Depression Of Breathing Research Articles

μ-Opioid receptor agonist injections into the presumed pre-Bötzinger complex and the surrounding region of awake goats do not alter eupneic breathing

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a mu-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO(2) and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5-10 mul, 1 nM-10 muM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (Vi)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions (P > 0.10). However, DAMGO attenuated (P < 0.05) the evoked increase in breathing frequency when inspired CO(2) was increased, and DAMGO attenuated the Vi response to reduction of inspired O(2) to 10.8% (P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

Abstracts

Background: Cases of hydrocarbon ingestion are frequentin man all around the world and the spectrum ofthe products involved are in the range from degreasingfluids to tyre cleansers. Reports in Germany have oftenshown that only some defined liquid products and substancescaused typical aspiration symptoms. For hazardassessment of liquid products and substances the BfRDocumentation Centre for Poisonings analysed appropriatedata pools containing poisonings with cases ofaspiration in the last 20 years. Methods: The BfRDocumentation Centre for Poisonings found appropriatedata only in its own compulsory data collection since1990. The main focus of the investigation of the casesof poisonings associated with aspiration risk weresymptoms and signs like coughing, depression ofbreath, cyanosis, aspiration and chemical pneumonia,The investigations had been in particular; 1) cases fromthe spontaneous German Federal Reporting SystemPara 16e of Physicians for cases of poisoning between1990-2008 enclosed with additional 2) cases from theBfR Study Dangerous Lamp Oils between 2000-2006with reports of about 450 German childrens' hospitals.The data were compiled and analysed by means of theSAS-System, seriousness rating by Poisoning SeverityScore. Results: Out of a total number of 57,093reports on cases of poisoning, concerning liquid productsand substances 472 cases were due to partly seriousaspiration / pneumonia (330 cases with paraffine- /petroleumdistillate- / kerosene - containing lamp oils /grilllighters, 30 cases with solvent petroleum containinginsectides, 26 cases with detergent-containing cleanersand other). Out of the total cases we could not documentcases with petrol, diesel, solvents, edible oil and otherhydrocarbons. Conclusion: Based on reports by Germanphysicians (1990-2008) enclosing cases of the BfRLamp Oil Study (2000-2006), we think a real aspirationrisk is only associated with ingestion involvingparaffine-, petroleumdistillate-, kerosene- and detergent-containing liquid products and substances. Basingon these figures on human ingestions only distincthydrocarbons carry a risk of aspiration and not thegroup in general.

Efficacy and safety of sulfentanyl(China) for patient-contrulled intravenous analgesia (PICA) in surgical patients with general anesthesia: a multiple-center, randomized, double-blind, parallel study

Objective To evaluate efficacy and safety of sulfentanyl (China) for PICA in surgical patients with general anes-thesia in a multiple-center, randomized, double-blind, parallel study. Methods 200 ASA grade Ⅰ -Ⅱ patients aged 18-55 undergo-ing surgery with general aneathesia enrolled from 3 hospitals were randomly and double-blindly divided into 2 groups: sulfentanyl (China, n=100) versus sulfentanyl(German, n=100). Sulfentanyl(China 0.1 μg/kg or German)was given before the end of surgery. VAS scores less than 3 after patient awake and PCA started after extubation(200 μg sulfentanyl was diluted with 50 ml saline solution, background dose 0.5 ml/h,bolus of 0.5 ml with lockout interval 15 min, continuous infusion 48 h). Vital signs including BP, HR, PR, SpO2 and side effects such as nausea, vomiting, urine retention, pruritus, breath depression, etc. And VAS scores with patients in quiet and cough were recorded at the beginning of infusion at 0, 1, 4, 12, 24, 48 h. The total number of PCA, the total effective number of PCA, and the ratio of both and other analgesics as well as the satisfactory degree of patients and the cumulative suffen-tanyl consumption were recorded at 24 h. Results There were no significant difference of BP, HR, PR, SpO2 and the adverse effect and VAS scores in quiet and cough between two groups at the beginning of infusion at 0, 1, 4, 12, 24, 48 h. There were no signifi-cant difference of the total number of PCA, the total effective number of PCA and other analgesics as well as the satisfactory degree of patients and the total dosage of sulfentanyl at 24 h. Conclusion The sulfentanyl (China) had satisfactory effects of postoperative analgesia and had no significant side effects compared with sulfentanyl (German). The efficacy and the side effects of both drugs had no significant difference. Key words: Sulfentanyl; PICA

