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- Differential Expressions of the Alternatively Spliced Variant mRNAs of the µ Opioid Receptor Gene, OPRM1, in Brain Regions of Four Inbred Mouse Strains. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e111267.
The µ opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing in rodents and humans, with dozens of alternatively spliced variants of the OPRM1 gene. The present studies establish a SYBR green quantitative PCR (qPCR) assay to more accurately quantify mouse OPRM1 splice variant mRNAs. Using these qPCR assays, we examined the expression of OPRM1 splice variant mRNAs in selected brain regions of four inbred mouse strains displaying differences in µ opioid-induced tolerance and physical dependence: C56BL/6J, 129P3/J, SJL/J and SWR/J. The complete mRNA expression profiles of the OPRM1 splice variants reveal marked differences of the variant mRNA expression among the brain regions in each mouse strain, suggesting region-specific alternative splicing of the OPRM1 gene. The expression of many variants was also strain-specific, implying a genetic influence on OPRM1 alternative splicing. The expression levels of a number of the variant mRNAs in certain brain regions appear to correlate with strain sensitivities to morphine analgesia, tolerance and physical dependence in four mouse strains.
- The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients. [JOURNAL ARTICLE]
- Oncologist 2014 Oct 23.
Cancer pain management guidelines recommend initial treatment with intermediate-strength analgesics such as hydrocodone and subsequent escalation to stronger opioids such as morphine. There are no published studies on the process of opioid rotation (OR) from hydrocodone to strong opioids in cancer patients. Our aim was to determine the opioid rotation ratio (ORR) of hydrocodone to morphine equivalent daily dose (MEDD) in cancer outpatients.We reviewed the records of consecutive patient visits at our supportive care center in 2011-2012 for OR from hydrocodone to stronger opioids. Data regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected from patients who returned for follow-up within 6 weeks. Linear regression analysis was used to estimate the ORR between hydrocodone and MEDD. Successful OR was defined as 2-point or 30% reduction in the pain score and continuation of the new opioid at follow-up.Overall, 170 patients underwent OR from hydrocodone to stronger opioid. The median age was 59 years, and 81% had advanced cancer. The median time between OR and follow-up was 21 days. We found 53% had a successful OR with significant improvement in the ESAS pain and symptom distress scores. In 100 patients with complete OR and no worsening of pain at follow-up, the median ORR from hydrocodone to MEDD was 1.5 (quintiles 1-3: 0.9-2). The ORR was associated with hydrocodone dose (r = -.52; p < .0001) and was lower in patients receiving ≥40 mg of hydrocodone per day (p < .0001). The median ORR of hydrocodone to morphine was 1.5 (n = 44) and hydrocodone to oxycodone was 0.9 (n = 24).The median ORR from hydrocodone to MEDD was 1.5 and varied according to hydrocodone dose.
- Oral Morphine Weaning for Neonatal Abstinence Syndrome at Home Compared with In-Hospital: An Observational Cohort Study. [JOURNAL ARTICLE]
- Paediatr Drugs 2014 Oct 24.
The objective of this observational study was to evaluate the safety and effectiveness of discharging stabilized neonates to complete their oral morphine weaning at home.This retrospective cohort study evaluated neonates treated with oral morphine at two hospitals in London, Ontario, Canada. Neonates who completed their morphine wean in hospital were compared with neonates who completed their morphine wean following discharge from hospital (at home).There were 80 neonates treated with oral morphine at two hospitals from 2006 to 2010. The majority (65 %, 52/80) of neonates completed their morphine weaning after hospital discharge and were significantly less likely to return to hospital for further withdrawal treatment (1/52 vs 4/28, p < 0.05). Neonates who were treated at home remained on morphine for more days (32 vs 19 days, p < 0.01).We present the first North American cohort of neonates weaned with morphine at home for neonatal abstinence syndrome (NAS). We found that more days on oral morphine resulted in fewer returns to hospital for continued withdrawal management. There was no evidence of increased effectiveness, measured by the number of returns to hospital for further NAS management with in-hospital weaning. The estimated cost savings of continued weaning upon discharge was approximately $11,000 per patient (Canadian dollars). While further prospective research is necessary, in some cases morphine weaning at home may present a safe and cost-effective strategy for NAS management.
