenylation site, and defined the role the 3'-UTR in mRNA stability using a luciferase reporter assay. Computer models predicted a conserved miR 103/107 targeting site in the 3'-UTR of both mouse and human MOR-1A. The functional relevance of miR-103/107 in regulating expression of MOR-1A protein through the consensus miR-103/107 binding sites in the 3'- UTR was established by using mutagenesis and a miR-107 inhibitor in transfected HEK293 cells and Be(2)C cells that endogenously express human MOR-1A. Chronic morphine treatment significantly upregulated miR-103 and miR-107 levels, leading to downregulation of polyribosome-associated MOR-1A in both Be(2)C cells and the striatum of a morphine tolerant mouse, providing a new perspective on understanding the roles of miRNAs and OPRM1 splice variants in modulating the complex actions of morphine in animals and humans.
- A comparison of anaesthetic recoveries in cats following induction with either alfaxalone or ketamine and diazepam. [JOURNAL ARTICLE]
- N Z Vet J 2013 Dec 3.
To determine if cats anaesthetised with alfaxalone have different recoveries to cats anaesthetised with a combination of ketamine and diazepam.Anaesthesia for ovariohysterectomy was induced in cats with either alfaxalone (n=23) or a combination of ketamine and diazepam (n=22). All cats were premedicated with combinations of acepromazine and morphine. Recoveries were scored using a categorical grading scheme applied to 18 parameters over 60 minutes following extubation. The parameters scored covered movement, sensitivity to touch, sound and light, body position, sneezing and vocalisation. One person scored all recoveries and they were blinded to the induction drug used. Scores were compared between drugs at different times using the Kruskal-Wallis rank sum test.Recovery scores were not normally distributed. Analysis of the data using the Kruskal-Wallis rank sum test revealed that cats induced with alfaxalone showed an increase in recovery scores at 5 minutes for pawing at the head (p=0.001). No parameters differed significantly at 10 and 20 minutes. For cats anaesthetised with ketamine and diazepam there was an increase at 30 minutes in pacing, jerky sudden movements, unsettledness and increased sensitivity to touch at the surgical site and on the head (p≤0.01). At 60 minutes cats anaesthetised with ketamine and diazepam still showed an increase in unsettledness compared to those cats anaesthetised with alfaxalone (p=0.005).The results suggest that recoveries of cats following alfaxalone induction are significantly different to recoveries after induction with ketamine and diazepam. Overall, cats induced with ketamine and diazepam had more active and unsettled recoveries than alfaxalone over the 60-minute period observed.Cats recovering from alfaxalone anaesthesia have more settled recoveries than cats recovering from ketamine and diazepam anaesthesia. If a quiet settled recovery is desired following a surgical procedure, alfaxalone is likely to be a better choice than ketamine and diazepam.
- Negative Pressure Pulmonary Oedema: A Rare Case Report of Two Brothers. [JOURNAL ARTICLE]
- J Clin Diagn Res 2013 Oct; 7(10):2308-2309.
Negative Pressure Pulmonary O/Edema (NPPE) is potentially life-threatening and it is a general anaesthesia side effect. We are mentioning a rare case report of two brothers who were referred to our hospital for elective surgeries (varicocele and septoplasty) in a 3 years period. Both of them were athletes and their coagulation factors were disturbed after surgeries. Pulmonary oedema was healed after treating it by reintubation, mechanical ventilation by Positive End-Expiratory Pressure (PEEP), diuretics, morphine, Fresh Frozen Plasma (FFP) and liquid bounding.
- Combined Cardioprotectant and Antithrombotic Actions of Platelet P2Y12 Receptor Antagonists in Acute Coronary Syndrome: Just What the Doctor Ordered. [JOURNAL ARTICLE]
- J Cardiovasc Pharmacol Ther 2013 Dec 2.
