Acute binge pattern cocaine administration induces region-specific effects in D1-r- and D2-r-expressing cells in eGFP transgenic mice.

Cocaine addiction is driven by genetic, neurologic and environmental components. The D1-like (D1 and D5) and D2-like (D2, D3 and D4) families of dopamine receptors play an important role in modulating the effects of cocaine administration on drug-seeking behavior. The advent of bacterial artificial chromosome-eGFP (enhanced green fluorescent protein) transgenic mice that express eGFP driven by the endogenous D1-receptor (D1-r) or D2-receptor (D2-r) promoters provides a unique opportunity to distinguish between these subpopulations of cells. In an effort to identify cocaine-induced alterations in D1-r- versus D2-r-expressing cells during the initial stages of addiction, we examined cells that expressed D1-rs in Drd1-eGFP mice, or D2-rs in Drd2-eGFP mice, after an acute, 1-day binge pattern of cocaine administration. We used multiphoton confocal microscopy and Visiopharm© software, to conduct unbiased stereological counts of D1-r-labeled or D2-r-labeled cells in various striatal regions. Mice were sacrificed at 30 min and 24-h post cocaine or saline administration. Compared to saline controls, Drd1-eGFP mice that received cocaine had a higher count of D1-r-labeled cells in the dorsolateral (DL) striatum, at the 30-min and 24-h time-points. No changes in the nucleus accumbens (NAc) core or shell were observed in Drd1-eGFP mice. Drd2-eGFP mice that received cocaine had fewer D2-r-labeled cells in the DL striatum and NAc core compared to saline controls. This effect was observed at the 30-min time-point but not at 24h. Drd2-eGFP mice that received cocaine also had fewer numbers of D2-r-labeled cells in the NAc core compared to saline controls, but no significant differences in the number of D2-r-labeled cells in the NAc shell. These results suggest that acute binge pattern cocaine administration may induce region-specific alterations in D1-r or D2-receptor gene expression, and may help elucidate the differential role of dopamine receptors in the initial stages of the addiction cycle.

Partial ablation of mu-opioid receptor rich striosomes produces deficits on a motor-skill learning task.

Basal ganglia striosomes, or patches, are rich in mu opioid receptors (MOR) and form a three-dimensional labyrinth of cells that extend throughout the mid- and anterior striatum in mice. Though previous studies have suggested that striosomes could affect drug-induced motor output in rodents, the functional role of these compartmentalized MOR-rich striosomes is not well understood. To investigate any relationship between the striosomes and motor behavior we used the toxin dermorphin-saporin (DS) to selectively ablate MOR-rich striosomal cells. FVB mice were bilaterally infused with DS in the midstriatum alone or in the mid- and anterior striatum, and were tested on three motor tasks and in an open field. Two volume measurement procedures and stereological cell counts were used to confirm the induced pathology. Mice that received DS injections showed significantly smaller volumes (-26% to -44%) and fewer cells (-30% to -49%) in the striosome compartment compared to mice that received control injections of saline or saporin. Striosome pathology was greatest in the dorsolateral striatum. The extrastriosomal matrix was not significantly affected, resulting in an imbalance in the ratio of striosome-to-matrix cells. Behaviorally, toxin injections caused deficits on an accelerating rotarod task and the deficit was worse in mice that received mid and anterior injections than those that received midstriatal injections alone. However, DS-injected mice did not differ from control mice on other motor tasks. We conclude that the MOR-rich cells of the striosomes are necessary for optimal rotarod performance, including learning and/or improvement on the task.

Functional architecture of the mammalian striatum: mouse vascular and striosome organization and their anatomic relationships.

To determine whether the general architecture of striatal vessels and mu opioid receptor-rich striosomes is similar, we investigated 3D reconstructions of coronal sections in 10 FVB mice. The sections were stained for striosomes using a mu opioid receptor antibody (MOR1). We used computerized procedures to detect striosomes and vessels and to calculate volume, number and colocalization of striosomes and vessels. The results showed a lattice-like pattern of striosomes similar to, and often surrounding, blood vessels. Furthermore, co-localization calculations suggested that the striosomes are more vascular than the matrix. Vessel volume was 5.0+/-1.3% per microm3 in striosomes versus 3.6+/-0.9%microm3 in matrix (p=0.01). The findings emphasize the probable importance of a grid- or lattice-like structure as an organizing principle of striatal anatomy and function. In addition, the greater vascularity of the striosomes compared to the matrix suggests a unique function of this compartment in relation to humoral signals and neurotropic drugs.

