naloxone and Hypercapnia

Topics: Acidosis; Adult; Alcohol Drinking; Alkalosis; Animals; Child, Preschool; Circadian Rhythm; Dogs; Electrolytes; Female; Humans; Hypercapnia; Hypertension; Hypotension; Hypoxia; Infant; Lung; Male; Mice; Naloxone; Narcotics; Neurotransmitter Agents; Rats; Temperature; Thyroid Gland; Time Factors

Ventilatory depression is a significant risk associated with the use of opioids. We assessed whether opioid-induced ventilatory depression can be selectively antagonized by an ampakine without reduction of analgesia. In 16 healthy men, after a single oral dose of 1,500 mg of the ampakine CX717, a target concentration of 100 ng/ml alfentanil decreased the respiratory frequency by only 2.9 +/- 33.4% as compared with 25.6 +/- 27.9% during placebo coadministration (P < 0.01).Blood oxygenation and the ventilatory response to hypercapnic challenge also showed significantly smaller decreases with CX717 than with placebo. In contrast, CX717 did not affect alfentanil-induced analgesia in either electrical or heat-based experimental models of pain. Both ventilatory depression and analgesia were reversed with 1.6 mg of naloxone. These results support the use of ampakines as selective antidotes in humans to counter opioid-induced ventilatory depression without affecting opioid-mediated analgesia.

Topics: Administration, Oral; Adult; Alfentanil; Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Humans; Hypercapnia; Isoxazoles; Male; Naloxone; Narcotic Antagonists; Oxygen; Pain; Respiratory Insufficiency; Young Adult

Severe respiratory stress causes dyspnea, and a sudden release of this stress frequently accompanies a euphoric sensation. We hypothesized that acute severe respiratory stress may result in an elaboration of endogenous opioids within the central nervous system, and that these opioids may play significant roles in relieving dyspnea and generating euphoric sensation after a sudden removal of the stress. To test this hypothesis, we examined the effects of naloxone (0.04 mg/kg, I.V.) and the placebo (normal saline) on changes in respiratory sensation before and after the release of severe respiratory stress in a double-blind, randomized, crossover study in 14 healthy adults. Acute severe respiratory stress was induced by loaded breathing with a combination of resistive loading and hypercapnia. The subjects rated their changes in sensation by using a bidirectional visual analogue scale. Naloxone pretreatment affected neither the ventilation nor the development of dyspneic sensation during loaded breathing. Naloxone pretreatment only slightly attentuated the euphoric sensation developed after the release of severe respiratory stress. These findings suggest a small role of opioids in relieving dyspnea and in generating euphoria before and after a sudden removal of stress.

Topics: Adult; Analysis of Variance; Area Under Curve; Dyspnea; Euphoria; Humans; Hypercapnia; Male; Naloxone; Respiration; Respiratory Mechanics; Sensation; Stress, Physiological

The effect of breathing CO2 on somatic sensitivity was studied in human subjects. Healthy humans breathed room air, 100% O2, or CO2 (5% or 8% in O2). Thresholds to heat pain, mechanical pain, electrically evoked pain, and electrically evoked perception were measured using psychophysical techniques. Also, the effects on sensory and affective components of experimental ischaemic pain, alertness and on cardiovascular parameters were observed. In addition, the effect of CO2 on heat pain threshold was determined in the ischaemic limb to exclude the possibility that the threshold elevation was due to an action on primary afferent fibres. Naloxone (0.8 mg), dexamethasone (0.1 mg) or placebo (0.9% NaCl) were applied intravenously in double blind tests to reverse the threshold elevations. In an electrophysiological experiment the effect of CO2 on a spinal nociceptive flexion reflex evoked by an electric stimulus was measured. The CO2 produced a dose-dependent elevation of the heat pain threshold. Similarly, the sensory and affective components of experimental ischaemic pain were attenuated by CO2. The heat pain threshold was significantly elevated by CO2 in the ischaemic limb, also. However, there was no effect on thresholds to mechanically or electrically induced pain or perception thresholds to electrically evoked sensations. One hundred percent O, did not elevate the heat pain threshold. In double blind tests the heat pain threshold elevation was not significant when the naloxone or dexamethasone was administered. The threshold to electrically evoked spinal flexion reflex was not elevated by CO2. The CO2 at the current dose produced sedation, an increase in blood pressure but no change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Arousal; Blood Pressure; Carbon Dioxide; Dexamethasone; Electroshock; Female; Heart Rate; Hot Temperature; Humans; Hypercapnia; Ischemia; Male; Middle Aged; Naloxone; Pain Threshold; Perception; Physical Stimulation

To assess the role of endogenous opioid peptides in ventilatory control in patients with chronic obstructive lung disease, we measured the ventilatory and mouth occlusion pressure responses to hypercapnia and the compensatory response to an inspiratory resistive load in 11 male patients with COPD before and after intravenous administration of naloxone or placebo on 2 separate days. There were no statistically significant differences between naloxone and placebo administration in any index of ventilatory response to CO2 or resistive loading. When an inspiratory resistive load was added during CO2 rebreathing, minute ventilation at PETCO2 = 50 mm Hg in all 11 patients decreased significantly (p less than 0.05) with placebo and naloxone. In response to the inspiratory resistive load, in eight of the 11 patients mouth occlusion pressure (P0.1) did not increase; these eight subjects were classified as noncompensators. Naloxone did not affect the P0.1 response to inspiratory resistive loading, either in the group as a whole or in the subgroup of eight patients classified as noncompensators. Our study was unable to demonstrate that increased activity of endogenous opioid peptides suppresses the ventilatory response to CO2 or resistive loading in patients with chronic obstructive lung disease.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Humans; Hypercapnia; Lung Diseases, Obstructive; Male; Middle Aged; Naloxone; Random Allocation; Respiration

In seven normal subjects the ventilatory responses to progressive isocapnic hypoxia and hyperoxic hypercapnia were measured during rebreathing. During an infusion of somatostatin (10 nmol/min) the mean hypoxic response decreased by 66% (control: -1.6 SD 1.2 litres min-1 %-1 SaO2; somatostatin: -0.6 SD 0.7) but the mean hypercapnic response was unchanged (control: 2.0 SD 0.8 litre min-1 mmHg-1; somatostatin: 2.3 SD 1.2). There was no change in resting VO2 or VCO2 during somatostatin infusion. The opiate antagonist, naloxone (0.1 mg/kg, intravenously), caused little change in either response (mean hypoxic response: -1.7 SD 1.0 litre min-1 %-1 SaO2; mean hypercapnic response: 2.4 SD 0.9 litre min-1 mmHg-1). In five of the subjects the dopamine antagonist, prochlorperazine (10 mg, intravenously), increased the mean hypoxic response by 134% (control: -1.9 SD 1.4 litres min-1 %-1 SaO2; after prochlorperazine: -3.8 SD 1.6; P less than 0.05). The mean hypercapnic response after this drug was also increased (control: 2.1 SD 1.0 litre min-1 mmHg-1; after prochlorperazine: 3.1 SD 1.0) but this change did not achieve significance. The selective effect of somatostatin on the hypoxic response, suggestive of an action on the carotid body, was not inhibited by prior injection of either naloxone or prochlorperazine, and its mode of action remains to be found.

