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- Elevation of BDNF Exon I-Specific Transcripts in the Frontal Cortex and Midbrain of Rat During Spontaneous Morphine Withdrawal is Accompanied by Enhanced pCreb1 Occupancy at the Corresponding Promoter. [JOURNAL ARTICLE]
- Neurochem Res 2014 Nov 13.
Brain-derived neurotrophic factor (BDNF) is believed to play a crucial role in the mechanisms underlying opiate dependence; however, little is known about specific features and mechanisms regulating its expression in the brain under these conditions. The aim of this study was to investigate the effects of acute morphine intoxication and withdrawal from chronic intoxication on expression of BDNF exon I-, II-, IV-, VI- and IX-containing transcripts in the rat frontal cortex and midbrain. We also have studied whether alterations of BDNF exon-specific transcripts are accompanied by changes in association of well-known transcriptional regulators of BDNF gene-phosphorylated (active form) cAMP response element binding protein (pCreb1) and methyl-CpG binding protein 2 (MeCP2) with corresponding regulatory regions of the BDNF gene. Acute morphine intoxication did not affect levels of BDNF exons in brain regions, while spontaneous morphine withdrawal in dependent rats was accompanied by an elevation of the BDNF exon I-containing mRNAs both in the frontal cortex and midbrain. During spontaneous morphine withdrawal, increased associations of pCreb1 were found with promoter of exon I in the frontal cortex and promoters of exon I, IV and VI in the midbrain. The association of MeCP2 with BDNF promoters during spontaneous morphine withdrawal did not change. Thus, BDNF exon-specific transcripts are differentially expressed in brain regions during spontaneous morphine withdrawal in dependent rats and pCreb1 may be at least partially responsible for these alterations.
- Factors Associated with Prolonged Anesthesia Recovery Following Laparoscopic Bariatric Surgery: a Retrospective Analysis. [JOURNAL ARTICLE]
- Obes Surg 2014 Nov 13.
Phase I postanesthesia recovery is often prolonged after laparoscopic bariatric surgery. We hypothesized that postoperative respiratory depression is a major contributor to this delayed recovery.Medical records of all patients who had a laparoscopic bariatric surgical operation from January 1, 2009, to December 31, 2012, were reviewed for clinical, anesthetic, and postanesthesia variables. Recoveries were defined as discharge from the recovery room in ≤90 min and in >90 min (prolonged postanesthesia recovery). We compared characteristics of patients without prolonged recovery to those with prolonged recovery.Of 781 bariatric patients, 304 (38.9 %) had prolonged recovery. These patients had more respiratory depression (29 vs 6 patients), more postoperative nausea and vomiting (106 vs 92 patients), more treatments of hypertension in the recovery room (49 vs 33 patients), and more opioid treatment (median intravenous morphine equivalents [interquartile range], 10.0 [3.0-15.0] vs 5.0 [0.0-10.5]) (P < 0.001 for all). On multivariable analysis, preoperative history of hypertension (P = 0.03), fewer prophylactic antiemetics received (P = 0.02), and longer surgical duration (P = 0.03) were associated with prolonged postanesthesia recovery.Inadequate antiemetic prophylaxis and the treatment of postoperative hypertension were associated with prolonged postanesthesia recovery. Surprisingly, diagnosis of obstructive sleep apnea was not associated with prolonged recovery, which may be attributable to use of continuous positive airway pressure devices following emergence from anesthesia. Prolonged recovery in patients treated for hypertension may be related to institutional guidelines that require additional monitoring time after these medications are administered.
- The UDP-glucuronosyltransferases of the blood-brain barrier: their role in drug metabolism and detoxication. [Journal Article, Review]
- Front Cell Neurosci 2014.:349.