Improved response by peers after witnessed heroin overdose in Melbourne

In response to concerns about the prevalence of heroin-related morbidity and mortality, overdose response training programs have been implemented in Victoria, with the aim of improving outcomes after heroin overdose. The aim of this study was to examine reported overdose response by current injecting drug users (IDU) during overdose events, in comparison with previous studies. A total of 99 IDU (median age 35 years, 72% male) were administered a questionnaire that collected information on knowledge and experience regarding recognition of heroin overdose and response. The primary outcome measure was the rate of ambulance notification and expired air resuscitation during witnessed heroin overdose. Data were analysed using descriptive statistics and univariate analysis. Sixty participants had overdosed at least once, and 84% had witnessed an overdose. 78% recognised altered consciousness as a sign of heroin overdose, but less were aware of depressed breathing (42%) or cyanosis (61%). Reported overdose interventions included correct positioning (39%), expired air resuscitation (32%), ambulance notification (76%) and staying with the victim (87%). Our study has found improved responses to heroin overdose during witnessed heroin overdose among current IDU, compared with earlier work. However, a lack of knowledge regarding appropriate first-aid response persists, which might improve with the development and implementation of training initiatives in this area, ranging from identification of overdose to the administration of life-saving measures.

Abdominal expiratory muscle activity in anesthetized vagotomized neonatal rats

The pattern of respiratory activity in abdominal muscles was studied in anesthetized, spontaneously breathing, vagotomized neonatal rats at postnatal days 0-3. Anesthesia (2.0% isoflurane, 50% O(2)) depressed breathing and resulted in hypercapnia. Under this condition, abdominal muscles showed discharge late in the expiratory phase (E2 activity) in most rats. As the depth of anesthesia decreased, the amplitude of discharges in the diaphragm and abdominal muscles increased. A small additional burst frequently occurred in abdominal muscles just after the termination of diaphragmatic inspiratory activity (E1 or postinspiratory activity). Since this E1 activity is not often observed in adult rats, the abdominal respiratory pattern likely changes during postnatal development. Anoxia-induced gasping after periodic expiratory activity without inspiratory activity, and in most rats, abdominal expiratory activity disappeared before terminal apnea. These results suggest that a biphasic abdominal motor pattern (a combination of E2 and E1 activity) is a characteristic of vagotomized neonatal rats during normal respiration.

Pain and opioids

Noxious stimuli cause pain to protect the body from harmful situations and attract attention to pathophysiologic changes of the body. Specific receptors of pain (nociceptors) can be found all over our body. Pain initiates protecting mechanisms such as vegetative and motor reflexes, and emotional, behavioral changes. However, chronic pain is practically useless and leads to psychopathological changes. There are several ways to relieve pain including non-steroid anti-inflammatory agents, opioids, neurosurgical and non-invasive methods. Central and peripheral effects of opioids can be realized through opioid receptors of the central and the enteric nervous system. In the central nervous system, they can inhibit the perception of pain or change the emotional reactions. Opioids are indicated in postoperative pain, neuropathic pain and cancer. However, the use of opioids has severe side-effects such as breathing depression and the development of tolerance and dependence which do not make opioids optimal painkillers. There are several laboratories in Hungary and abroad working on the design of optimal pain relievers. Furthermore, the euphoric effects of opioids lead to abuse which makes the research important on the mechanisms of opioid addiction. Taken together, opioid research, the design of new compounds and the exploration of the mechanisms of opiate addiction are very important.

Ambulant colonoscopies in sedation

Introduction: Colonoscopy is an unpleasant, occassionally painful examination, with the degree of pain varying by each patient. The sedo-analgesia is the most frequently applied type of sedation used during colonoscopy worldwide, but it can cause various endoscopic and anestesiologic complications as well. Patients and Methods: The authors regularly apply ambulant colonoscopies in sedation with the contribution of anaesthesiologists since July, 2005. The examinations are booked in advance and are performed monthly on a fixed date. The preparation of examinations include anaesthesiologist consultation and risk tests. The determining factors of selecting the patients are intestinal adhesions suspected by previous abdominal surgery, the inefficiency of preceding examinations caused by technical reasons, presumably time consumpting therapic procedure and the expressed distress of the patient. In a period of nearly three years 161 patients (26 male and 135 female, mean age of 41,2 years) were examined. The indications of sedation were: 84 inflammatory bowel diseases, 23 previous abdominal surgeries, 34 previous insufficient, painful colonoscopies (with 12 difficult multiple polypectomy), 20 anorectal diseases with the anxiety of patient. Results: 98% reach-the-cecum rate was found. Endoscopic complication was not caused. The most frequently used sedo-analgetic medications was a combination of midazolam with proprofol and/or fentanyl. There was no clinically relevant anaesthesiologic complication detected, in a few cases transient bradycardia and transient breath depression was found. Conclusions: Colonoscopy in sedation is seen as a more bearable, more pleasant examination for the patient and it is associated with a higher percentage of complete examinations. It can be considered a safe method with seleced patients. The technique of endoscopic examinations is different from those of the ones used without sedation, since the lack of the patient's sense of pain demands more careful treatment from both doctor and assistant.

