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Biomedical subjects

M Maze

Publications and source records attributed to M Maze.

At least 19 recordsLinked to original sources
PubMed2007

Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat.

BACKGROUND: Neonatal asphyxia causes long-term neurological and behavioural impairment in the developing brain. Concurrent administration of xenon and hypothermia synergistically reduces long-term damage in a rat model of neonatal asphyxia. This study sought to investigate whether asynchronous administration of xenon and hypothermia is capable of combining synergistically to provide neuroprotection. METHODS: Seven-day-old rats were subjected to right common carotid artery occlusion followed by 90 min hypoxia with 8% oxygen. After a 1 h recovery period, rats received asynchronous administration of mild hypothermia (35 degrees C) and xenon (20%) with a 1 or 5 h gap between interventions, xenon (20%) alone, or mild hypothermia (35 degrees C) alone. Infarct volume in the brain was measured 4 days after injury. RESULTS: Administration of hypothermia or xenon alone, 1 and 6 h after the hypoxic ischaemic insult, respectively, provided no neuroprotection. Asynchronous administration of xenon and hypothermia at a 1 h interval produced a significant reduction in infarct volume [93 (7) vs 74 (8); P < 0.05]. Reduction in infarct volume was also present when hypothermia and xenon were asynchronously administered with an intervening gap of 5 h [97 (5) vs 83 (3); P < 0.05]. CONCLUSIONS: This finding provides a rationale for investigating the combined use of hypothermia and xenon in a progressive manner for the management of neonatal asphyxia. Thus, hypothermia can be administrated at the site of delivery and xenon can be administered later.

Animals↗
PubMed2007

Adrenergic and cholinergic compounds.

Adrenergic and cholinergic signalling contributes significantly to the endogenous antinociceptive system. Exogenous alpha 2 adrenergic agonists have a well-established analgesic profile; however, recent investigations suggest that this class of agents is underused, and herein we highlight the potential for both current application and future development of these agents. Nicotinic and muscarinic cholinergic ligands represent a novel class of agents with much promise for the management of problematic pain. In this chapter we review advances in both preclinical and clinical arenas and highlight potential avenues for further research.

Adrenergic Agents↗
PubMed2005

Isoflurane exerts antinociceptive and hypnotic properties at all ages in Fischer rats.

BACKGROUND: Some anaesthetic agents exhibit an age-dependent analgesic effect, for example nitrous oxide, which is ineffective in newborn rats. We investigated whether a similar time dependency existed for the responses to the volatile anaesthetic isoflurane. METHODS: The analgesic and hypnotic properties of isoflurane at various ages was assessed using four cohorts of Fischer rats aged approximately 7, 16, and 28 days and adults (11-12 weeks old). Intraplantar administration of formalin mimicked inflammatory pain, and its effects were assessed using immunohistochemical (c-Fos staining) and behavioural paradigms. The hypnotic properties of isoflurane were assessed using loss of righting reflex. RESULTS: Formalin administration produced a typical nociceptive response observed both behaviourally and immunohistochemically in all age groups; these nociceptive responses were significantly attenuated by isoflurane 0.5% at each age (P<0.05). Interestingly 7-day-old animals showed a significantly more potent hypnotic response than older animals (P<0.01): with adult rats being most resistant to isoflurane induced hypnosis (P<0.05). CONCLUSION: In contrast to nitrous oxide, isoflurane is an effective antinociceptive agent in neonatal rats. If the data can be extrapolated to clinical scenarios these results suggest that isoflurane may be analgesic in newborns as well as adult humans. In addition, isoflurane is a potent hypnotic, especially in the very young, which is in contrast to the neonate's relative resistance to anaesthesia as assessed by minimum alveolar concentration.

Aging↗
PubMed2005

Alpha-2 agonists: can they modify the outcomes in the Postanesthesia Care Unit?

While most patients recover uneventfully from the effects of anesthesia and surgery, for a small percentage of patients the immediate postoperative period can be a period of significant physiological stress. Hence the goal for a Post Anesthesia Care Unit (PACU) is to provide a safe environment for a patient to recover, while avoiding the undesirable side effects of pain, nausea, vomiting and shivering, and to monitor for potentially life threatening hemodynamic and respiratory complications that may require admission into the intensive care unit (ICU). Anesthetic techniques in the operating room are extremely important as these may have significant bearing on the post-operative course. The type of surgery, the patients' co morbid conditions, anticipated extubation and recovery of the patient, as well as the sophistication of the PACU and the expertise of its staff, all influence the choice of anesthetic technique. These agents, however, may themselves contribute to some of the complications and unpleasant events encountered in the PACU. Therefore, evaluation of newer and safer agents, which promote a smoother PACU transition, are warranted. Alpha 2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression and low and predictable side effect profile.