Since the P2Y12 receptor antagonists were first introduced, they have been extensively tested in patients with acute coronary syndrome and are now standard of care. These antiplatelet drugs are very effective in reducing subsequent cardiovascular events, stent thromboses, and mortality in patients with acute myocardial infarction undergoing reperfusion therapy. Although the prevailing view is that their benefit derives from their antithrombotic properties, other unrelated pleiotropic effects appear to be equally beneficial. Accumulating clinical and animal evidence indicates that, if present at the time of reperfusion, these drugs have a direct anti-infarct effect similar to that of ischemic postconditioning. Four oral antagonists have been developed in rapid succession: ticlopidine, clopidogrel, prasugrel, and ticagrelor. Each agent had a more consistent and rapid onset of action than the previous one, and this has correlated with improved clinical outcomes when given early in treatment. Unfortunately, gut absorption causes an appreciable delay in the onset of effect, especially when morphine is used, and the constant push to minimize the door-to-balloon time has made it difficult to achieve adequate platelet inhibition at the time of percutaneous coronary intervention with an oral agent. An intravenous P2Y12 antagonist such as cangrelor may optimize treatment because it produces nearly maximal inhibition of platelet aggregation within minutes. If antiplatelet agents do protect through postconditioning's mechanism, then they would render any other intervention that protects through that mechanism redundant. Indeed, animals treated with cangrelor cannot be further protected by pre- or postconditioning. However, interventions that use a different mechanism such as mild hypothermia or cariporide, a Na(+)-H(+) exchange blocker, do add to cangrelor's protection. Future research should be directed toward identifying interventions that can augment the protection from antiplatelet therapy and finding a way to optimize P2Y12 inhibition at reperfusion in all patients.
- Preoperative narcotic use and its relation to depression and anxiety in patients undergoing spine surgery. [Journal Article]
- Spine (Phila Pa 1976) 2013 Dec 1; 38(25):2196-200.
Prospective review of registry data at a single institution from October 2010 to June 2012.To assess whether the amount of preoperative narcotic use is associated with preoperative depression and anxiety in patients undergoing spine surgery for a structural lesion.Previous work suggests that narcotic use and psychiatric comorbidities are significantly related. Among other psychological considerations, depression and anxiety may be associated with the amount of preoperative narcotic use in patients undergoing spine surgery.Five hundred eighty-three patients undergoing lumbar (60%), thoracolumbar (11%), or cervical spine (29%) were included. Self-reported preoperative narcotic consumption was obtained at the initial preoperative visit and converted to daily morphine equivalent amounts. Preoperative Zung Depression Scale (ZDS) and Modified Somatic Perception Questionnaire (MSPQ) scores were also obtained at the initial preoperative visit and recorded as measures of depression and anxiety, respectively. Resistant and robust bootstrapped multivariable linear regression analysis was performed to determine the association between ZDS and MSPQ scores and preoperative narcotics, controlling for clinically important covariates. Mann-Whitney U tests examined preoperative narcotic use in patients who were categorized as depressed (ZDS ≥ 33) or anxious (MSPQ ≥ 12).Multivariable analysis controlling for age, sex, smoking status, preoperative employment status, and prior spinal surgery demonstrated that preoperative ZDS (P = 0.006), prior spine surgery (P = 0.007), and preoperative pain (0.014) were independent risk factors for preoperative narcotic use. Preoperative MSPQ (P = 0.083) was nearly a statistically significant risk factor. Patients who were categorized as depressed or anxious on the basis of ZDS and MSPQ scores also showed higher preoperative narcotic use than those who were not (P < 0.0001).Depression and anxiety as assessed by ZDS and MSPQ scores were significantly associated with increased preoperative narcotic use, underscoring the importance of thorough psychological and substance use evaluation in patients being evaluated for spine surgery.Level of Evidence: 2.
- Inhibitory effect of spinal mGlu5 receptor antisense oligonucleotide on the up-regulated expression of spinal G protein associated with chronic morphine treatment. [JOURNAL ARTICLE]
- Eur J Pharmacol 2013 Nov 29.