UDP-glucuronosyltransferases (UGTs) form a multigenic family of membrane-bound enzymes expressed in various tissues, including brain. They catalyze the formation of β-D-glucuronides from structurally unrelated substances (drugs, other xenobiotics, as well as endogenous compounds) by the linkage of glucuronic acid from the high energy donor, UDP-α-D-glucuronic acid. In brain, UGTs actively participate to the overall protection of the tissue against the intrusion of potentially harmful lipophilic substances that are metabolized as hydrophilic glucuronides. These metabolites are generally inactive, except for important pharmacologically glucuronides such as morphine-6-glucuronide. UGTs are mainly expressed in endothelial cells and astrocytes of the blood brain barrier (BBB). They are also associated to brain interfaces devoid of BBB, such as circumventricular organ, pineal gland, pituitary gland and neuro-olfactory tissues. Beside their key-role as a detoxication barrier, UGTs play a role in the steady-state of endogenous compounds, like steroids or dopamine (DA) that participate to the function of the brain. UGT isoforms of family 1A, 2A, 2B and 3A are expressed in brain tissues to various levels and are known to present distinct but overlapping substrate specificity. The importance of these enzyme species with regard to the formation of toxic, pharmacologically or physiologically relevant glucuronides in the brain will be discussed.
- Codeine-induced hyperalgesia and allodynia: investigating the role of glial activation. [Journal Article]
- Transl Psychiatry 2014.:e482.
Chronic morphine therapy has been associated with paradoxically increased pain. Codeine is a widely used opioid, which is metabolized to morphine to elicit analgesia. Prolonged morphine exposure exacerbates pain by activating the innate immune toll-like receptor-4 (TLR4) in the central nervous system. In silico docking simulations indicate codeine also docks to MD2, an accessory protein for TLR4, suggesting potential to induce TLR4-dependent pain facilitation. We hypothesized codeine would cause TLR4-dependent hyperalgesia/allodynia that is disparate from its opioid receptor-dependent analgesic rank potency. Hyperalgesia and allodynia were assessed using hotplate and von Frey tests at days 0, 3 and 5 in mice receiving intraperitoneal equimolar codeine (21 mg kg(-1)), morphine (20 mg kg(-1)) or saline, twice daily. This experiment was repeated in animals with prior partial nerve injury and in TLR4 null mutant mice. Interventions with interleukin-1 receptor antagonist (IL-1RA) and glial-attenuating drug ibudilast were assessed. Analyses of glial activation markers (glial fibrillary acid protein and CD11b) in neuronal tissue were conducted at the completion of behavioural testing. Despite providing less acute analgesia (P=0.006), codeine induced similar hotplate hyperalgesia to equimolar morphine vs saline (-9.5 s, P<0.01 and -7.3 s, P<0.01, respectively), suggesting codeine does not rely upon conversion to morphine to increase pain sensitivity. This highlights the potential non-opioid receptor-dependent nature of codeine-enhanced pain sensitivity-although the involvement of other codeine metabolites cannot be ruled out. IL-1RA reversed codeine-induced hyperalgesia (P<0.001) and allodynia (P<0.001), and TLR4 knock-out protected against codeine-induced changes in pain sensitivity. Glial attenuation with ibudilast reversed codeine-induced allodynia (P<0.001), and thus could be investigated further as potential treatment for codeine-induced pain enhancement.
- Adductor canal block for postoperative pain treatment after revision knee arthroplasty: a blinded, randomized, placebo-controlled study. [Journal Article]
- PLoS One 2014; 9(11):e111951.
Revision knee arthroplasty is assumed to be even more painful than primary knee arthroplasty and predominantly performed in chronic pain patients, which challenges postoperative pain treatment. We hypothesized that the adductor canal block, effective for pain relief after primary total knee arthroplasty, may reduce pain during knee flexion (primary endpoint: at 4 h) compared with placebo after revision total knee arthroplasty. Secondary endpoints were pain at rest, morphine consumption and morphine-related side effects.We included patients scheduled for revision knee arthroplasty in general anesthesia into this blinded, placebo-controlled, randomized trial. Patients were allocated to an adductor canal block via a catheter with either ropivacaine or placebo; bolus of 0.75% ropivacaine/saline, followed by infusion of 0.2% ropivacaine/saline. Clinicaltrials.gov ID: NCT01191593.We enrolled 36 patients, of which 30 were analyzed. Mean pain scores during knee flexion at 4 h (primary endpoint) were: 52±22 versus 71±25 mm (mean difference 19, 95% CI: 1 to 37, P = 0.04), ropivacaine and placebo group respectively. When calculated as area under the curve (1-8 h/7 h) pain scores were 55±21 versus 69±21 mm during knee flexion (P = 0.11) and 39±18 versus 45±23 mm at rest (P = 0.43), ropivacaine and placebo group respectively. Groups were similar regarding morphine consumption and morphine-related side effects (P>0.05).The only statistically significant difference found between groups was in the primary endpoint: pain during knee flexion at 4 h. However, due to a larger than anticipated dropout rate and heterogeneous study population, the study was underpowered.Clinicaltrials.gov NCT01191593.