Opioidergic and dopaminergic modulation of respiration.

Opioids, dopamine and their receptors are present in many regions of the bulbar respiratory network. The physiological importance of endogenous opioids to respiratory control has not been explicitly demonstrated. Nonetheless, studies of opioidergic respiratory mechanisms are important because synthetic opiate drugs have respiratory side effects that in some situations pose health risks and limit their therapeutic usefulness. They can depress breathing depth and rate, blunt respiratory responsiveness to CO2 and hypoxia, increase upper airway resistance and reduce pulmonary compliance. The opiate respiratory disturbances are mainly due to agonist activation of mu- and delta-subtypes of receptor and involve specific types of respiratory-related neurons in the ventrolateral medulla and the dorsolateral pons. Endogenous dopaminergic modulation in the CNS and carotid bodies enhances CO2-dependent respiratory drive and depresses hypoxic drive. In the CNS, synthetic agonists with selectivity for D1-and D4-types of receptor slow respiratory rhythm, whereas D2-selective agonists modulate acute and chronic responses to hypoxia. D1-receptor agonists also act centrally to increase respiratory responsiveness to CO2, and counteract opiate blunting of CO2-dependent respiratory drive and depression of breathing. Cellular targets and intracellular mechanisms responsible for opioidergic and dopaminergic respiratory effects for the most part remain to be determined.

Remifentanil-Induced Cerebral Blood Flow Effects

In Response: Pattinson et al.1 and Ramani2 raise interesting methodological issues that should be useful for future investigators doing similar research on anesthetics and other drugs which may alter Paco2 and thus confound evaluation of regional cerebral blood flow (rCBF) changes. In our report,3 we found widespread increases in rCBF with increasing remifentanil dose, but also noted a significant increase in Paco2 with remifentanil. There are published guidelines on normal rCBF response to changes in Paco2. However, concerned that such correction factors may not apply to humans receiving remifentanil and that they may not apply homogeneously across the brain, we rejected that approach. Rather, we chose to normalize the cerebral blood flow (CBF) measures by dividing each rCBF region of interest by global CBF. This takes into account some of the aforementioned issues, but not all, as detailed in our report. Nonetheless, this approach did allow us to ascertain some regional effects of remifentanil on rCBF. Notably, in a similar human remifentanil study by Wagner et al.4 using positron emission tomography, they chose to deal with the CO2 issue by coaching subjects to breathe more as the remifentanil depressed breathing, producing a rather flat CO2 change with increasing doses. This produced other potential issues but they clearly addressed the issue of remifentanil-induced hypercapnea. Notably, they also observed an element of limbic system activation from sedative dose remifentanil in humans. Pattinson et al.1 suggest that administering CO2 to the subjects separate from remifentanil administration would have solved the problem. Indeed, their suggestion would allow generation of regional CO2 reactivity maps, specific to the individual patient which could be used for a voxel-by-voxel correction for CO2 effect. We agree that such an approach would have been a meaningful improvement, particularly with respect to possible regional variations in CO2 reactivity, and should be considered in future similar studies. However, we suggest two caveats leading to caution in fully embracing this approach. The first is the assumption that the CO2 response will be unchanged by the drug being evaluated. The second is that the logistics of doing the CO2 reactivity map could be problematic. Is the CO2 administered in the same setting? If so does this produce any sensations of anxiety or dyspnea that may impact on subsequent tests? Is the CO2 given in a separate session producing other issues in reproducibility? Dr. Ramani suggests that the BOLD fMRI technique should be employed concurrently with the arterial spin labeling rCBF technique.2 He suggests that it is little affected by changes in Paco2. This is a puzzling statement to us given previous reports that hypercapnea does affect BOLD measures.5,6 BOLD contrast reflects a complex interaction between CBF, cerebral blood volume, and oxygen utilization. Thus, the suggestion to combine arterial spin labeling rCBF studies with BOLD is potentially useful for future studies, as also suggested by Davis et al.5 Such an approach could help separate metabolically induced flow increases from those due solely to CO2 changes. Thus and although perhaps for different reasons, we welcome Ramani’s suggestion and agree that it could be a meaningful improvement to the methods we employed. W. Andrew Kofke, MD, MBA FCCM Professor, Director of Neuroanesthesia Co-Director Neurocritical Care Departments of Anesthesia and Neurosurgery University of Pennsylvania Philadelphia, PA [email protected] John A. Detre, MD Associate Professor Departments of Neurology and Radiology Director, Center for Functional Neuroimaging University of Pennsylvania Philadelphia, PA Jiongjiong Wang, PhD Research Assistant Professor Departments of Neurology and Radiology University of Pennsylvania Philadelphia, PA Patricia A. Blissitt, RN, M.S.N., PhD, CCRN, CNRN, CCM, APRN, BC Staff Nurse, Neuroscience Intensive Care Unit Duke University Hospital Durham, NC