Butorphanol-mediated antinociception in mice: partial agonist effects and mu receptor involvement.

In the present experiments, we characterized the agonist and antagonist effects of butorphanol in mice. In the mouse radiant-heat tail-flick test, the mu agonists morphine and fentanyl and the kappa agonist U50,488H were fully effective as analgesics, whereas butorphanol was partially effective (producing 82% of maximal possible analgesic effect). Naltrexone was approximately equipotent in antagonizing the effects of morphine, fentanyl and butorphanol; in vivo apparent pA2 values for these naltrexone/agonist interactions were 7.5 (unconstrained). Naltrexone was approximately 10 times less potent in antagonizing the effect of U50,488H (average apparent pK(B) = 6.7). The selective mu antagonist beta-funaltrexamine (0.1-1.0 mg/kg) antagonized the effects of butorphanol in a dose-dependent insurmountable manner. Pretreatment with nor-binaltorphimine (32 mg/kg), a kappa-selective antagonist, did not reliably antagonize butorphanol, and naltrindole (20 and 32 mg/kg), a delta-selective antagonist, failed to antagonize the effects of butorphanol. Low doses of butorphanol (1.0, 1.8 or 3.2 mg/kg) caused parallel, rightward shifts in the dose-effect curve for morphine and parallel leftward shifts in the dose-effect curve for U50,488H. Taken together, the results of the present study suggest that butorphanol is a partial agonist in the mouse radiant-heat tail-flick test and that activity at mu receptors accounts for the majority of its antinociceptive effects.

Caudal epidural butorphanol plus bupivacaine versus bupivacaine in pediatric outpatient genitourinary procedures.

STUDY OBJECTIVE: To investigate the efficacy of adding butorphanol to bupivacaine administered in the caudal epidural space in children undergoing genitourinary (GU) procedures. DESIGN: Randomized, double-blinded, controlled study. SETTING: University affiliated pediatric hospital. PATIENTS: 200 ASA physical status I and II male patients between 6 months and 10 years of age. INTERVENTIONS: Patients were randomized to receive either 0.25% bupivacaine with 1:200,000 epinephrine alone (Group 1) or 0.25% bupivacaine with 1:200,000 epinephrine plus 30 micrograms/kg butorphanol (Group 2) administered via the caudal epidural space prior to surgical incision. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated postoperatively until discharge. Measurements included requirement of additional analgesic, sedation, pain/ comfort scores, and a 24-hour analgesic follow-up. Significantly fewer patients in the butorphanol group required rescue morphine sulfate in the postanesthesia care unit (p < or = 0.001). The total number of morphine doses administered to Group 2 was significantly less than Group 1 (p < or = 0.001). 52% of patients in Group 1 compared with 28% in Group 2 required administration of additional analgesics following discharge from the hospital (p < or = 0.003), with 23% of Group 1 requiring a codeine compound compared with 8% in Group 2 (p < 0.03). CONCLUSIONS: The addition of 30 micrograms/kg butorphanol to 0.25% bupivacaine with epinephrine via the caudal epidural space is a safe, effective means to increase duration of analgesia following GU procedures.

Ondansetron dose response curve in high-risk pediatric patients.