- Anesthesia in swine : Optimizing a laboratory model to optimize translational research. [JOURNAL ARTICLE]
- Anaesthesist 2014 Nov 12.
In order to extrapolate novel therapies from the bench to the bedside (translational research), animal experiments are scientifically necessary. Swine are popular laboratory animals as their cardiorespiratory physiology is very similar to humans. Every study has to be approved by the local and/or national animal ethical committees. As swine are extremely sensitive to stress the primary goal is therefore to provide a calm, stress-free environment in both housing and experimental facilities. Swine should be properly sedated for transport and normothermia needs to be ensured. It is recommended to commence anesthesia by injecting ketamine and propofol followed by endotracheal intubation during spontaneous breathing. After intubation, anesthesia maintenance is performed with morphine or piritramide, propofol and rocuronium and routine monitoring is applied analogue to a clinical operating theater for humans. Normothermia (38.5 °C) needs to be ensured. While surgical procedures can be readily extrapolated from a human operating theater to swine, non-anesthesiologist scientists may lose the animal rapidly due to airway management problems. Vascular access can be secured by cut-downs or ultrasound-guided techniques in the inguinal and the neck region. For humane euthanasia of pigs, morphine, followed by propofol, rocuronium and potassium chloride are recommended. As radical animal right groups may threaten scientists, it is prudent that animal laboratories have unmarked entrance doors, are located in buildings that are not accessible to the public and strictly controlled access of laboratory staff is enforced. In conclusion, swine are an excellent laboratory animal for bench to bedside research and can be managed properly when basic knowledge and adequate skills on careful handling, anesthesia and surgical considerations are present.
- Role of Spinal CXCL1 (GROα) in Opioid Tolerance: A Human-to-rodent Translational Study. [JOURNAL ARTICLE]
- Anesthesiology 2014 Nov 7.
The pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats.Cerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance.CXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r = 0.49, P < 0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist.CXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.
- Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma. [JOURNAL ARTICLE]
- Pediatr Blood Cancer 2014 Nov 8.
Addition of anti-GD2 antibody ch14.18 to the treatment of neuroblastoma has improved outcomes. The most common side effect of ch14.18 is neuropathic pain, which may in part be complement-mediated. Hu14.18K322A is a humanized anti-GD2 antibody designed to diminish complement activation and induce less pain. We compare the pain outcomes in patients treated with ch14.18 and those treated with hu14.18K322A, and explore dose-dependent relationships between pain scores, opioid requirements, and complement levels in patients treated with hu14.18K322A.Opioid (morphine equivalent mg/kg) and anxiolytic requirements during course 1 (4 days) in patients treated with hu14.18K322A and ch14.18 were reviewed. Correlations between antibody dose and pain scores, opioid requirements, and complement levels were examined for patients receiving hu14.18K322A.Patients treated with hu14.18K322A (n = 19) had lower opioid requirements than those who received ch14.18 (n = 9). The differences in median opioid requirements (mg/kg) were statistically significant for the overall course (1.57 vs. 2.41, P = 0.019) as well as for Days 3 (0.34 vs. 0.65, P = 0.005), and 4 (0.32 vs. 0.64, P = 0.010). No difference in anxiolytic use was observed between the two groups. In the group treated with hu14.18K322A, we found a positive correlation between antibody dose administered and pain scores, but no correlation between antibody dose and opioid requirements or changes in complement levels.In this retrospective analysis, hu14.18K322A induced less pain than ch14.18 based on opioid requirements. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- Evaluation of Celecoxib Addition to Pain Protocol after Total Hip and Knee Arthroplasty Stratified by Opioid Tolerance. [JOURNAL ARTICLE]
- Clin J Pain 2014 Nov 6.