Adrenergic alpha-Agonists↗
PubMed2003

Evaluation of high fidelity patient simulator in assessment of performance of anaesthetists.

BACKGROUND: There is increasing emphasis on performance-based assessment of clinical competence. The High Fidelity Patient Simulator (HPS) may be useful for assessment of clinical practice in anaesthesia, but needs formal evaluation of validity, reliability, feasibility and effect on learning. We set out to assess the reliability of a global rating scale for scoring simulator performance in crisis management. METHODS: Using a global rating scale, three judges independently rated videotapes of anaesthetists in simulated crises in the operating theatre. Five anaesthetists then independently rated subsets of these videotapes. RESULTS: There was good agreement between raters for medical management, behavioural attributes and overall performance. Agreement was high for both the initial judges and the five additional raters. CONCLUSIONS: Using a global scale to assess simulator performance, we found good inter-rater reliability for scoring performance in a crisis. We estimate that two judges should provide a reliable assessment. High fidelity simulation should be studied further for assessing clinical performance.

Anesthesia↗
PubMed2002

The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway.

We investigated the role of regionally discrete GABA (gamma-aminobutyric acid) receptors in the sedative response to pharmacological agents that act on GABA(A) receptors (muscimol, propofol and pentobarbital; 'GABAergic agents') and to ketamine, a general anesthetic that does not affect GABA(A) receptors. Behavioral studies in rats showed that the sedative response to centrally administered GABAergic agents was attenuated by the GABA(A) receptor antagonist gabazine (systemically administered). The sedative response to ketamine, by contrast, was unaffected by gabazine. Using c-Fos as a marker of neuronal activation, we identified a possible role for the tuberomammillary nucleus (TMN): when gabazine was microinjected directly into the TMN, it attenuated the sedative response to GABAergic agents. Furthermore, the GABA(A) receptor agonist muscimol produced a dose-dependent sedation when it was administered into the TMN. We conclude that the TMN is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.

Anesthesia↗
PubMed2002

Neuroprotective and neurotoxic properties of the 'inert' gas, xenon.

BACKGROUND: Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors have been shown not only to have neuroprotective effects but also to exhibit neurotoxic properties. In this study, we used c-Fos, a protein product of an immediate early gene, as a marker of neuronal injury to compare the neuroprotective effects of xenon and the neurotoxic properties of xenon, nitrous oxide, and ketamine, three anaesthetics with NMDA receptor antagonist properties. METHODS: We used an in vivo rat model of brain injury in which N-methyl-DL-aspartic acid (NMA) is injected subcutaneously (s.c.) and c-Fos expression in the arcuate nucleus is used as a measure of injury. To examine the neurotoxic potential of each of the three anaesthetics with NMDA receptor antagonist properties, c-Fos expression in the posterior cingulate and retrosplenial (PC/RS) cortices was measured. RESULTS: Xenon dose-dependently suppressed NMA-induced c-Fos expression in the arcuate nucleus with an IC(50) of 47 (2)% atm. At the highest concentration tested (75% atm) NMA-induced neuronal injury was decreased by as much as that observed with the prototypical NMDA antagonist MK801 (0.5 mg kg(-1) s.c.). Both nitrous oxide and ketamine dose-dependently increased c-Fos expression in PC/RS cortices; in contrast, xenon produced no significant effect. If the dopamine receptor antagonist haloperidol was given before either nitrous oxide or ketamine, their neurotoxic effects were eliminated. CONCLUSIONS: Uniquely amongst anaesthetics with known NMDA receptor antagonist action, xenon exhibits neuroprotective properties without co-existing neurotoxicity. The reason why ketamine and nitrous oxide, but not xenon, produce neurotoxicity may involve their actions on dopaminergic pathways.

Animals↗
PubMed2001

Glucocorticoid inhibition of neuropathic limb edema and cutaneous neurogenic extravasation.