- Sertraline influence on morphine-induced conditioned place preference in rats. [Journal Article]
- Rev Med Chir Soc Med Nat Iasi 2014 Jul-Sep; 118(3):712-6.
Serotonine reuptake inhibitors are an important pharmacological arsenal for treating major depression, a severe disease with poorly understood pathogenic mechanisms. Also, little is known about the action of antidepressants on reward system, the function of which is severely affected in this disorder.To assess the influence of sertraline on brain reward system by conditioned place preference technique in rats.Both 3 and 5 mg/kg doses of sertraline determined a significant rewarding effect, whereas only the 5 mg/kg dose increased the morphine-induced rewarding effect (in the morphine-only group time spent in the conditioning chamber increased by 184.92 +/- 21.43% post-conditioning vs. preconditioning, whereas the increase was 195.56 +/- 18.3% in the group treated with morphine and sertraline 5 mg/kg, p < 0.05).The stimulant effect of sertraline on brain reward function might be involved in its therapeutic efficacy.
- Impact of a palliative care program on end-of-life care in a neonatal intensive care unit. [JOURNAL ARTICLE]
- J Perinatol 2014 Oct 23.
Objective:Evaluate changes in end-of-life care following initiation of a palliative care program in a neonatal intensive care unit.Study design:Retrospective study comparing infant deaths before and after implementation of a Palliative Care Program comprised of medication guidelines, an individualized order set, a nursing care plan and staff education.Result:Eighty-two infants died before (Era 1) and 68 infants died after implementation of the program (Era 2). Morphine use was similar (88% vs 81%; P =0.17), whereas benzodiazepines use increased in Era 2 (26% vs 43%; P=0.03). Withdrawal of life support (73% vs 63%; P=0.17) and do-not-resuscitate orders (46% vs 53%; P=0.42) were similar. Do-not-resuscitate orders and family meetings were more frequent among Era 2 infants with activated palliative care orders (n=21) compared with infants without activated orders (n=47).Conclusion:End-of-life family meetings and benzodiazepine use increased following implementation of our program, likely reflecting adherence to guidelines and improved communication.Journal of Perinatology advance online publication, 23 October 2014; doi:10.1038/jp.2014.193.
- Effects of phosphodieastrase type 5 inhibitions on morphine withdrawal symptoms in mice. [JOURNAL ARTICLE]
- Psicothema 2014 Nov; 26(4):511-515.
Background: Chronic morphine exposure creates dependence and, upon cessation, withdrawal symptoms. Studies indicate the phosphodiesterase type 5 (PDE5) inhibitor sildenafil may provide centrally mediated benefits against withdrawal, and therefore, this study evaluated morphine withdrawal signs in dependent mice with and without sildenafil treatment. Method: Dependence was induced by repeated treatments with morphine over 5 consecutive days. The morphine-dependent mice received sildenafil (1, 5, 10, or 20 mg/kg, i.p.) 15 min prior to the precipitation of morphine withdrawal. On the last day, naloxone was injected 2 hours after the last morphine injection, and withdrawal signs were evaluated for 30 min after naloxone injection. Results: The administration of sildenafil reduced all of the morphine withdrawal symptoms. Conclusions: The administration of sildenafil diminished morphine withdrawal signs in morphine-dependent mice. We hypothesize that the mechanism involves enhanced cyclic guanosine monophosphate (cGMP) activity, but further studies are recommended for a better understanding.
- Effect of UGT2B7 -900G>A (-842G>A; rs7438135) on morphine glucuronidation in preterm newborns: results from a pilot cohort. [JOURNAL ARTICLE]
- Pharmacogenomics 2014 Sep; 15(12):1589-1597.