Knockdown of spinal metabotropic glutamate 5 (mGlu5) receptor was shown to inhibit the development of intrathecal morphine antinociceptive tolerance. The present work was designed to evaluate the expression of spinal G-protein during morphine tolerance and knockdown of spinal mGlu5 receptor with antisense oligonucleotide (ODN). Rats were treated with saline, morphine, mGlu5 receptor antisense or mismatch ODN intrathecally. Behavioral tests were employed to test the thermal and mechanical pain thresholds. Five days later, rats were scarified and spinal expression of spinal Gαi, Gαo, Gαq and Gβ were detected. Consistent with previous results, knockdown of spinal mGlu5 receptor could inhibit spinal morphine antinociceptive tolerance in behavioral tests (P<0.05). The mGlu5 receptor antisense ODN produced a significant reduction in mGlu5 receptor protein of about 56.6% compared with the control group (P<0.05). Expression of spinal Gαi, Gαo, Gαq and Gβ were up-regulated while morphine tolerance developed (P<0.05). Antisense ODN of spinal mGlu5 receptor, but not mismatched ODN, reduced the spinal dorsal horn levels of Gαi, Gαo, Gαs, Gαq and Gβ (P<0.05). We conclude that expression of spinal G (αi, αo, αs, αq and β) protein may be up-regulated after chronic morphine treatment which could be attenuated by knockdown of spinal mGlu5 receptor with antisense ODN.
- Microbe associated molecular patterns from rhizosphere bacteria trigger germination and Papaver somniferum metabolism under greenhouse conditions. [JOURNAL ARTICLE]
- Plant Physiol Biochem 2013 Nov 19.:133-140.
Ten PGPR from different backgrounds were assayed on Papaver somniferum var. Madrigal to evaluate their potential as biotic elicitors to increase alkaloid content under the rationale that some microbe associated molecular patterns (MAMPs) are able to trigger plant metabolism. First, the 10 strains and their culture media at two different concentrations were tested for their ability to trigger seed germination. Then, the best three strains were tested for their ability to increase seedling growth and alkaloid levels under greenhouse conditions. Only three strains and their culture media enhanced germination. Then, germination enhancing capacity of these best three strains, N5.18 Stenotrophomonas maltophilia, Aur9 Chryseobacterium balustinum and N21.4 Pseudomonas fluorescens was evaluated in soil. Finally, the three strains were applied on seedlings at two time points, by soil drench or by foliar spray. Photosynthesis was measured, plant height was recorded, capsules were weighted and alkaloids analyzed by HPLC. Only N5.18 delivered by foliar spray significantly increased plant height coupled to an increase in total alkaloids and a significant increase in opium poppy straw dry weight; these increases were supported by a better photosynthetic efficiency. The relative contents of morphine, thebaine, codeine and oripavine were affected by this treatment causing a significant increase in morphine coupled to a decrease in thebaine, demonstrating the effectivity of MAMPs from N5.18 in this plant species. Considering the increase in capsule biomass and alkaloids together with the acceleration of germination, strain N5.18 appears as a good candidate to elicit plant metabolism and consequently, to increase productivity of Papaver somniferum.
- Regional Expression of Extracellular Signal-Regulated Kinase 1 and 2 mRNA In a Morphine-Induced Conditioned Place Preference Model. [JOURNAL ARTICLE]
- Brain Res 2013 Nov 29.
Chronic morphine administration has been shown to change the expression of extracellular signal-regulated kinase (ERK), which is a molecule known to play an important role in homeostatic adaptations caused by addictive drugs. In the present study, we investigated the expression of ERK messenger ribonucleic acid (mRNA) of the prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus, and caudate putamen (CPu) in morphine-induced conditioned place preference (CPP) by real-time reverse transcriptase polymerase chain reaction (real-time PCR). CPP was established by alternate morphine (10mg/kg) injections, extinguished after a 10-day extinction training, and reinstated by a priming injection of morphine (10mg/kg). During three phases of morphine-induced CPP, the expression levels of ERK1 and ERK2 mRNA were altered in various brain regions. In the PFC, the expression levels of ERK1 and ERK2 mRNA were increased after chronic morphine injection (p=0.003, p=0.000), and did not return to the basal level after extinction training (p=0.025, p=0.000), but decreased after a priming injection (p=0.000, p=0.000). In the CPu, ERK1 mRNA had an abrupt increase following a priming injection (p=0.000). Different from other brain regions, the expression levels of ERK1 and ERK2 mRNA were decreased in three phases of morphine-induced CPP in the hippocampus (ERK1: p=0.000, p=0.040, p=0.000; ERK2: p=0.000, p=0.000, p=0.000, respectively). These results suggest region-specific changes of ERK1 and ERK2 mRNA expression during morphine-induced CPP.
