Differential regulation of locomotor activity to acute and chronic cocaine administration by acid-sensing ion channel 1a and 2 in adult mice.

Acid-sensing ion channels (ASICs) are densely expressed in the brain with ASIC1a and ASIC2 channels being the predominant subtypes. These channels are enriched at synaptic sites and are central for the regulation of normal synaptic transmission. Moreover, increasing evidence links ASICs to the pathogenesis of various neurological and neuropsychiatric disorders. In this study, we explore the putative role of ASIC1a and ASIC2 in the regulation of behavioral sensitivity to the psychostimulant cocaine by utilizing ASIC1a or ASIC2 knockout mice. Acute cocaine injection induced a typical dose-dependent increase in locomotor activities in wild-type (WT) mice. However, in ASIC1a and ASIC2 mutant mice, different motor responses to cocaine were observed. In ASIC1a(-/-) mice, cocaine induced a significantly less motor response at all doses (5, 10, 20, and 30 mg/kg), while in ASIC2(-/-) mice, cocaine (5-20 mg/kg) stimulated locomotor activity to an extent comparable to WT mice. Only at 30 mg/kg, the cocaine-stimulated motor activity was reduced in ASIC2(-/-) mice. In a chronic cocaine administration model (20mg/kg, once daily for 5 days), a challenge injection of cocaine (10mg/kg, after 2-week withdrawal) caused an evident behavioral sensitization in the cocaine-pretreated WT mice. This behavioral sensitization to challenge cocaine was also displayed in ASIC1a(-/-) and ASIC2(-/-) mice. However, ASIC2(-/-) mice showed less sensitization to challenge cocaine when compared to WT and ASIC1a(-/-) mice. Our results demonstrate the important role of ASIC1a and ASIC2 channels in the modulation of behavioral sensitivity to cocaine. The two synapse-enriched ASIC subtypes are believed to play distinguishable roles in the regulation of behavioral responses to acute and chronic cocaine administration.

Loss of surface N-methyl-D-aspartate receptor proteins in mouse cortical neurones during anaesthesia induced by chloral hydrate in vivo.

BACKGROUND: Anaesthetics may target ionotropic glutamate receptors in brain cells to produce their biological actions. Membrane-bound ionotropic glutamate receptors undergo dynamic trafficking between the surface membrane and intracellular organelles. Their subcellular distribution is subject to modulation by changing synaptic inputs and determines the efficacy and strength of excitatory synapses. It has not been explored whether anaesthesia has any impact on surface glutamate receptor expression. In this study, the effect of general anaesthesia on expression of N-methyl-D-aspartate (NMDA) receptors in the surface and intracellular pools of cortical neurones was investigated in vivo. METHODS: General anaesthesia was induced by intraperitoneal injection of chloral hydrate in adult male mice. Surface protein cross-linking assays were performed to detect changes in distribution of NMDA receptor subunits (NR1, NR2A, and NR2B) in the surface and intracellular compartments of cerebral cortical neurones. RESULTS: Chloral hydrate did not alter the total amounts of NR1, NR2A, and NR2B proteins in cortical neurones. However, the drug reduced NR1 proteins in the surface pool of these neurones, and induced a proportional increase in NR1 in the intracellular pool. Similar redistribution of NR2B subunits was observed between the two distinct pools. The changes in NR1 and NR2B were rapid and remained throughout the duration of anaesthesia. NR2A proteins were not altered in the surface or intracellular pool in response to chloral hydrate. CONCLUSIONS: These data demonstrate that subcellular expression of NR1 and NR2B in cortical neurones is sensitive to anaesthesia. Chloral hydrate reduces surface-expressed NMDA receptors (specifically NR2B-containing NMDA receptors) in these neurones in vivo.

Modulation of AMPA receptor GluR1 subunit phosphorylation in neurons by the intravenous anaesthetic propofol.