Topics: Adult; Carbon Dioxide; Female; Humans; Hypercapnia; Hypoxia; Male; Middle Aged; Naloxone; Oxygen Consumption; Prochlorperazine; Respiration; Somatostatin

Ethanol depresses the ventilatory responses to hypercapnia and hypoxia. We hypothesized that this ventilatory depression, like some other central nervous system effects of ethanol, might be mediated via endorphins. In a double-blind placebo-controlled study, we assessed the effect of the opiate antagonist naloxone on ventilatory responses during ethanol intoxication in 18 normal men. Standard rebreathing studies were done at baseline, after ethanol (1.5 ml/kg, p.o.), and after each of 2 intravenously administered injections. One of the injection sequences PP, NP, or PN (N = naloxone, 0.8 mg; P = placebo, 2 ml) was randomly assigned to each subject. The ventilatory responses were reduced after ethanol administration compared with those at baseline (p less than 0.05). In groups NP and PN, naloxone restored the hypercapnic response (p less than 0.05). Placebo injection did not significantly alter the response slopes. Hypoxic ventilatory responses showed the same trends but did not reach statistical significance. This study shows that naloxone reverses ethanol-induced depression of hypercapnic drive, suggesting that an opiate-mediated mechanism is responsible for this depression.

Topics: Adult; Alcoholic Intoxication; Clinical Trials as Topic; Double-Blind Method; Ethanol; Humans; Hypercapnia; Hypoxia; Male; Naloxone; Respiration

Recent reports suggest that endogenously released endorphins may exert a modifying influence on respiratory center drive in patients with respiratory disease. In this report, we employed respiratory inductive plethysmography to noninvasively assess breathing patterns with particular attention to respiratory center drive as reflected by mean inspiratory flow. We studied 10 patients with documented chronic obstructive pulmonary disease (6 with hypercapnia and 4 with normocapnia) after treatment with placebo and the opiate antagonist, naloxone. No significant change in breathing pattern was observed in either patient group after treatment with placebo or naloxone, although individual patients displayed greater respiratory drive after naloxone than placebo. Therefore, endorphins do not exert a consistent influence on respiratory center output in patients with chronic obstructive pulmonary disease.

Topics: Aged; Female; Humans; Hypercapnia; Lung Diseases, Obstructive; Male; Middle Aged; Naloxone; Plethysmography; Respiration

To investigate the role of endorphins in central respiratory control, the effect of naloxone, a specific opiate antagonist, on resting ventilation and ventilatory control was investigated in a randomised double-blind, placebo-controlled study of normal subjects and patients with chronic airways obstruction and mild hypercapnia due to longstanding chronic bronchitis. In 13 normal subjects the ventilatory response to hypercapnia increased after an intravenous injection of naloxone (0.1 mg/kg), ventilation (VE) at a PCO2 of 8.5 kPa increasing from 55.6 +/- SEM 6.2 to 75.9 +/- 8.21 min-1 (p less than 0.001) and the delta VE/delta PCO2 slope increasing from 28.6 +/- 4.4 to 34.2 +/- 4.21 min-1 kPa-1 (p less than 0.05). There was no significant change after placebo (saline) injection. Naloxone had no effect on resting ventilation or on the ventilatory response to hypoxia in normal subjects. In all six patients naloxone significantly (p less than 0.02) increased mouth occlusion pressure (P 0.1) responses to hypercapnia. Although there was no change in resting respiratory frequency or tidal volume patients showed a significant (p less than 0.01) decrease in inspiratory timing (Ti/Ttot) and increase in mean inspiratory flow (VT/Ti) after naloxone. These results indicate that endorphins have a modulatory role in the central respiratory response to hypercapnia in both normal subjects and patients with airways obstruction. In addition, they have an inhibitory effect on the control of tidal breathing in patients with chronic bronchitis.

Topics: Adult; Aged; Bronchitis; Double-Blind Method; Endorphins; Female; Humans; Hypercapnia; Lung Diseases, Obstructive; Male; Middle Aged; Naloxone; Random Allocation; Respiration; Respiratory Function Tests

The authors compared the effects of naloxone and saline solution on the respiratory changes following diazepam in a double-blind crossover trial in six subjects. Following baseline measurements of respiration, each subject was given diazepam, 15 mg, intravenously. Sixty and ninety-five minutes later each subject received either two doses of naloxone, 15 mg, intravenously, or two doses of the equivalent volume of saline solution. Forty-five minutes after diazepam administration the slopes of the curves of the ventilatory responses to rebreathing carbon dioxide (VE/PETCO2) were depressed to 53 per cent of control (P < 0.05). Following the two doses of naloxone, the slopes of VE/PETCO2 recovered, until, 120 minutes after the second dose of naloxone, slopes had returned to control values. After saline solution, however, slopes remained depressed at 68 per cent of control (P < 0.05). A similar recovery following naloxone was observed in the PETCO2 intercept of the VE/PETCO2 response curve and in the slope of the mouth-occlusion-pressure response curve to rebreathing carbon dioxide. End-tidal carbon dioxide during quiet breathing and during inspiratory resistive-loaded breathing (80 cm H2O/l/s) showed small increases after diazepam, which were not significantly reduced by naloxone. The results of this study show that diazepam produces respiratory depression, and that this may be relieved by large doses of naloxone.

Topics: Adult; Carbon Dioxide; Diazepam; Dose-Response Relationship, Drug; Humans; Hypercapnia; Middle Aged; Naloxone; Respiration; Sodium Chloride

Endogenous opiates are found in large concentrations in the brainstem of vertebrate animals, suggesting that they play a possible role in the central control of breathing. To examine this possible role in human ventilatory control we evaluated the effect of nalozone, a specific opiate antagonist, on the ventilatory and mouth occlusion pressure (P0.1) responses to hypercapnia and hypoxia in 6 normal men 22 to 48 yr of age. In a random double-blind crossover study, each subject received both an intravenous infusion of 50 mg of naloxone and a placebo infusion of normal saline. Ventilatory responses were measured before and 5 min after each infusion. Ventilatory responses to hypercapnia and hypoxia were more marked after both the saline and naloxone infusions, but there was no significant difference in the responses between the 2 infusions. Similarly there was no significant difference in respiratory timing or mean inspiratory flow between the 2 infusions at an arterial oxygen saturation (SaO2) > 95%. We concluded that endogenous opiates have no major influence on the chemical control of breathing in normal humans.