- Changes in the Levels of p-ERK, p-CREB, and c-fos in Rat Mesocorticolimbic Dopaminergic System After Morphine-Induced Conditioned Place Preference: The Role of Acute and Subchronic Stress. [JOURNAL ARTICLE]
- Cell Mol Neurobiol 2013 Dec 1.
ERK pathway plays a critical role in the cellular adaptive responses to environmental changes. Stressful conditions can induce the activation of activate ERK, and its downstream targets, CREB and c-fos, in neural cells. Exposure to opioids has the same effect. In this study, we investigated the effects of morphine-induced conditioned place preference (CPP) on p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the mesocorticolimbic dopaminergic system including the nucleus accumbens (NAc), amygdala (AMY), striatum (Str), and prefrontal cortex (PFC).Our aim was to determine if acute and subchronic stress would affect these alterations. Male Wistar rats were divided into two saline- and morphine-treated groups. Each group contained of control, acute stress, and subchronic stress subgroups. The CPP procedure was performed for all of the rats. We dissected out the NAc, AMY, Str, and PFC regions and measured the mentioned ratios and c-fos level by Western blot analysis. The results revealed that in saline-treated animals, all factors enhanced significantly after performing acute and subchronic stress while there was an exception in p-ERK/ERK ratio in the Str and PFC; the changes were not significant during acute stress. Conditioning score decreased after applying the subchronic but not acute stress. In morphine-treated animals, all factors were increased after application of acute and subchronic stress, and conditioning scores also decreased after stress. Our findings suggest that in saline- or morphine-treated animals, acute and subchronic stress increases p-ERK, p-CREB, and c-fos levels in the mesocorticolimbic system. It has been shown that morphine induces the enhancement of the mentioned factors; on the other hand, our result demonstrates that stress can amplify these changes.
- The effects of juvenile capsaicin desensitization in rats: Behavioral impairments. [JOURNAL ARTICLE]
- Physiol Behav 2013 Nov 27.
Capsaicin desensitization leads to behavioral changes, some of which are related to schizophrenia, but investigations into these effects have been scarce. The goal of this study was to characterize the consequences of juvenile capsaicin desensitization on different functions: acute and inflammation-induced thermal and mechanical sensitivity, urinary bladder capacity and thermoregulation, and also on the potentially schizophrenia-related impairments in sensory-motor gating, motor activity and cognitive functioning. Male Wistar rats desensitized with increasing doses of subcutaneous capsaicin after weaning were investigated. Heat and mechanical pain sensitivity did not change significantly; however, morphine produced a prolonged decrease in the nociceptive response to inflammation in desensitized animals. Ultrasound examination of the bladder revealed enhanced bladder volume in treated animals. Capsaicin-treated animals had higher body temperature at 22 °C in both dark and light periods, and they also showed prolonged hyperthermia in new environmental circumstances. Warm environment induced a profound impairment of thermoregulation in desensitized animals. The treated animals also showed higher levels of activity during the active phase and at both cool and warm temperatures. The amplitude of the responses to auditory stimuli and prepulse inhibition did not differ between the two groups, but the desensitized animals showed learning impairments in the novel object recognition test. These results suggest that juvenile capsaicin desensitization leads to sustained changes in several functions that may be related to schizophrenia. We propose that capsaicin desensitization, together with other interventions, may lead to an improved chronic animal model of schizophrenia.