Sciatic nerve section in rats evokes chronic limb edema, pain behavior, and hindpaw hyperalgesia, a syndrome resembling the complex regional pain syndrome type II (CRPS II or causalgia) in man. Glucocorticoids such as methylprednisolone (MP) have been used as analgesic and anti-edematous agents in patients suffering from CRPS, and interestingly these therapeutic effects appear to persist in some patients after stopping the medication. Similar to the CRPS clinical response to glucocorticoids, we now demonstrate that chronic hindpaw edema in the sciatic transection CRPS model is reversed by a continuous infusion of MP (3 mg/kg/day over 21 days), and this anti-edematous effect persists for at least 1 week after discontinuing MP. Furthermore, there is a chronic increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous hands of CRPS patients. A 2-week infusion of MP (3 mg/kg/day) reduced spontaneous protein extravasation in the hindpaw skin by 80%. We postulated that increased spontaneous neurogenic extravasation resulted in development of limb edema in both the animal model and the CRPS patient, and that the anti-edematous effects of MP are due to an inhibition of spontaneous extravasation. Additional experiments examined the inhibitory effects of MP infusion on electrically-evoked neurogenic extravasation in the hindpaw skin of normal rats. MP inhibition was dose- and time-dependent, with an ED(50) of 1.2 mg/kg/day for a 14-day continuous infusion of MP, and a maximum inhibitory effect requiring 17 days of MP infusion (3 mg/kg/day). MP (3 mg/kg/day for 14 days) also blocked both capsaicin- and SP-evoked neurogenic extravasation, indicating a post-junctional inhibitory effect. Our interpretation is that increased spontaneous neurogenic extravasation in this CRPS model contributed to the development and maintenance of hindpaw edema, and that chronic MP administration dose- and time-dependently blocked neurogenic extravasation at a post-junctional level, thus reversing spontaneous extravasation and limb edema in this model.

Animals↗
PubMed2001

New agents for sedation in the intensive care unit.

Several advances are likely to benefit the ICU patient requiring sedation, analgesia, and anxiolysis. The cooperative sedation induced by dexmedetomidine is a unique and valuable state that allows patients to be aroused easily and interferes little with ventilation. Remifentanil is the prototype of short-acting drugs, providing fast onset and offset; its relatively high cost may be balanced by limiting the risk for long-lasting respiratory depression. Lorazepam seems to be finding more proponents, especially in long-term ICU sedation where the costs of the newer agents may be prohibitive.

Adrenergic alpha-Agonists↗
PubMed2001

Glucocorticoid inhibition of neuropathic hyperalgesia and spinal Fos expression.

Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK(1) receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg. kg(-1). d(-1) for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK(1) immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids.

Animals↗
PubMed2001

Sedative but not analgesic alpha2 agonist tolerance is blocked by NMDA receptor and nitric oxide synthase inhibitors.

BACKGROUND: Studies show that the sedative and analgesic effects of alpha2 adrenergic agonists decrease over time, which is a form of synaptic plasticity referred to as tolerance. Because both the N-methyl-D-aspartate (NMDA) receptor complex and nitric oxide synthase are pivotal for some forms of synaptic plasticity, their role in tolerance to the hypnotic and analgesic effects of alpha2 agonists was investigated. METHODS: After institutional approval, rats were made tolerant to the hypnotic or analgesic action of an alpha2 agonist, dexmedetomidine. The hypnotic response to dexmedetomidine was assessed by the duration of loss of righting reflex, and the analgesic response to dexmedetomidine was assessed by the tail-flick assay. In separate cohorts, either the NMDA receptors or nitric oxide synthase was antagonized by coadministration of MK-801, ketamine, or NO2-arginine, respectively, during induction of tolerance. In a separate series of experiments, after tolerance was induced, the hypnotic and analgesic responses to dexmedetomidine were assessed in the presence of acutely administered MK-801 or NO2-arginine. RESULTS: Induction of tolerance to the hypnotic effect of dexmedetomidine is blocked by coadministration of MK-801, ketamine, and NO2-arginine. However, after tolerance developed, acute administration of MK-801, ketamine, or NO2-arginine did not prevent the expression of tolerance. Coadministration of MK-801 or NO2-arginine neither prevents the development nor reverses the expression of tolerance to the analgesic action of dexmedetomidine. CONCLUSION: The underlying processes responsible for the development of tolerance to the hypnotic and analgesic actions of systemically administered alpha2 agonists were different, with only the sedative tolerance involving the NMDA receptor and nitric oxide synthase system.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2001

Nitrous oxide activates GABAergic neurons in the spinal cord in Fischer rats.