Topics: Adult; Endorphins; Humans; Hypercapnia; Hypoxia; Male; Middle Aged; Naloxone; Respiration

Topics: Adult; Alkalosis, Respiratory; Analgesics; Anesthesia, Intravenous; Bicarbonates; Blood; Carbon Dioxide; Clinical Trials as Topic; Depression, Chemical; Dose-Response Relationship, Drug; Drug Antagonism; Drug Synergism; Humans; Hydrogen-Ion Concentration; Hypercapnia; Infusions, Parenteral; Male; Morphinans; Naloxone; Oxymorphone; Placebos; Respiration; Sodium Chloride; Spirometry

A 74-year-old man was referred to our hospital due to deteriorating level of consciousness and desaturation. His Glasgow Coma Scale was 6, and his pupils were constricted but responded to light. Chest radiograph was negative for significant findings. Arterial blood gas evaluation on supplemental oxygen revealed severe acute on chronic respiratory acidosis: pH 7.15; PCO2, 133 mm Hg; PO2,64 mm Hg; and HCO3, 31 mmol/L. He regained full consciousness (Glasgow Coma Scale, 15) after receiving a 0.4 mg dose of naloxone, but because of persistent severe respiratory acidosis (pH 7.21; PCO2, 105 mm Hg), he was immediately commenced on noninvasive positive pressure ventilation (NIV) displaying a remarkable improvement in arterial blood gas values within the next few hours. However, in the days that followed, he remained dependent on NIV, and he was finally discharged on a home mechanical ventilation prescription. In cases of drug-induced respiratory depression, NIV should be regarded as an acceptable treatment, as it can provide ventilatory support without the increased risks associated with invasive mechanical ventilation.

Topics: Acidosis; Aged; Analgesics, Opioid; Combined Modality Therapy; Fentanyl; Humans; Hypercapnia; Male; Naloxone; Narcotic Antagonists; Positive-Pressure Respiration; Tramadol

At birth, asphyxial stressors such as hypoxia and hypercapnia are important physiological stimuli for adrenal catecholamine release that is critical for the proper transition to extrauterine life. We recently showed that chronic opioids blunt chemosensitivity of neonatal rat adrenomedullary chromaffin cells (AMCs) to hypoxia and hypercapnia. This blunting was attributable to increased ATP-sensitive K(+) (KATP) channel and decreased carbonic anhydrase (CA) I and II expression, respectively, and involved μ- and δ-opioid receptor signaling pathways. To address underlying molecular mechanisms, we first exposed an O2- and CO2-sensitive, immortalized rat chromaffin cell line (MAH cells) to combined μ {[d-Arg(2),Ly(4)]dermorphin-(1-4)-amide}- and δ ([d-Pen(2),5,P-Cl-Phe(4)]enkephalin)-opioid agonists (2 μM) for ∼7 days. Western blot and quantitative real-time PCR analysis revealed that chronic opioids increased KATP channel subunit Kir6.2 and decreased CAII expression; both effects were blocked by naloxone and were absent in hypoxia-inducible factor (HIF)-2α-deficient MAH cells. Chronic opioids also stimulated HIF-2α accumulation along a time course similar to Kir6.2. Chromatin immunoprecipitation assays on opioid-treated cells revealed the binding of HIF-2α to a hypoxia response element in the promoter region of the Kir6.2 gene. The opioid-induced regulation of Kir6.2 and CAII was dependent on protein kinase A, but not protein kinase C or calmodulin kinase, activity. Interestingly, a similar pattern of HIF-2α, Kir6.2, and CAII regulation (including downregulation of CAI) was replicated in chromaffin tissue obtained from rat pups born to dams exposed to morphine throughout gestation. Collectively, these data reveal novel mechanisms by which chronic opioids blunt asphyxial chemosensitivity in AMCs, thereby contributing to abnormal arousal responses in the offspring of opiate-addicted mothers.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adrenal Cortex; Adrenal Medulla; Analgesics, Opioid; Animals; Basic Helix-Loop-Helix Transcription Factors; Calcium-Calmodulin-Dependent Protein Kinases; Carbonic Anhydrase I; Carbonic Anhydrase II; Cell Hypoxia; Cell Line; Chromaffin Cells; Cyclic AMP-Dependent Protein Kinases; Dopamine; Enkephalin, D-Penicillamine (2,5)-; Enzyme Inhibitors; Female; Hypercapnia; Indoles; Isoquinolines; KATP Channels; Maleimides; Morphine; Naloxone; Narcotic Antagonists; Norepinephrine; Oligopeptides; Potassium Channels, Inwardly Rectifying; Pregnancy; Promoter Regions, Genetic; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, mu; Sulfonamides

Since its introduction into clinical practice, it has been known that fentanyl and other synthetic opioids may cause skeletal muscle rigidity. Involvement of the respiratory musculature, laryngeal structures, or the chest wall may impair ventilation, resulting in hypercarbia and hypoxemia. Although most common with the rapid administration of large doses, this rare adverse effect may occur with small doses especially in neonates and infants. We present 2 infants who developed chest wall rigidity, requiring the administration of neuromuscular blocking agents and controlled ventilation after analgesic doses of fentanyl. Previous reports regarding chest wall rigidity after the administration of low-dose fentanyl in infants and children are reviewed, the pathogenesis of the disorder is discussed, and treatment options offered.