This study seeks to determine the impact that celecoxib has on patients' postoperative opioid consumption based on whether the patient is opioid naïve or opioid tolerant for total hip and knee arthroplasty (THA/TKA).This was a retrospective study over 1.5 years that encompassed a pre- and post-period for adding celecoxib to the pain protocol. Prescriptions for opioids dispensed six months prior to surgery were analyzed to assess for preoperative opioid tolerance. Unadjusted results were presented. Primary outcome measure was change in milligrams of morphine per day associated with celecoxib use as per linear regression analysis. Secondary outcome measures included total opioid dose, average pain score, length of stay, and as needed opioid doses.Analysis included 142 patients. Unadjusted results showed opioid naïve patients had greater reductions in opioid dose per day with celecoxib (49.1 mg vs. 80.8 mg) compared to tolerant patients (86.6 mg vs. 100.1 mg). Regression results showed similar results, with opioid naïve patients having a 29.9 mg reduction (95% confidence interval [CI] -47.9 to -12.1; P=0.009) in opioid use per day associated with celecoxib use versus 5.5 mg reduction (95% CI -33.6 to 22.5; P=0.69) for opioid tolerant group. Opioid naïve patients also saw significant reductions in pain scores, as needed opioid doses, and total opioid dose. Opioid tolerant patients saw significant reductions only in pain scores.Both opioid tolerant and naïve patients benefited from celecoxib therapy, however in different ways. Opioid tolerant patients saw benefits other than reductions in opioid use; opioid naïve patients saw similar benefits, but also had significant reductions in opioid use.
- Subtotal colectomy in severe ulcerative and Crohn's colitis: what benefit does the laparoscopic approach confer? [Journal Article]
- Dis Colon Rectum 2014 Dec; 57(12):1349-57.
Comparative outcome data for laparoscopic and open subtotal colectomy in IBD are lacking and often difficult to interpret owing to low case volumes, heterogeneity in case mix, and variation in laparoscopic technique.This study aimed to determine the safety of laparoscopic subtotal colectomy in severe colitis and to determine whether the laparoscopic approach improved short-term outcomes in comparison with the open approach.This was a retrospective cohort study using data from a prospectively maintained clinical database.This study was conducted at a single center, Mount Sinai Hospital, Toronto.All patients undergoing subtotal colectomy for either ulcerative or Crohn's colitis between 2000 and 2011 were included.A standardized operative technique was used for both laparoscopic and open subtotal colectomies. Cases performed by non-laparoscopic surgeons were excluded.Perioperative outcome measures were operative duration, estimated blood loss, total morphine requirement, and length of postoperative stay. Postoperative outcome measures were the rates of minor and major complications.Laparoscopic subtotal colectomies were performed in 131 of 290 cases (45.2%). Nine patients required conversion to an open procedure (6.9%). The uptake of laparoscopic subtotal colectomy increased from 10.2% in 2000/2001 to 71.7% in 2010/2011. Regression analysis with propensity-score adjustment for operative approach revealed that the operative duration was 25.5 minutes longer in laparoscopic cases (95% CI 12.3-38.6; p < 0.001), but that patients experienced fewer minor complications (OR 0.47; 95% CI 0.23-0.96; p = 0.04) and required less morphine (adjusted difference, -72.8 mg; 95% CI 4.9-141; p = 0.04).The inherent selection bias of this retrospective cohort study may not be accounted for by multivariate analysis with propensity-score adjustment.Laparoscopic subtotal colectomy is safe and may reduce the rate of minor postoperative complications. The increase in operative duration reflects the technical demands associated with this procedure (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A160).