Aim: Assess association between UGT2B7 polymorphism -900G>A (rs7438135, also known as -842G>A) with morphine kinetics in preterm newborns undergoing mechanical ventilation. Materials & methods: Thirty-four infants were enrolled in a randomized clinical trial and allocated to rapid sequence intubation with remifentanil (1 µg/kg) or morphine (0.3 mg/kg). The latter group was included in our study. Results: Morphine plasma concentrations at 20 min post intubation were associated with postnatal age (p = 0.017) and UGT2B7 -900G>A (p = 0.036). UGT2B7 -900A allele carriers (n = 13) had lower morphine levels compared with UGT2B7 -900G/G patients (n = 2). Morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations were only found to be associated with gestational and postnatal age. However, -900A allele carriers had a higher morphine-3-glucuronide:morphine metabolic ratio compared with patients genotyped as -900G/G (p = 0.005), as determined by linear regression. Conclusion: Our small pilot study illustrates that in addition to gestational and postnatal age, the UGT2B7 -900G>A polymorphism significantly alters morphine pharmacokinetics in preterm infants. Original submitted 8 April 2014; Revision submitted 22 July 2014.
- The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders. [Journal Article, Review]
- Front Cell Neurosci 2014.:302.
The function of the blood-brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major eﬄux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood-spinal cord barrier and blood-nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine.
- Impact of potential pregabalin or duloxetine drug-drug interactions on health care costs and utilization among Medicare members with fibromyalgia. [Journal Article]
- Clinicoecon Outcomes Res 2014.:389-99.
To examine the impact of newly initiated pregabalin or duloxetine treatment on fibromyalgia (FM) patients' encounters with potential drug-drug interactions (DDIs), the health care cost and utilization consequences of those interactions, and the impact of treatment on opioid utilization.Subjects included those with an FM diagnosis, a pregabalin or duloxetine prescription claim (index event), ≥1 inpatient or ≥2 outpatient medical claims, and ≥12 months preindex and ≥6 postindex enrollment. Propensity score matching was used to help balance the pregabalin and duloxetine cohorts on baseline demographics and comorbidities. Potential DDIs were defined based on Micromedex 2.0 software and were identified by prescription claims.No significant differences in baseline characteristics were found between matched pregabalin (n=794) and duloxetine cohorts (n=794). Potential DDI prevalence was significantly greater (P<0.0001) among duloxetine subjects (71.9%) than among pregabalin subjects (4.0%). There were no significant differences in all-cause health care utilization or costs between pregabalin subjects with and without a potential DDI. By contrast, duloxetine subjects with a potential DDI had higher mean all-cause costs ($9,373 versus $7,228; P<0.0001) and higher mean number of outpatient visits/member (16.0 versus 13.0; P=0.0009) in comparison to duloxetine subjects without a potential DDI. There was a trend toward a statistically significant difference between pregabalin and duloxetine subjects in their respective pre- versus post-differences in use of ≥1 long-acting opioids (1.6% and 3.4%, respectively; P=0.077).The significantly higher prevalence of potential DDIs and potential cost impact found in FM duloxetine subjects, relative to pregabalin subjects, underscore the importance of considering DDIs when selecting a treatment.
- Functional Interaction between the Shell Sub-Region of the Nucleus Accumbens and the Ventral Tegmental Area in Response to Morphine: an Electrophysiological Study. [Journal Article]
- Basic Clin Neurosci 2013; 4(2):159-68.
This study has examined the functional importance of nucleus accumbens (NAc)-ventral tegmental area (VTA) interactions. As it is known, this interaction is important in associative reward processes. Under urethane anesthesia, extracellular single unit recordings of the shell sub-region of the nucleus accumbens (NAcSh) neurons were employed to determine the functional contributions of the VTA to neuronal activity across NAcSh in rats. The baseline firing rate of NAcSh neurons varied between 0.42 and 11.44 spikes/sec and the average frequency of spontaneous activity over 45-minute period was 3.21±0.6 spikes/sec. The majority of NAcSh neurons responded excitatory in the first and second 15-min time blocks subsequent to the inactivation of VTA. In the next set of experiments, eight experimental rats received morphine (5 mg/kg; sc). Three patterns of neuronal activity were found. Among the recorded neurons only three had an increase followed by morphine administration. Whereas the other three neurons were attenuated following morphine administration; and there were no changes in the firing rates of the two neurons left. Finally, unilateral reversible inactivation of VTA attenuated the firing activity of the majority of ipsilateral NAcSh neuron in response to morphine, except for a single cell. These results suggest that transient inactivation of VTA reduces the ability of neurons in the NAcsh to respond to systemic morphine, and that NAcSh neuron activity depends on basal firing rate of VTA inputs.