Topics: Analgesics, Opioid; Dose-Response Relationship, Drug; Female; Fentanyl; Follow-Up Studies; Humans; Hypercapnia; Infant; Infant, Newborn; Injections, Intravenous; Muscle Rigidity; Naloxone; Narcotic Antagonists; Thoracic Wall

Expiratory muscle action is prominent during anaesthesia and can impair lung function. This activity is exaggerated by the use of opioids. Airway pressure during occlusion of expiration would be a valuable measure in the study of expiratory muscle activation. However, this would only be valid if the imposed occlusion did not itself alter muscle activation. This possibility can be checked by directly assessing muscle activity by electromyography; varying arterial carbon dioxide tensions and opioid action should be considered.. We studied seven spontaneously breathing patients, anaesthetized with nitrous oxide and isoflurane, in four conditions: during an infusion of fentanyl and after naloxone, breathing normally and with breathing stimulated with CO(2). We compared diaphragm and external oblique abdominal electromyogram (EMG) signals during normal and occluded breaths. We also measured chest wall volume and compared airway occlusion pressure, during inspiration and expiration, with the EMG results.. Inspiratory occlusion increased the duration of inspiration during hypercapnia by 20%, but not the rate of electrical activation of the diaphragm, indicating that occlusion does not cause a reflex increase in diaphragm contraction. In contrast, expiratory occlusion did not affect either the duration of expiration or the electrical activity of the external oblique muscles.. In these conditions, except for a change in inspiratory duration, respiratory muscle activity is unaffected by airway occlusion. Airway occlusion will permit valid measures of muscle activity in inspiration and expiration and provide simple measurements of respiratory muscle function during anaesthesia.

Topics: Abdominal Muscles; Adult; Aged; Airway Obstruction; Analgesics, Opioid; Anesthetics, Inhalation; Carbon Dioxide; Child; Electromyography; Female; Fentanyl; Humans; Hypercapnia; Isoflurane; Male; Middle Aged; Naloxone; Nitrous Oxide; Respiratory Muscles

Though the mechanics of breathing differ fundamentally between amniotes and "lower" vertebrates, homologous rhythm generators may drive air breathing in all lunged vertebrates. In both frogs and rats, two coupled oscillators, one active during the inspiratory (I) phase and the other active during the preinspiratory (PreI) phase, have been hypothesized to generate the respiratory rhythm. We used opioids to uncouple these oscillators. In the intact rat, complete arrest of the external rhythm by opioid-induced suppression of the putative I oscillator, that is, pre-Bötzinger complex (PBC) oscillator, did not arrest the putative PreI oscillator. In the unanesthetized frog, the comparable PreI oscillator, that is, the putative buccal/gill oscillator, was refractory to opioids even though the comparable I oscillator, the putative lung oscillator, was arrested. Studies in en bloc brainstem preparations derived from both juvenile frogs and metamorphic tadpoles confirmed these results and suggested that opioids may play a role in the clustering of lung bursts into episodes. As the frog and rat respiratory circuitry produce functionally equivalent motor outputs during lung inflation, these data argue for a close homology between the frog and rat oscillators. We suggest that the respiratory rhythm of all lunged vertebrates is generated by paired coupled oscillators. These may have originated from the gill and lung oscillators of the earliest air breathers.

Topics: Action Potentials; Analysis of Variance; Animals; Biological Clocks; Brain Stem; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Fentanyl; Gills; Hypercapnia; In Vitro Techniques; Larva; Lung; Male; Models, Biological; Naloxone; Narcotic Antagonists; Narcotics; Nerve Net; Periodicity; Photoplethysmography; Physical Conditioning, Animal; Ranidae; Rats; Rats, Wistar; Respiration; Respiratory Physiological Phenomena; Vagotomy

H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA, dDAL), a highly selective mu-opioid peptide, produces potent analgesia without respiratory depression after intrathecal administration. Despite carrying 3+ net charge, dDAL is also a potent analgesic after systemic administration. We compared the respiratory effects of dDAL and morphine after subcutaneous administration in mice using whole body plethysmography. Analgesic doses of 3 and 10 times ED(50) were examined. Both drugs dose-dependently decreased respiratory frequency and minute volume in room air. Tidal volume was increased by the lower dose of morphine, while it was decreased by the higher dose of dDAL. The decrease in minute volume by dDAL and morphine was completely reversed by naloxone. No difference in ventilatory response to CO(2) was observed between dDAL and morphine at three times ED(50). Ventilatory response to hypoxia was significantly diminished by dDAL compared to morphine and saline, and this effect of dDAL was naloxone-irreversible. Thus dDAL likely reduces the sensitivity of the peripheral chemoreflex loop through a non-opioid action.

Topics: Analysis of Variance; Animals; Body Temperature; Dose-Response Relationship, Drug; Hypercapnia; Hypoxia; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Oligopeptides; Respiration; Tidal Volume; Time Factors

Opioids are among the most effective analgesics, but a major limitation for their therapeutic usefulness is their induction of respiratory depression. Endomorphin-1 (EM1), in contrast to several other mu opioids, exhibits a threshold for respiratory depression that is well above its threshold for analgesia. Its effect on sensitivity to CO(2), however, remains unknown. Minute ventilation (V(E)) in 2, 4, and 6% CO(2) was measured before and after systemic administration of EM1, endomorphin-2 (EM2), DAMGO, and morphine in the conscious rat. EM1 and EM2 attenuated the hypercapnic ventilatory response (HCVR) only in high doses, while DAMGO and morphine diminished the HCVR in much lower doses. The ventilatory effects of high doses of all 4 agonists were blocked by the mu-opioid antagonist naloxone (0.4 mg/kg i.v.), but not by the peripherally restricted mu-opioid antagonist, methyl-naloxone (0.4 mg/kg i.v.). It was concluded that the endomorphins attenuated the HCVR only in large doses, well beyond the analgesic threshold, and did so through a centrally mediated mu-opioid mechanism.

Topics: Adaptation, Physiological; Analgesics, Opioid; Animals; Carbon Dioxide; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Hypercapnia; Male; Morphine; Naloxone; Oligopeptides; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Respiration; Respiratory Insufficiency

The effects of dermorphin, a mu-selective opioid agonist, on respiratory responses to altered O(2) and CO(2) during postnatal development were investigated in conscious, unrestrained Wistar rats aged 2-21 days. Respiration was recorded by barometric plethysmography. Dermorphin (4 mg kg(-1)) was administered subcutaneously, and the ventilatory responses to hypoxia (11% O(2), 89% N(2)) in 2-21-day-old pups and hyperoxia (100% O(2)), and hypercapnia (8% CO(2), 92% O(2)) in 2-13-day-old pups were assessed in the presence and absence of the mu(1) receptor antagonist naloxonazine (10 mg kg(-1) s.c.) administered 1 day before testing. Six minutes of hypoxia increased ventilation in all age groups, largely via an increase in frequency. Dermorphin inhibited the ventilatory response to hypoxia, and this inhibition was insensitive to naloxonazine. After 5 min of hyperoxia, ventilation was the same as with air breathing except in the presence of dermorphin, when hyperoxic ventilation was depressed by a naloxonazine-insensitive decrease in frequency. Following this 5 min 100% O(2) exposure, pups were exposed to hypercapnia, and respiratory parameters were measured 5 min later. The ventilatory response to CO(2) was inhibited by dermorphin in a naloxonazine-insensitive manner. There was no evidence for endogenous mu(1) receptor modulation of the ventilatory responses to altered gases in rat pups of any age. Thus, mu opioid-induced inhibition of the hypoxic and hypercapnic responses in young rats does not occur via activation of mu(1) opioid receptors.