Targeting of opioid-producing leukocytes for pain control

It is accepted that inflammatory mediators released from leukocytes contribute to the generation of pain. However, it is less well known that immune cells also produce mediators that can effectively counteract pain. These include anti-inflammatory cytokines and opioid peptides. This article concentrates on recent evidence that interactions between leukocyte-derived opioid peptides and their receptors on peripheral sensory neurons can result in potent, clinically relevant inhibition of pathological pain. Inflammation of peripheral tissues leads to increased synthesis and axonal transport of opioid receptors in dorsal root ganglion neurons. This results in opioid receptor upregulation and enhanced G-protein coupling at peripheral sensory nerve terminals. These events are dependent on neuronal electrical activity, production of proinflammatory cytokines and nerve growth factor within the inflamed tissue. Together with the disruption of the perineurial barrier, all these changes lead to an enhanced peripheral analgesic efficacy of opioids. The major source of local endogenous opioid ligands (beta-endorphin, enkephalins, endomorphins and dynorphin) are leukocytes. These cells contain and upregulate signal-sequence encoding mRNA of the beta-endorphin precursor proopiomelanocortin and the entire enzymatic machinery necessary for its processing into the functionally active peptide. Opioid-containing immune cells extravasate using adhesion molecules and chemokines to accumulate in inflamed tissues. Upon stressful stimuli or in response to releasing agents such as corticotropin-releasing factor, cytokines, chemokines and catecholamines, leukocytes secrete opioids. Depending on the cell type, this release is contingent on extracellular Ca(2+) or on inositol triphosphate receptor-triggered release of Ca(2+) from endoplasmic reticulum. Once secreted opioid peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur without central untoward side effects such as depression of breathing, clouding of consciousness or addiction. Future aims include the selective targeting of opioid-containing leukocytes to sites of painful injury and the augmentation of opioid peptide and receptor synthesis.

Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges

Serotonin (5HT) is a powerful modulator of respiratory circuitry in vitro but its role in the development of breathing behavior in vivo is poorly understood. Here we show, using 5HT neuron-deficient Pet-1 (Pet-1(-/-)) neonates, that serotonergic function is required for the normal timing of postnatal respiratory maturation. Plethysmographic recordings reveal that Pet-1(-/-) mice are born with a depressed breathing frequency and a higher incidence of spontaneous and prolonged respiratory pauses relative to wild type littermates. The wild type breathing pattern stabilizes by postnatal day 4.5, while breathing remains depressed, highly irregular and interrupted more frequently by respiratory pauses in Pet-1(-/-) mice. Analysis of in vitro hypoglossal nerve discharge indicates that instabilities in the central respiratory rhythm generator contribute to the abnormal Pet-1(-/-) breathing behavior. In addition, the breathing pattern in Pet-1(-/-) neonates is susceptible to environmental conditions, and can be further destabilized by brief exposure to hypoxia. By postnatal day 9.5, however, breathing frequency in Pet-1(-/-) animals is only slightly depressed compared to wild type, and prolonged respiratory pauses are rare, indicating that the abnormalities seen earlier in the Pet-1(-/-) mice are transient. Our findings provide unexpected insight into the development of breathing behavior by demonstrating that defects in 5HT neuron development can extend and exacerbate the period of breathing instability that occurs immediately after birth during which respiratory homeostasis is vulnerable to environmental challenges.