BACKGROUND: The ionotropic glutamate receptor is a potential molecular site in the central nervous system that general anaesthetics may interact with to produce some of their biological actions. Protein phosphorylation has been well documented to occur in the intracellular C-terminal domain of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors, which represents a pivotal mechanism for the post-translational modulation of AMPA receptor functions. In this study, we investigated a possible influence of an i.v. anaesthetic agent propofol on the phosphorylation of AMPA receptor GluR1 subunits in cultured neurons. METHODS: The effect of propofol on phosphorylation of GluR1 subunits at serine 831 and 845 was assayed in cultured rat striatal and cortical neurons by western blot with phospho- and site-specific antibodies. RESULTS: Propofol consistently elevated phosphorylation of GluR1 subunits at the C-terminal serine 845 site in both striatal and cortical neurons. The elevation in phosphorylation was concentration-dependent and started at a low concentration (3 microM). This increase in serine 845 phosphorylation was rapid and sustained during the entire course of propofol exposure. In contrast to serine 845, phosphorylation of GluR1 at serine 831 was not altered by propofol in striatal and cortical neurons. Total GluR1 abundance remained unchanged in response to propofol incubation. CONCLUSIONS: These data indicate that propofol possesses the ability to upregulate AMPA receptor GluR1 subunit phosphorylation at a specific serine 845 site in neurons and provide evidence supporting the AMPA receptor as a molecular target for general anaesthetics.

Postoperative analgesia using a low-dose, oral-transdermal clonidine combination: lack of clinical efficacy.

STUDY OBJECTIVE: To determine if a lower than previously reported oral-transdermal clonidine regimen could reduce postoperative morphine requirements without producing systemic side effects. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: University-affiliated hospital. PATIENTS: 29 healthy, ASA physical status I and II females undergoing elective abdominal hysterectomy. INTERVENTIONS: Patients received preoperative oral clonidine 4 to 5 mu/kg and a 7 cm2 transdermal clonidine patch (0.2 mg/24 hours) or a placebo tablet and patch. MEASUREMENTS AND MAIN RESULTS: Postoperative patient-controlled analgesia pumps provided morphine during the 48-hour study period. Morphine use, hemodynamic changes, and nonhemodynamic side effects were recorded. Additionally, visual analog pain scales (VAPS) and plasma concentrations of morphine and clonidine were measured. We found that low-dose clonidine had no potentiating effect on morphine analgesia. Postoperative morphine use, VAPS, and morphine plasma levels were similar between the control and clonidine-treated groups. Nevertheless, patients in the clonidine group experienced a significantly greater incidence of intraoperative and postoperative hypotension and bradycardia than did the control group. No differences were noted in the incidence of nonhemodynamic side effects. CONCLUSIONS: The low-dose oral-transdermal clonidine regimen evaluated failed to reduce postoperative morphine requirements, although patients who received clonidine were still at risk for developing hypotension.

Autonomic hyperreflexia in a pregnant paraplegic patient. Case report.

BACKGROUND AND OBJECTIVES: Pregnant patients with spinal cord injuries are predisposed to autonomic hyperreflexia, which if unrecognized or untreated can lead to death. Hypertension occurring in laboring patients at risk for autonomic hyperreflexia must be managed aggressively. METHODS: Epidural anesthesia can safely control autonomic hyperreflexia during labor and delivery, but because spinal cord impaired patients lack sensory and motor function below the level of injury, it is difficult to determine the dermatomal spread of epidural anesthesia by the usual methods. This difficulty is highlighted by the following case, reporting an epidural that failed during labor, with the subsequent development of autonomic hyperreflexia. RESULTS: Previously, autonomic hyperreflexia occurring in pregnant patients (undergoing surgical procedures) was treated with intravenous antihypertensive agents. During labor, however, titrating these agents to coincide with uterine contractions is difficult. In this case, epidural anesthesia was repeated and the autonomic hyperreflexia resolved. CONCLUSIONS: Autonomic hyperreflexia can develop in unanesthetized laboring paraplegic patients (failed epidural) but it can be successfully managed with adequate epidural anesthesia.

Uncommon applications for continuous spinal anesthesia.

The role that uncommon agents of antinociception, placed intrathecally, play in the control of nociceptive signal transmission in the spinal cord is described. Three specific agents are discussed in detail: baclofen, a gamma aminobutyric acid mimetic agent; clonidine, an alpha-2 agonist; and somatostatin, a neuroinhibitory peptide. In addition, the efficacy of using an implanted pump-catheter system for the long-term infusion of baclofen and octreotide, a somatostatin-like analog, is reviewed.

Effect of oxygenator type and bypass flow pattern on the P(a-ET)CO2 gradient.