Topics: Age Factors; Analgesics, Opioid; Animals; Hypercapnia; Hypoxia; Naloxone; Narcotic Antagonists; Oligopeptides; Opioid Peptides; Oxygen; Rats; Rats, Wistar; Receptors, Opioid, mu; Respiratory Mechanics

To assess the occurrence of muscle rigidity after fentanyl administration in premature and term neonates.. Prospective case series, observational study.. A university hospital neonatal intensive care unit.. 8/89 preterm and term infants (25-40 wks gestational age) who received fentanyl for perioperative analgesia and sedation or intensive care procedures.. Mechanical or bag mask ventilation and antagonization with naloxone.. We observed chest wall rigidity in 8 patients after low dosage of fentanyl (3-5 microg/kg body weight). All patients presented with respiratory distress, hypercapnia, and hypoxemia leading to bradycardia. In two patients, laryngospasm was noted and associated with muscle rigidity, thus making intubation impossible. Naloxone (20-40 microg/kg body weight) reversed the laryngospasm and muscle rigidity immediately, allowing restitution within 1 min. In our patient population, we found fentanyl-induced chest wall rigidity in 4% of neonates after fentanyl administration.. Even low doses of fentanyl can lead to thoracic rigidity in neonates. Additionally, we observed laryngospasm in two patients and speculate that it might be a variant of muscle rigidity.

Topics: Fentanyl; Humans; Hypercapnia; Hypoxia; Infant, Newborn; Infant, Premature; Laryngismus; Naloxone; Narcotic Antagonists; Narcotics; Prospective Studies; Respiratory Distress Syndrome, Newborn; Thoracic Diseases

Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially binds to the high affinity micro(1) sites, is often used to discriminate between pharmacological effects mediated by micro(1) and micro(2) binding sites. The present series of experiments were undertaken to compare the opioid antagonistic properties of naloxonazine and naloxone (NLX) (a non-selective micro(1)-antagonist) on intravenous (i.v.) and intrathecal (i.t.) sufentanil (SUF)-induced antinociception and respiratory depression. The opioid antagonists were given either intravenously at 5 min after SUF, or subcutaneously (s.c.) 24 h prior to the opioid. Intravenous NLX and NLZ reduced the i.v. and i. t. SUF-induced antinociception, hypercapnia and hypoxia when given directly after the opioid. There were no major differences in activity between both antagonists. Pretreatment with 30 mg/kg NLX did not reverse the i.v. or i.t. SUF-induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg NLX only partially antagonized the i.v. SUF-induced antinociception, while a complete reversal was present of the opioid-induced hypercapnia and hypoxia. With regard to i.t. SUF, doses up to 30 mg/kg NLZ were unable to reduce the antinociception. The respiratory depression was partially affected; with 30 mg/kg NLZ, the i.t. SUF-induced hypercapnia returned to baseline levels, whereas the SUF-induced hypoxia was only minimally affected. These results challenge the classical view of the selectivity of NLZ for the high affinity micro(1) binding sites. They further fail to conform an exclusive role for micro(2) receptor sites in the respiratory depression and spinal analgesia induced by a strong lipophilic opioid such as SUF in rats.

Topics: Analgesics, Opioid; Anesthesia, Spinal; Animals; Hypercapnia; Hypoxia; Injections, Intravenous; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Rats; Rats, Wistar; Receptors, Opioid, mu; Respiration; Sufentanil

1. Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]dermorphin and its main metabolites, [1-5]dermorphin and [1-4]dermorphin. 2. Fifteen minutes after injection, doses of [Lys7]dermorphin producing antinociception (i.c.v., 36-120 nmol; s.c., 0.12-4.7 micromol kg(-1)) significantly increased respiratory frequency and minute volume of rats breathing air or hypoxic inspirates. This respiratory stimulation was reversed to depression by the 5-HT receptor antagonist ritanserin (2 mg kg(-1), s.c.), was blocked by naloxone (0.1 mg kg(-1), s.c.), significantly reduced by the mu1 opioid receptor antagonist naloxonazine (10 mg kg(-1), s.c., 24 h before) but unaffected by peripherally acting opioid antagonist naloxone methyl bromide (3 mg kg(-1), s.c.). Forty five minutes after injection, doses of the peptide producing catalepsy (s.c., 8.3-14.2 micromol kg(-1), i.c.v., 360 nmol) significantly reduced respiratory frequency and volume of rats breathing air and blocked the hypercapnic ventilator response of rats breathing from 4% to 10% CO2. I.c.v. administration of [1-5]dermorphin and [1-4]dermorphin (from 36 to 360 nmol) never stimulated respiration but significantly reduced basal and CO2-stimulated ventilation. Opioid respiratory depression was only antagonized by naloxone. 3. In awake rats, [Lys7]dermorphin (0.1-1 mg kg(-1), s.c.) decreased blood pressure. This hypotensive response was abolished by naloxone, reduced by naloxone methyl bromide and unaffected by naloxonazine. 4. In conclusion, the present study indicates that analgesic doses of [Lys7]dermorphin stimulate respiration by activating central mu1 opioid receptors and this respiratory stimulation involves a forebrain 5-hydroxytryptaminergic excitatory pathway.