The contribution of VR1 and CB1 receptors and the role of the afferent vagal pathway in modelling of cardio-respiratory effects of anandamide in rats

Anaesthetized and spontaneously breathing rats were used to study the cardio-respiratory effects of intravenous anandamide administration. To investigate the role of particular levels of the afferent pathway in this response rats were challenged with bolus injection of anandamide (1 mg kg − 1 ) into the femoral vein while intact, following bilateral superior laryngeal nerves (SLNs) section and after midcervical vagotomy. To test the hypothesis that the activation of the vanilloid receptors (VR1) as well as cannabinoid receptors (CB1) contributes to the anandamide-induced response administrations of anandamide were preceded by nonselective VR1 antagonist ruthenium red or selective CB1 antagonist AM281. Anandamide evoked apnoea of mean duration of 4.84 ± 0.75 s in all animals while intact which was shortened by subsequent neurotomies, after SLNs section to 3.3 ± 0.57 s ( P < 0.05) and after midcervical vagi section to 1.99 ± 0.24 s ( P < 0.01). In post-apnoeic breathing tidal volume ( V T) was reduced in all neural states. Anandamide evoked hypotension in the intact and SLNs neurotomized rats. Midcervical vagotomy reduced this fall in blood pressure. Both antagonists ruthenium red and AM281 eliminated post-anandamide apnoea and hypotension but had no effect on post-apnoeic depression of V T. Subsequent SLNs and cervical vagi sections did not eliminate but only reduced post-anandamide depression of breathing. Midcervical vagotomy lessened anandamide-induced hypotension. Apnoeic and hypotensive response to anandamide was mediated by both VR1 and CB1 receptors. Post-anandamide decline of V T might depend on different type of receptors.

P2Y1Receptor Modulation of the Pre-Bötzinger Complex Inspiratory Rhythm Generating NetworkIn Vitro

ATP is released during hypoxia from the ventrolateral medulla (VLM) and activates purinergic P2 receptors (P2Rs) at unknown loci to offset the secondary hypoxic depression of breathing. In this study, we used rhythmically active medullary slices from neonatal rat to map, in relation to anatomical and molecular markers of the pre-Bötzinger complex (preBötC) (a proposed site of rhythm generation), the effects of ATP on respiratory rhythm and identify the P2R subtypes responsible for these actions. Unilateral microinjections of ATP in a three-dimensional grid within the VLM revealed a "hotspot" where ATP (0.1 mM) evoked a rapid 2.2 +/- 0.1-fold increase in inspiratory frequency followed by a brief reduction to 0.83 +/- 0.02 of baseline. The hotspot was identified as the preBötC based on histology, overlap of injection sites with NK1R immunolabeling, and potentiation or inhibition of respiratory frequency by SP ([Sar9-Met(O2)11]-substance P) or DAMGO ([D-Ala2,N-MePhe4,Gly-ol5]-enkephalin), respectively. The relative potency of P2R agonists [2MeSADP (2-methylthioadenosine 5'-diphosphate) approximately = 2MeSATP (2-methylthioadenosine 5'-triphosphate) approximately = ATPgammas (adenosine 5'-[gamma-thio]triphosphate tetralithium salt) approximately = ATP >> UTP approximately = alphabeta meATP (alpha,beta-methylene-adenosine 5'-triphosphate)] and attenuation of the ATP response by MRS2179 (2'-deoxy-N6-methyladenosine-3',5'-bisphosphate) (P2Y1 antagonist) indicate that the excitation is mediated by P2Y1Rs. The post-ATP inhibition, which was never observed in response to ATPgammas, is dependent on ATP hydrolysis. These data establish in neonatal rats that respiratory rhythm generating networks in the preBötC are exquisitely sensitive to P2Y1R activation, and suggest a role for P2Y1Rs in respiratory motor control, particularly in the P2R excitation of rhythm that occurs during hypoxia.

A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA B receptor (GABA BR). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA BR1 and rat GABA BR2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA BR1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA BR antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA BR that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.