Changes in pre-bypass and post-bypass P(a-ET)CO2 gradients were evaluated regarding the type of bypass flow (pulsatile or nonpulsatile) and oxygenator (membrane or bubble). Duration of bypass and hemodynamic changes were analyzed also to determine their possible influence on PaCO2, PETCO2, and P(a-ET)CO2. A total of 36 adult patients undergoing cardiopulmonary bypass were anesthetized using a sufentanil-pancuronium-oxygen technique. Patients were divided into three groups based on the type of oxygenator and pump flow: group 1 (control group) consisted of a bubble oxygenator with nonpulsatile flow (BN), group 2 consisted of a bubble oxygenator with pulsatile flow (BP), and group 3 consisted of a membrane oxygenator with nonpulsatile flow (MN). Cardiac parameters (MAP, CI, SVR, and PVR) PaCO2, PETCO2, and P(a-ET)CO2 were determined pre-bypass and post-bypass following steady-state conditions. For the entire group there was a trend for the P(a-ET)CO2 gradient to increase in the post-bypass period (pre-bypass = 3.5 +/- 0.5 mm Hg, post-bypass = 4.3 +/- 0.5 mm Hg.). However, this increase was not statistically significant. Pulsatile flow (group 2) demonstrated a significant correlation with the change in P(a-ET)CO2 gradients from the pre-bypass to the post-bypass period (r = 0.85) when compared with the other two groups (group 1: r = -0.09 and group 3: r = 0.37). Thus, the P(a-ET)CO2 gradient tended to remain constant from the pre-bypass to the post-bypass period in group 2, whereas it increased in groups 1 and 3. Changes in MAP, CI, SVR, and PVR and the duration of CPB did not influence the P(a-ET)CO2 gradient.

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)

Transorally obtained oxygen tension as an indicator of arterial oxygen tension.

Transcutaneous oxygen electrodes have been used with success in neonates as indicators of arterial oxygenation, but with less success in adults because of differences in skin thickness and vascularity. In this study, a prototype transoral oxygen electrode was evaluated to determine if a heated mucous membrane would yield arterialized values of oxygen tension in adults. Using a miniaturized Clark electrode, we measured transoral oxygen tension (PtoO2) in 29 subjects at steady-state conditions. Simultaneously a sample was anaerobically obtained from a radial artery for measurement of arterial oxygen tension (PaO2). Data were analyzed using linear regression analysis, Student's t test, and analysis of variance. There was no statistically significant difference between nonwhite and white subjects or male and female subjects. There was a highly significant difference (P less than 0.001) between the pooled, matched values for PtoO2 versus PaO2, and the regression between the PtoO2 and the PaO2 was linear (slope 0.92, y-intercept -8.37, r = 0.62, P less than 0.003). The calculated ratio of PtoO2 to PaO2 was 0.83 +/- 0.03 (standard error). We concluded that the PtoO2 was linearly related to the PaO2, although its accuracy in reflecting PaO2 was low. This finding correlates with previously published data that suggested that the PtoO2 reflects tissue oxygen tension rather than arterialized oxygen tension. Gender and race appeared not to affect the function of the electrode in our study.

A clinical evaluation of the accuracy of the Nellcor N-100 and Ohmeda 3700 pulse oximeters.

Two pulse oximeters, the Nellcor N-100 and the Ohmeda 3700, were compared with arterial blood values and with each other in a clinical evaluation of performance. Three hundred twenty-nine simultaneously sampled blood/oximeter data pairs from use of both makes of pulse oximeters on each of 152 test subjects were included in the comparison analysis for each oximeter. Among the patients, disease type and severity and hospital location varied widely. Basic descriptive statistics and linear regression analysis were employed to facilitate comparison. Both oximeters displayed a statistically significant but clinically insignificant bias when compared with arterial blood oxyhemoglobin: -0.31 (P = 0.023) and 0.59 (P = 0.001) for the Ohmeda 3700 pulse oximeter and the Nellcor N-100 pulse oximeter, respectively. Relative to arterial blood oxyhemoglobin, the 95% tolerance intervals were +4.84 to -5.45 (10.3) for the Ohmeda 3700 and +6.94 to -5.76 (12.7) for the Nellcor N-100. Regressed against [oxyhemoglobin + carboxyhemoglobin + methemoglobin] as x, the Nellcor N-100 read y = 0.85(x) + 12.5, r = 0.83, P less than 0.0001, and the Ohmeda 3700 read y = 1.02(x) - 5.3, r = 0.86, P less than 0.0001.