BACKGROUND: Findings to date indicate that nitrous oxide exerts its antinociceptive effect by activating descending noradrenergic neurons. The mechanism whereby descending inhibitory neurons, including noradrenergic neurons, produce antinociceptive effect remains unclear. Using c-Fos protein as a marker for neuronal activation, we examined whether spinal cord neurons activated by nitrous oxide are y-aminobutyric acid-mediated (GABAergic) neurons. METHODS: Adult male Fischer (a strain in which nitrous oxide shows strong antinociceptive properties) and Lewis (a strain in which nitrous oxide lacks antinociceptive properties) rats were exposed to either air (control) or nitrous oxide. Frozen sections of the spinal cord were either stained for c-Fos or double-stained for c-Fos and glutamic acid decarboxylase (a rate-limiting enzyme for GABA synthesis) and analyzed by standard or confocal microscopy. RESULTS: In Fischer rats, 90 min of 75% N2O administration increased the number of c-Fos-positive cells in the spinal cord approximately threefold as compared with the control group. The c-Fos-positive cells induced by nitrous oxide were almost entirely colocalized with glutamic acid decarboxylase-positive cells. In contrast, exposure did not change the number of c-Fos-positive cells in the spinal cord in Lewis rats. CONCLUSIONS: Exposure to nitrous oxide activates GABAergic neurons in the spinal cord. The dose-dependence of GABAergic neuronal activation in the Fischer rats and its absence in the Lewis rat correlate with antinociceptive responses previously reported in these same circumstances. Together, we interpret these data to indicate that activation of GABAergic neurons in the spinal cord are involved in the antinociceptive action of nitrous oxide.

Anesthetics, Inhalation↗
PubMed2000

Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors.

Although nitrous oxide (N(2)O) has been used to facilitate surgery for >150 years, its molecular mechanism of action is not yet defined. Having established that N(2)O-induced release of norepinephrine mediates the analgesic action at alpha(2) adrenoceptors in the spinal cord, we now investigated whether activation of noradrenergic nuclei in the brainstem is responsible for this analgesic action and which alpha(2) adrenoceptor subtype mediates this property. In rats, Fos immunoreactivity was examined in brainstem noradrenergic nuclei after exposure to nitrous oxide. After selective lesioning of noradrenergic nuclei by intracerebroventricular application of the mitochondrial toxin saporin, coupled to the antibody directed against dopamine beta hydroxylase (DbetaH-saporin), the analgesic and sedative actions of N(2)O were determined. Null mice for each of the three alpha(2) adrenoceptor subtypes (alpha(2A), alpha(2B), and alpha(2C)), and their wild-type cohorts, were tested for their antinociceptive and sedative response to N(2)O. Exposure to N(2)O increased expression of Fos immunoreactivity in each of the pontine noradrenergic nuclei (A5, locus coeruleus, and A7). DbetaH-saporin treatment eliminated nearly all of the catecholamine-containing neurons in the pons and blocked the analgesic but not the sedative effects of N(2)O. Null mice for the alpha(2B) adrenoceptor subtype exhibited a reduced or absent analgesic response to N(2)O, but their sedative response to N(2)O was intact. Our results support a pivotal role for noradrenergic pontine nuclei and alpha(2B) adrenoceptors in the analgesic, but not the sedative effects of N(2)O. Previously we demonstrated that the analgesic actions of alpha(2) adrenoceptor agonists are mediated by the alpha(2A) subtype; taken together with these data we propose that exogenous and endogenous alpha(2) adrenoceptor ligands activate different alpha(2) adrenoceptor subtypes to produce their analgesic action.

Analgesics↗
PubMed2000

Strain differences in the antinociceptive effect of nitrous oxide on the tail flick test in rats.

UNLABELLED: To study strain differences in antinociceptive effects of nitrous oxide (N2O), we examined various outbred and inbred stains of rats by using tail flick latency response. All outbred strains, i.e., Sprague-Dawley from two different breeders, Wistar, and Long-Evans, showed a similar antinociceptive response. Namely, the peak response occurred after 30 min of exposure, and tolerance to N2O developed within 60 to 90 min. Each of the four inbred stains examined, i.e., Wistar-Kyoto, Brown-Norway, Fischer, and Lewis, displayed a unique pattern of antinociceptive response to N2O. Wistar-Kyoto and Brown-Norway strains showed somewhat similar patterns as those observed in outbred strains, apart from the fact that the Wistar-Kyoto displayed a more distinct development of tolerance, whereas, the Brown-Norway strain had a lower peak effect. The Fischer strain displayed the greatest antinociceptive response to N2O, and did not develop tolerance. The Lewis strain showed no antinociceptive response to N2O. These results indicate differences in the durability and the magnitude of the antinociceptive response to N2O among various strains of rats. IMPLICATIONS: Because of the variability that already exists, we recommend that animal studies examining the antinociceptive effects of nitrous oxide should be performed on inbred rat strains.

Analgesics, Non-Narcotic↗