The Association of Symptoms with Health Outcomes in Chronically Ill Adults

Persons with chronic disease experience multiple symptoms. Understanding the association between these symptoms and health outcomes would facilitate a targeted approach to symptom assessment and treatment. Our objectives were to determine the association of a range of symptoms with quality of life, self-rated health, and functional status among chronically ill adults, and to assess methods for evaluating the independent associations of symptoms that may be interrelated. We consecutively enrolled 226 cognitively intact, community-dwelling adults, aged 60 years or older with chronic obstructive pulmonary disease, heart failure, or cancer. Seven symptoms (physical discomfort, pain, fatigue, problems with appetite, feelings of depression, anxiety, and shortness of breath) assessed using the Edmonton Symptom Assessment Scale were examined for their association with self-rated quality of life, self-rated health, and functional status. Principal component analysis and logistic regression revealed similar results. The latter demonstrated that physical discomfort was associated with lower self-rated health (adjusted odds ratio [OR] 1.9; 95% confidence interval 1.2–2.9) and functional disability (adjusted OR 1.8; 95% confidence interval 1.2–2.7). Feelings of depression were associated with poorer quality of life (adjusted OR 1.7; 95% confidence interval 1.1–2.6), and shortness of breath was associated with lower self-rated health (adjusted OR 1.5; 95% confidence interval 1.1–2.0). The association between a range of symptoms and quality of life, self-rated health, and functional status differed across outcomes, but only three symptoms—physical discomfort, feelings of depression, and shortness of breath—maintained their associations when multiple symptoms were examined concurrently. These findings suggest that interventions targeting these symptoms could improve several health-related outcomes.

Inhibitory effects of repeated hyperoxia on breathing in newborn mice

Brief oxygen therapy is commonly used for resuscitation at birth or prevention of hypoxaemia before procedures during the neonatal period. However, O(2) may severely depress breathing, especially when administered repeatedly. The aim of the present study was to test the effects of repeated hyperoxia on breathing control in newborn mice. A total of 97 Swiss mouse pups were assigned to O(2) or air on post-natal day 0, 1 or 2. Each pup in the O(2) group was subjected to four hyperoxic tests (100% O(2) for 3 min followed by 12 min normoxia), whereas pups in the air group were maintained in normoxia. Breathing variables were measured using flow-through barometric plethysmography. O(2) significantly decreased minute ventilation as seen in a decrease in respiratory rate. This decrease became significantly larger with repeated exposure and ranged -17- -26% for all ages combined. Furthermore, hyperoxia increased total apnoea duration, as compared with the baseline value. In newborn mice, repeated hyperoxia increasingly depressed breathing. This finding further supports a need for stringent control of oxygen therapy, most notably repeated oxygen administration in the neonatal period for premature newborn infants and those carried to term.

Ampakines Alleviate Respiratory Depression in Rats

There is a need for improved therapeutic interventions to treat both drug- and sleep-induced respiratory depression. Increased understanding of the neurochemical control of respiration will help identify a basis for advances. Activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors positively modulates respiratory drive and rhythmogenesis in several brain regions including the pre-Bötzinger complex. Ampakines are a diverse group of small molecules that activate subsets of these receptors. We determined whether the ampakine CX546 would enhance respiratory drive and rhythmogenesis across various stages of development and whether this ampakine could counter opioid- and barbiturate-induced respiratory depression. Respiratory frequency and amplitude were measured in the following rat models: (1) perinatal in vitro brainstem-spinal cord, (2) neonatal in vitro medullary slice, (3) juvenile in situ perfused, working heart-brainstem preparation, and (4) newborn and adult in vivo. Administration of CX546 stimulated baseline respiratory frequency in perinatal in vitro preparations but not in older animals (greater than Postnatal Day 0). Furthermore, pharmacologic depression of respiratory frequency and amplitude was countered at all ages studied by the administration of CX546 in vitro, in situ, and in vivo. Significantly, CX546 countered opioid-induced breathing depression in all preparations, without altering analgesia as assessed by measuring the time to foot withdrawal in response to a thermal stimulus. CX546 effectively reverses opioid- and barbiturate-induced respiratory depression without reversing the analgesic response. These studies suggest that ampakines may be useful in preventing or reversing opioid-induced respiratory depression and identify the potential of ampakines for alleviating other forms of respiratory depression including sedative use and sleep apnea.