Topics: Analgesia; Animals; Blood Pressure; Hypercapnia; Injections, Intravenous; Injections, Intraventricular; Injections, Subcutaneous; Male; Naloxone; Narcotic Antagonists; Oligopeptides; Prosencephalon; Pulmonary Ventilation; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, Opioid, mu; Ritanserin; Serotonin Antagonists; Tidal Volume

Ventilation, oxygen consumption, the ventilatory equivalent for oxygen, and ventilatory responses to hypoxia and to hypercapnia were evaluated in conscious male rats who received each of four treatments: (1) microinjection of artificial cerebrospinal fluid (aCSF) into the arcuate nucleus and subcutaneously saline (CS); (2) aspartic acid into the arcuate nucleus and saline subcutaneously (AS); (3) aCSF into the arcuate nucleus and naloxone subcutaneously (CN); and (4) aspartic acid into the arcuate nucleus and naloxone subcutaneously (AN). Rats treated with CN exhibited a depression of ventilation, ventilatory equivalent, ventilatory response to hypercapnia, and tidal volume response to hypoxia and to hypercapnia. AS had no effect on any parameters. Administration of both aspartic acid and naloxone attenuated all the effects of CN except the depression of minute ventilation in response to hypercapnia. Therefore the naloxone (a mu opioid receptor antagonist) induced a depression of ventilation that was attenuated by aspartic acid acting on N-methyl-D-aspartic acid receptors in the arcuate nucleus.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Aspartic Acid; Hypercapnia; Hypoxia; Injections, Subcutaneous; Male; Microinjections; Naloxone; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Respiration; Sodium Chloride

Poststimulatory depression in respiratory activity induced by superior laryngeal nerve (SLN) stimulation was quantitatively investigated in 20 adult cats. The role played in this phenomenon by endogenous opioids was studied using the opiate antagonist naloxone. The effects of hypercapnia on the same phenomenon were also investigated for comparison. Experiments were performed on cats anesthetized with pentobarbitone or alpha-chloralose, vagotomized, paralyzed, and artificially ventilated with 100% O2. Some animals were also carotid sinus denervated. Respiratory output was monitored as integrated phrenic nerve activity. SLN stimulation produced apnea, which outlasted the stimulation period; when respiration resumed, it was markedly depressed as revealed mainly by a decrease in phrenic minute output, respiratory frequency, and rate of rise of inspiratory activity. Phrenic output recovered gradually to control levels following an exponential time course. These effects varied as a function of the duration of SLN stimulation. Naloxone administration (0.8 mg/kg iv) significantly reduced the duration of poststimulatory apnea and attenuated the depression of phrenic minute output of the first recovery breath as a result of changes in peak phrenic activity; it also accelerated the time course of recovery. Hypercapnia did not affect the duration of poststimulatory apnea, but attenuated the initial poststimulatory depression because of changes in respiratory frequency; the rate of recovery was reduced. The results provide characterization of poststimulatory respiratory depression of laryngeal origin in the adult cat and suggest a role of endogenous opioids in its genesis or modulation.

Topics: Animals; Carbon Dioxide; Cats; Electric Stimulation; Female; Hypercapnia; Laryngeal Nerves; Male; Naloxone; Partial Pressure; Respiration

Acute resistive loading of the airway has been shown to activate the endogenous opioid system, with subsequent depression of ventilation. The present investigation was designed to assess the effect of chronic airway loading on ventilation and CO2 sensitivity, and to determine whether the endogenous opioid system contributes to long-term modulation of ventilatory control in this setting. A flow-resistive ventilatory load was imposed in 2-mo-old rats by surgical implantation of a circumferential tracheal band that approximately tripled tracheal resistance. Respiration and CO2 sensitivity were serially and noninvasively assessed by barometric plethysmography over a period of 21 wk. Ventilatory output was assessed as minute inspiratory effort, which was defined as the product of plethysmograph signal amplitude, inspiratory time, and respiratory rate (RR). CO2 sensitivity was calculated as the percent change in minute inspiratory effort from room air to CO2 exposure. The effect of naloxone administration on these parameters was also determine. Arterial blood gases demonstrated hypercapnia with maintenance of normoxia in loaded rats; these findings persisted for the duration of the study. Two days after surgery, rats with tracheal obstruction demonstrated a lower RR than controls during room air breathing and during CO2 stimulation. CO2 sensitivity was significantly depressed in obstructed animals at this time. Escape from suppression of RR and CO2 sensitivity was evident by 14 to 21 d after obstruction; however, suppression of these parameters reappeared and was maintained from 56 to 147 d after obstruction. Naloxone augmented minute inspiratory effort during CO2 stimulation at 2 d after obstruction but not thereafter; naloxone had no effect in control rats. These data indicate that chronic airway loading suppresses RR and CO2 sensitivity in a triphasic manner. The early suppression is partially reversible by naloxone; late-appearing suppression is unaffected by naloxone and is presumably mediated by mechanisms that do not involve endogenous opioids.

Topics: Airway Obstruction; Airway Resistance; Animals; Carbon Dioxide; Chronic Disease; Disease Models, Animal; Eating; Hypercapnia; Inhalation; Male; Naloxone; Opioid Peptides; Oxygen; Oxygen Consumption; Plethysmography; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiration; Tracheal Diseases

This study evaluated the modulatory role of endogenous opioids on ventilation in young and mature, lean and obese male Zucker rats. Naloxone, an opioid receptor antagonist, and saline (control) were administered subcutaneously to awake rats, and ventilation in air and in response to an hypoxic and an hypercapnic gas challenge measured. In response to naloxone young, obese but not lean rats exhibited a marked increase of ventilation in all three conditions. Older obese Zucker rats that were morbidly obese breathed at a frequency of over 200 breaths per minute and showed only a modest increase of ventilation in response to naloxone. Older lean rats increased ventilation with naloxone only when exposed to hypercapnia. Unlike the stimulatory effects hypoxia and hypercapnia had on ventilation in older, lean rats, the ventilatory responses of the obese, older rats to hypoxia and to hypercapnia were blunted. We conclude that the obese Zucker rat may be a good animal model to assess how chest wall loading and endogenous opioids interact in the development of ventilatory control abnormalities.

Topics: Animals; Disease Models, Animal; Hypercapnia; Hypoxia; Male; Naloxone; Obesity; Opioid Peptides; Pulmonary Ventilation; Rats; Rats, Zucker; Respiration

The role of endogenous opioids in respiratory control in the pentobarbital anaesthetised rat was investigated using a rebreathing technique to generate a progressively increasing hypercapnic stimulus to the respiratory centers following administration of an opioid antagonist or agonist. Respiratory output was measured by intraesophageal pressure (IEP) changes, and a ventilatory equivalent (VEq) was calculated by multiplying IEP by respiratory rate (mmHg.min-1). A non-selective opioid antagonist, naloxone (0.4 mg/kg i.v.), significantly enhanced the slope of the CO2 response curve for VEq (20 +/- 3 mmHg.min-1.%CO2-1) compared with the control (14 +/- 2 mmHg.min-1.%CO2(-1)) (P < 0.05; n = 14). A similar enhancement of the hypercapnic response by naloxone was found in rats anaesthetised with urethane (n = 5). The mu receptor agonist dermorphin (1 mg/kg i.v.) significantly depressed the slope of the CO2 response curve for IEP (-0.01 +/- 0.03) compared with the control (0.10 +/- 0.03) in pentobarbital anaesthetised rats (P < 0.05; n = 5) but had no significant effect on respiratory rate. These results suggest a role of endogenous opioids in the modulation of respiration during hypercapnia.