STUDY OBJECTIVE: To establish a dose-response relationship for ondansetron, and to evaluate any effects of oral premedication with metoclopramide in pediatric patients undergoing tonsillectomy and adenoidectomy and strabismus surgery. DESIGN: Prospective, randomized, double blind study. SETTING: University affiliated, 280-bed pediatric hospital. PATIENTS: 320 ASA physical status l and II patients between the ages of 2 and 12 years undergoing tonsillectomy and adenoidectomy or strabismus surgery. INTERVENTIONS: Patients were randomized to eight investigational groups. Patients in all eight groups underwent a standard anesthetic. Groups 1, 2, 3, and 4 received intravenous (i.v.) saline or i.v. ondansetron at doses of 0.05 mg/kg, 0.1 mg/kg and 0.15 mg/kg, respectively. Groups 5, 6, 7, and 8 received oral metoclopramide 0.15 mg/kg as well as i.v. saline, and ondansetron 0.05 mg/kg, 0.1 mg/kg, or 0.15 mg/kg. Patients were evaluated for emetic episodes prior to and following discharge. MEASUREMENTS AND MAIN RESULTS: All doses of ondansetron 0.05 mg/kg, 0.1 mg/kg, and 0.15 mg/kg were significantly more effective than placebo in reducing the incidence of emesis prior to, following discharge, and during the first 24 postoperative hours (p < 0.001). There were no significant differences in the occurrence of emesis between the groups receiving ondansetron 0.05 mg/kg, 0.1 mg/kg, and 0.15 mg/kg. The addition of oral metoclopramide 0.15 mg/kg had no effect on the incidence of emesis in the ondansetron or placebo study groups. CONCLUSIONS: Ondansetron is an effective medication for the treatment and prevention of postoperative nausea and vomiting, and a dose of ondansetron 0.05 mg/kg is as effective as 0.1 mg/kg and 0.15 mg/kg. Metoclopramide 0.15 mg/kg has no effect on the incidence of postoperative nausea and vomiting.

Intravenous ondansetron in established postoperative emesis in children. S3A-381 Study Group.

BACKGROUND: In pediatric postsurgical patients, postoperative vomiting is a common occurrence that can delay recovery and result in unplanned hospital admissions after outpatient surgery. This randomized, double-blind, placebo-controlled, multicenter study evaluated the efficacy and safety of ondansetron in the control of established postoperative emesis in outpatients aged 2-12 yr. METHODS: Screened for the study were 2,720 ASA physical status 1-3 children undergoing outpatient surgery during general anesthesia, which included nitrous oxide. Children experiencing two emetic episodes within 2 h of discontinuation of nitrous oxide were given intravenous ondansetron (n = 192; 0.1 mg/kg for children weighing < or = 40 kg; 4 mg for children weighing > 40 kg) or placebo (n = 183). RESULTS: The proportion of children with no emetic episodes and no use of rescue medication was significantly greater (P < 0.001) in the ondansetron group compared with placebo for both 2- and 24-h periods after study drug administration (78% of the ondansetron group and 34% of the placebo group for 2 h; 53% of the ondansetron group and 17% of the placebo group for 24 h). Among patients with at least one emetic episode or with rescue medication use, the median time to onset of emesis or rescue was 127 min in the ondansetron group compared with 58 min in the placebo group (P < 0.001). The median time from study drug administration until discharge was significantly shorter (P < 0.01) in the ondansetron group (153 min, range 44-593 min) compared with the placebo group (173 min, range 82-622 min). The incidence of potentially drug-related adverse events was similar in the ondansetron (3% of patients) and the placebo (4% of patients) groups. CONCLUSION: A single dose of ondansetron (0.1 mg/kg up to 4 mg) is effective and well tolerated in the prevention of further episodes of postoperative emesis in children after outpatient surgery. Administration of ondansetron also may result in a shorter time to discharge.

Ondansetron decreases postoperative vomiting in pediatric patients undergoing tonsillectomy and adenoidectomy.

One of the most frequently performed pediatric surgical procedures is tonsillectomy and adenoidectomy. Nausea and vomiting and the inability to tolerate oral fluids lead to unplanned hospitalizations. Despite treatment with metoclopramide and droperidol, nausea and vomiting continue to be high after this procedure. We designed this investigation to compare currently utilized antiemetics to ondansetron, a new serotonin antagonist, in hopes of decreasing the occurrence of nausea and vomiting in patients undergoing tonsillectomy and adenoidectomy. This prospective, randomized, double-blinded clinical trial compared ondansetron, droperidol, and placebo administered at the induction of general anesthesia and the incidence of vomiting postoperatively. One-hundred sixty-five children between the ages of 2 and 12 years undergoing ambulatory adenotonsillectomy were enrolled and completed this investigation. The primary outcome measure was the elimination of vomiting during the 24-h investigative period following surgery. Both ondansetron and droperidol significantly lowered the incidence of postoperative emesis after tonsillectomy and adenoidectomy (P < 0.012) compared to placebo. Ondansetron was significantly more effective than droperidol in reducing emesis after discharge (P < 0.025). Both ondansetron and droperidol are effective in decreasing emesis when given before surgical incision in pediatric patients undergoing tonsillectomy and adenoidectomy. Ondansetron's antiemetic effect persists for up to 24 h following surgery with significant reductions in emesis. Ondansetron's effectiveness in eliminating vomiting without sedation or other side effects suggests that it should be considered as part of the standard management in pediatric patients undergoing tonsillectomy and adenoidectomy.