Neurosteroid modulation of respiratory rhythm in rats during the perinatal period

Neurosteroids regulate neuronal excitability and are expressed at particularly high levels in the CNS during the perinatal period. Further, neurosteroid levels are increased by a variety of stressors including hypoxia, asphyxia, parturition, ethanol exposure and infection. One mechanism by which neurosteroids regulate neuronal activity is by negative or positive modulation of GABA(A) receptor function. Perinatal respiration is strongly modulated by GABAergic synaptic drive, and GABA release is increased during hypoxia to contribute to hypoxia-induced depression of neonatal ventilation. Here, we use in vitro and in vivo rat models to test the hypothesis that GABA(A) receptor-mediated modulation of perinatal respiration is markedly influenced by the presence of neurosteroids. The principal finding of this study was that the efficacy of GABA(A) receptor-mediated modulation of respiratory membrane potential and rhythmogenesis is markedly enhanced by allopregnanolone and depressed by dehydroepiandrosterone sulphate. These data demonstrate that the modulation of breathing via GABA(A) receptor activation will be determined by the overall balance of negative and positive neurosteroid modulators within respiratory nuclei. This adds a level of complexity that must be considered when examining the depression of breathing in mammals associated with various behavioural states and pathogenic conditions such as apnoea and sudden death suspected to be associated with central respiratory dysfunction.

Characterization of [ 125I]ZM 241385 binding to adenosine A 2A receptors in the pineal of sheep brain

Adenosine is a ubiquitous neuromodulator and homeostatic regulator that exerts its physiologic actions through activation of A 1, A 2A, A 2B and A 3 adenosine receptor subtypes. In the central nervous system, adenosine's action in neurons is manifested in its modulation of tonic inhibitory control. Adenosine released in the brain during hypoxia has critical depressant effects on breathing in fetal and newborn mammals, an action suggested to be mediated by A 2A receptors in the posteromedial thalamus. In an effort to more accurately define the spatial distribution of adenosine A 2A receptors in fetal sheep diencephalon, we have used a receptor autoradiographic technique utilizing an iodinated radioligand [ 125I]ZM 241385, which has greater sensitivity and resolution than the tritiated compound. The distribution of ligand binding sites in the fetal sheep diencephalon indicated that the highest levels of binding were in select thalamic nuclei, including those implicated in hypoxic depression of fetal breathing, and the pineal. Given the high density of labeled A 2A receptors in the pineal, these sites were characterized more fully in homogenate radioligand binding assays. These data indicate that [ 125I]ZM 241385 binding sites display a pharmacological signature consistent with that of adenosine A 2A receptors and are expressed at similar levels in fetal, lamb and adult ovine brain. The adenosine A 2A receptor pharmacologic signature of the [ 125I]ZM 241385 binding site in pineal cell membranes generalized to the site characterized in membranes derived from other portions of the lamb thalamus, including the sector involved in hypoxic inhibition of fetal breathing. These results have important implications for the functional roles of adenosine A 2A receptors in the thalamus and pineal of sheep brain.

Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats

Ventilation of the lungs is mediated by neurons of the respiratory network in the lower brainstem. The activity of rhythmogenic respiratory network neurons seems to depend greatly on cellular levels of the second messenger cAMP. Accordingly, depression of breathing in (preterm) infants associated with clinical administration of opioids and prostaglandins results likely from a fall of cAMP in these cells caused by G i/o proteins that are activated via μ-opiate or EP 3 prostanoid receptors, respectively. Typically, such drug-induced depression of infant breathing is treated with high doses of methylxanthines that have notable adverse effects. It was the aim of our study to investigate whether clinically applicable blockers of cAMP-hydrolyzing phosphodiesterase-4 counteract the inhibition of the respiratory network associated with a drug-induced fall of cAMP. For this purpose, inspiratory-related cervical nerve activity was measured in isolated brainstem-spinal cord preparations from newborn rats. Respiratory frequency was depressed by >80% (from >5 bursts/min to <1 burst/min) with nociceptin (1 μM) which decreases cAMP via a G i/o protein-coupled opioid-like receptor. The nociceptin-induced respiratory depression was reversed by the activator of adenylyl cyclase, forskolin (5–25 μM) and the phosphodiesterase-4 blockers rolipram (0.1–1 μM) and RO-201724 (1–5 μM). Blocking phosphodiesterases 3 and 5 with milrinone (25–100 μM) and zaprinast (25–100 μM), respectively, was not effective. The results indicate that phosphodiesterase-4 blockers are strong stimulants of the respiratory network. We hypothesize that these or related agents may be potent tools for a treatment of drug-induced disturbances of breathing in (preterm) infants.