Topics: Amino Acid Sequence; Analgesics, Opioid; Animals; Hypercapnia; Injections, Intravenous; Male; Molecular Sequence Data; Naloxone; Narcotics; Oligopeptides; Opioid Peptides; Oxygen; Rats; Rats, Wistar; Respiration; Urethane

Unlike individuals with comparable degrees of respiratory muscle weakness from other causes, quadriplegic patients have a blunted ventilatory and P0.1 response to hypercapnia. This suggests that the diminished response in quadriplegia is due, in part, to an alteration in respiratory drive. We measured the hypercapnic response in 9 subjects with chronic quadriplegia (Q) and 8 normal controls (N). Ventilatory muscle strength, maximum voluntary ventilation (MVV), and lung volumes were measured in all subjects. The ventilatory response (HCVR) in Q was significantly less than in N (0.73 +/- 0.37 vs 2.95 +/- 0.4 L.min-1.mmHg-1; P less than 0.001), even when normalized for indices of respiratory muscle performance (e.g., vital capacity, MVV). There was no significant change in the HCVR in Q after the administration of naloxone. We also serially studied 2 subjects with acute quadriplegia, and found that despite progressive improvement in respiratory muscle performance, there was no accompanying increase in the response to hypercapnia. These data suggest that muscle weakness alone cannot explain the blunted hypercapnic response in quadriplegia, and are consistent with the hypothesis that these subjects have a reduced ventilatory drive.

Topics: Adult; Functional Residual Capacity; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Quadriplegia; Respiratory Mechanics; Respiratory Muscles

To clarify whether endogenous opioids play modulatory roles in control of breathing and have any specific effects on the intensity of dyspnea, healthy volunteers were examined for two protocols of ventilatory response tests. 1) The ventilatory response to hypercapnic progressive hypoxia and the withdrawal response to assess peripheral chemoreceptor activity were compared before and after intravenous infusion of 3 mg naloxone in 21 healthy adults. The average ventilatory response increased significantly after naloxone infusion (p less than 0.05), whereas there were no significant changes between two tests with normal saline in the control study (n = 7). Because there was considerable interindividual variation in the response to naloxone administration, "high responders" (n = 8) who showed larger increases with naloxone than the upper limit of the 95% confidence interval for the change with the second saline in the control study were selected. They showed greater ventilatory responses before naloxone infusion than did the other subjects (p less than 0.01). There was no significant change in the withdrawal response before and after naloxone infusion, even in such high responders. 2) The ventilatory and peak mouth pressure responses to hypoxic progressive hypercapnia with inspiratory flow-resistive loading were measured after the intravenous infusion of 3 mg naloxone or saline in 11 male volunteers, while the intensity of dyspnea was simultaneously assessed. Naloxone administration increased the peak mouth pressure response (p less than 0.05) although the increase in ventilatory response did not reach statistical significance. The intensity of dyspnea tended to be greater after naloxone infusion than after saline infusion at end-tidal PCO2 levels of 55 Torr and 60 Torr (p = 0.06 and 0.09, respectively). However, the intensity of dyspnea was quite similar between trials with and without naloxone when compared at equivalent levels of either minute ventilation or peak mouth pressure. These findings suggest that endogenous opioids suppress respiratory outputs under a strong, acute respiratory stress in normal humans. This may be particularly true for those subjects who have greater chemosensitivity. Endogenous opioids appear to act centrally rather than peripherally, but do not have any specific modulatory role on the sensation of dyspnea.

Topics: Adult; Aged; Dyspnea; Endorphins; Female; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Respiration

Reversal of opioid effects by naloxone (NX) can lead to significant cardiovascular problems. We have reported previously that hypercapnic dogs develop greater increases in blood pressure and plasma catecholamine (CA) levels than hypocapnic ones when reversed with naloxone. We have also demonstrated differences between NX and nalbuphine (NBPH) in producing excitatory adrenergic responses when administered during normocapnia. The present study was designed to investigate possible dissimilarities in cardiovascular and sympathetic events after administration of either NX or NBPH in dogs made hypercapnic following fentanyl administration. After induction of anaesthesia with thiopentone and intubation, two groups of dogs were maintained with controlled ventilation on enflurane in oxygen anaesthesia and given 50 micrograms.kg-1 fentanyl IV. This caused a significant decrease in heart rate (HR) (P less than 0.001), mean arterial blood pressure (MAP) (P less than 0.001), and plasma concentrations of norepinephrine (NE) (P less than 0.002). Then, ventilation was decreased to produce a PaCO2 of 60 mmHg; this was accompanied by a significant elevation in plasma level of both epinephrine (EPI) (P less than 0.02) and NE (P less than 0.001). Administration of 20 micrograms.kg-1 NX to six dogs resulted in immediate increases in HR (P less than 0.01) and MAP (P less than 0.01), and a further rise in CA levels to greater than pre-fentanyl baseline values. In six other dogs, NBPH (0.3 mg.kg-1) caused increases in HR (P less than 0.001) and MAP (P less than 0.001) only, and the MAP rise was significantly less than that seen in the NX group (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Blood Pressure; Dogs; Epinephrine; Fentanyl; Heart Rate; Hypercapnia; Morphinans; Nalbuphine; Naloxone; Norepinephrine

Hypoventilation produces hypercapnia which can elevate pain thresholds. Hypercapnia is a potent stressor which releases catecholamines and activates the sympathetic nervous system. Some stressors produce analgesia by releasing endogenous opioids. To determine the roles of endogenous opioids and catecholamines in hypercapnic analgesia, we administered CO2 in the inspired gas mixture to conscious rats. CO2 in the range 5-10% elevated tail flick and leg flexion latencies 2- to 3-fold in both intact and spinalised animals. The effects on reflex latencies but not on paCO2 or pHa were blocked by naloxone (2 mg/kg), and were not present in morphine-tolerant animals. The effects were reduced by dexamethasone but were not changed either by adrenalectomy or by systemic guanethidine, propanolol or phentolamine. Hypercapnia delayed the onset of the late phase of behavioural responses to formalin injected into the plantar surface of the hindpaw. We conclude that moderate hypercapnia powerfully depresses flexor withdrawal responses to noxious stimuli, by a mechanism involving release of endogenous opioids but not systemic catecholamines. This effect may account in part for the elevation in pain threshold during hypoventilation.