Topical lidocaine for postoperative analgesia following myringotomy and tube placement.

One of the most frequently performed surgical procedures in pediatrics is myringotomy and tube placement. Analgesia is often difficult to achieve and children may be uncontrollable, distressing both parents and nursing staff. We designed this investigation to determine if topical lidocaine instilled in the ear canal after myringotomy and tube placement could improve postoperative analgesia. This prospective, randomized, double-blind clinical trial compared topical 4% lidocaine combined with antibiotic drops to placebo and antibiotic drops placed in the external auditory canal following completion of myringotomy and tube placement. One hundred twenty-two ASA class I or II patients were enrolled and completed this investigation. Primary outcome measure was relief of pain based on pain scores and the need for acetaminophen. Patients who received 4% lidocaine with gentamicin had better pain scores (2.81; P = 0.002) than those receiving placebo (4.77). Twenty-seven patients (45%) in the control group received acetaminophen for treatment of postoperative pain compared to eight (13%) in the lidocaine group (P < 0.001). No reports or complaints of vertigo or tinnitus were noted in any patient. The application of 4% lidocaine in antibiotic drops significantly improves postoperative analgesia in patients undergoing myringotomy and tube insertion under general anesthesia. Utilizing this technique should help improve analgesia, specifically in the early postoperative period, and decrease the presence of stress following surgery.

Continuous epidural morphine/butorphanol infusion following selective dorsal rhizotomy in children.

The authors prospectively evaluated 15 patients who had undergone selective dorsal rhizotomy who were given a continuous morphine/butorphanol infusion, to determine whether variations in the postoperative pain control and side effects seen using a bolus technique could be reduced. Patients had an epidural catheter placed at the end of the operative procedure through which 50-60 micrograms/kg preservative-free morphine and 15-20 micrograms/kg butorphanol was administered. A continuous epidural infusion of 5 micrograms/kg h morphine and 1.2 micrograms/kg h butorphanol was then initiated. Postoperatively, mean pain scores were excellent. No patient required additional systemic analgesics during the 72-h investigational period. A low incidence of nausea, and no vomiting, pruritus, or respiratory depression was reported by the cohort. All patients maintained oxygen saturations above 95%. This indicates that the use of a continuous epidural infusion provides excellent pain control, decreases the occurrence of untoward side effects, and allows the early initiation of occupational and physical therapy postoperatively.

The effects of oral droperidol versus oral metoclopramide versus both oral droperidol and metoclopramide on postoperative vomiting when used as a premedicant for strabismus surgery.

STUDY OBJECTIVE: To compare the efficacy of oral droperidol versus oral metoclopramide, or both oral droperidol and metoclopramide, on postoperative vomiting when used as a premedicant for strabismus surgery. DESIGN: Double-blind, randomized, prospective study. SETTING: Academic children's hospital. PATIENTS: 154 ASA physical status I and II ambulatory patients, ages 1 to 15 years, scheduled for strabismus surgery. INTERVENTIONS: Patients were randomly assigned to receive colored sugar water containing either droperidol 300 mcg/kg orally, metoclopramide 0.15 mg/kg orally, both droperidol 300 mcg/kg and metoclopramide 0.15 mg/kg orally, or no active ingredient (placebo group) as a premedicant. The premedications were given orally 1 to 1.5 hours prior to the operation. MEASUREMENTS AND MAIN RESULTS: Patients were analyzed for the number of episodes of vomiting from the time of their emergence from anesthesia through the first 24 hours postoperatively, including the convalescent period at home. Patients were also analyzed for length of hospital stay. There were no statistically significant differences between groups regarding age, premedication time, surgery time, or discharge time. Droperidol and droperidol-metoclopramide were significantly more effective (p < 0.012) than either the metoclopramide group or the placebo group in preventing postoperative nausea and vomiting following strabismus surgery. CONCLUSIONS: Our data suggest that oral droperidol 300 mcg/kg and the combination of oral droperidol 300 mcg/kg and metoclopramide 0.15 mg/kg are effective in reducing the frequency of vomiting within the first 24 hours after strabismus surgery. The combination of oral droperidol and oral metoclopramide is highly effective in reducing the frequency of vomiting postoperatively in strabismus ambulatory surgery patients (p = 0.017). This combination seems to represent an inexpensive alternative to the more costly ondansetron.

Epidural morphine with butorphanol in pediatric patients.

STUDY OBJECTIVE: To determine whether the addition of butorphanol to epidural morphine is effective in reducing the frequency of side effects caused by neuraxial opioids. DESIGN: Randomized, double-blind study. SETTING: Large tertiary care pediatric hospital. PATIENTS: 20 children between the ages of 2 and 17 years undergoing spinal, abdominal, or thoracic procedures. INTERVENTIONS: Patients were divided randomly into one of two groups to receive either 80 micrograms/kg of preservative-free epidural morphine (Group 1) or 80 micrograms/kg of preservative-free epidural morphine with 40 micrograms/kg of butorphanol (Group 2). MEASUREMENTS AND MAIN RESULTS: Blood pressure, heart rate, respiratory rate, and the first need for additional opioids were monitored in the two groups. In addition, pruritus, nausea and vomiting, and supplemental oxygen (O2) required to maintain oxygen saturation (SpO2) above 90% were monitored. Children who received butorphanol in addition to epidural morphine were much less likely to develop pruritus or nausea and vomiting or to require supplemental O2 to maintain SpO2 above 90%. CONCLUSION: Butorphanol 40 micrograms/kg added to epidural morphine 80 micrograms/kg is effective in decreasing the occurrence of side effects caused by neuraxial opioids in pediatric patients.

Epidural pain management in the postrhizotomy patient.

The authors report a randomized double-blind prospective study comparing epidural morphine 80 micrograms/kg to epidural morphine 80 micrograms/kg plus butorphanol 40 micrograms/kg in children undergoing rhizotomy. Up to 50% of children receiving epidural morphine alone will experience side effects of nausea, vomiting, pruritus, urinary retention or respiratory depression. The addition of the narcotic agonist-antagonist butorphanol virtually eliminated these side effects without compromising analgesia or causing undue sedation. Parent satisfaction was greater than 90%.

Epidural morphine with butorphanol for postoperative analgesia after cesarean delivery.

Epidural morphine has been used more and more to provide long-lasting postoperative analgesia after cesarean delivery. However, the incidence of pruritus (20%-93%) and nausea (17%-60%) detract from the usefulness of epidural morphine. The purpose of this study was to evaluate, in 30 patients having epidural anesthesia for cesarean delivery, the analgesic efficacy and side effects when a combination of epidural morphine, a mu-receptor agonist, and butorphanol, a mu-receptor antagonist and kappa-receptor agonist, was administered. After clamping of the umbilical cord, patients received 4 mg epidural morphine with 3 mL of normal saline (group 1), 4 mg epidural morphine with 1 mg butorphanol and 2 mL of normal saline (group 2), or 4 mg epidural morphine with 3 mg butorphanol (group 3). Patients were monitored for 24 h after administration of the study medications. There were no significant differences between the groups in visual analogue pain scores, time to first analgesic request, respiratory rate, or Trieger dot test performance in the 24 h immediately after these epidural injections. There were three patients in group 1 and one patient in group 2 who experienced oxygen saturations less than 90%. (No patients in group 3 developed an oxygen saturation less than 92%.) The patients in group 3 did not require treatment for pruritus or nausea, a response significantly different (P less than 0.001 and P less than 0.05, respectively) from group 1 or group 2.(ABSTRACT TRUNCATED AT 250 WORDS)