Topics: Analgesia; Animals; Catecholamines; Endorphins; Female; Hypercapnia; Naloxone; Nociceptors; Pain; Pain Measurement; Rats; Rats, Inbred Strains

The ventilatory response to hypercapnic progressive hypoxia and the breathing pattern during steady-state hypercapnic hypoxia were compared before and after intravenous infusion of 3 mg of naloxone in a relatively large number of healthy adults (n = 21). In addition, the withdrawal response from hypercapnic hypoxia (modified transient O2 test) was measured to investigate the possible role of endogenous opioids in the peripheral chemoreceptors. The average ventilatory response (delta VE/delta SaO2) increased significantly from 0.51 +/- SD 0.26 to 0.65 +/- 0.42 L/min/% (p less than 0.05) after naloxone infusion, whereas there were no significant changes between two tests with normal saline in the control study (n = 7). Because there was considerable interindividual variation in the response to naloxone administration, we selected "high responders" (n = 8) who showed larger increases with naloxone than the upper limit of the 95% confidence interval for the change with the second saline in the control study. They showed greater delta VE/delta SaO2 (p less than 0.01), respiratory frequency (p less than 0.01), and mean inspiratory flow (p less than 0.01) during hypercapnic hypoxia before naloxone infusion than did the other subjects. There was no significant change in the withdrawal response before and after naloxone infusion, even in such high responders. We conclude that endogenous opioids participate in the control of breathing in normal adults during hypercapnic hypoxia. This may be particularly true for those subjects who exhibit greater chemosensitivity to hypercapnic hypoxia. Endogenous opioids appear to act centrally rather than peripherally.

Topics: Adult; Chemoreceptor Cells; Endorphins; Female; Humans; Hypercapnia; Hypoxia; Male; Middle Aged; Naloxone; Pulmonary Gas Exchange

The effect of naloxone on fetal breathing and the respiratory sensitivity to CO2 was tested on chronically prepared fetal lambs on days one and four post-surgery. After a control period the fetus was challenged with hypercapnia for 10 min and after another control period 9 mg naloxone was administered to the fetus followed by another CO2 test 15 min later. An index of fetal breathing (Veq), tidal volume (VT) and frequency of breathing (f) was determined from tracheal pressure deflections and from the integrated diaphragmatic EMG, expressed as power of diaphragmatic activity per min. Naloxone consistently caused fetal arousal but the duration was variable. The respiratory response to naloxone was also variable and not statistically different from control. The respiratory sensitivity to CO2 (% delta Veq/Torr delta PaCO2 or % delta Diaph. Power/min/Torr delta PaCO2) was not changed by naloxone on either day. We conclude that endorphins do not have a significant direct role in the fetal respiratory response to CO2 but may be involved in the control of state.

Topics: Animals; Carbon Dioxide; Endorphins; Fetus; Hypercapnia; Naloxone; Respiration; Sheep

Clinical reports, as well as animal studies, have described cardiovascular and sympathetic stimulation after the administration of naloxone (NX) to reverse opioid-induced respiratory depression. This investigation examines the effect of PaCO2 on hemodynamic and adrenergic responses to NX, by means of 24 experiments carried out in six dogs. Each dog underwent NX reversal of fentanyl (FEN) at three different PaCO2 levels: 20, 35, and 60 mm Hg. In a final series of six experiments, the dogs were exposed to increasing PaCO2 after autonomic block by total spinal anesthesia and vagotomy. During enflurane anesthesia, 50 micrograms/kg FEN decreased mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine (EPI) significantly. NX 0.4 mg promptly returned HR and MAP to baseline or above in all experiments; catecholamine (CA) levels increased only in hypercapnic dogs. Increases in HR were the same in all series. MAP, EPI, and NE levels were significantly greater than pre-FEN baseline values only in hypercapnic dogs 1 minute after NX and were also significantly higher in hypercapnic than in hypocapnic dogs at this time. NE levels were greater in hypercapnic dogs at all time periods after NX. In blocked dogs, neither F nor NX had any effects on hemodynamic functions or plasma CA levels; the institution of hypercapnia caused significant decreases in HR, MAP, and systemic vascular resistance. This direct circulatory depressant action of an elevated PCO2 may have attenuated the indirectly mediated excitatory hemodynamic effects of NX in intact dogs, thus explaining the relatively greater effect of hypercapnia on adrenergic than on hemodynamic responses to reversal.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Carbon Dioxide; Cardiac Output; Dogs; Epinephrine; Fentanyl; Heart Rate; Hypercapnia; Naloxone; Norepinephrine; Vascular Resistance

The effects of ethanol ingestion and subsequent intravenously administered naloxone on the ventilatory response to hypercapnic hypoxia in 8 normal males and 8 normal females were examined. The responses of controls were lower in the females (-0.63 +/- 0.07 L/min/% SaO2) than the males (-1.11 +/- 0.18 L/min/% SaO2). Alcohol depressed the male response to a mean of -0.50 +/- 0.08 L/min/%SaO2 (p less than 0.01) but increased the mean female response to -0.87 +/- 0.11 L/min/%SaO2 (p less than 0.01). Naloxone reversed the ethanol-induced depression of the hypercapnic hypoxic response in males, but had no effect on the female response. In males there was a direct correlation between the magnitude of the initial hypoxic response and the extent of depression by ethanol; the higher the response the greater the depression. Females showed a significant direct correlation between the blood alcohol and the increase in hypercapnic hypoxic slope, whereas males showed a weaker inverse correlation to blood alcohol level. These results demonstrate that ethanol depresses male but not female hypoxic ventilatory responsiveness and suggest that this is mediated by opioid-like mechanisms. Because the alcohol-induced depression was seen in subjects with a high control hypoxic response, the male-female difference might simply reflect initially lower control responses in females. This suggests a qualitative difference in hypoxic ventilatory control mechanisms between sexes.

Topics: Adult; Ethanol; Humans; Hypercapnia; Hypoxia; Male; Naloxone; Respiration; Sex Characteristics

To assess the effects of endogenous opiates on respiratory muscle responses to CO2, naloxone was administered intravenously to paralyzed, vagotomized and artificially ventilated cats anesthetized with alpha-chloralose. Neural activity was recorded from the phrenic, hypoglossal (HG), glossopharyngeal (GP) and recurrent laryngeal (RL) nerves. Before naloxone, phasic activity began first in the phrenic at a PETCO2 of 30.0 +/- 1.8 Torr, followed by the RL at a PETCO2 of 33.5 +/- 1.7 Torr, the HG at a PETCO2 of 39.9 +/- 2.1 Torr and the GP at a PETCO2 of 42.5 +/- 2.2 Torr during CO2 rebreathing. Naloxone had no significant effect on the apneic threshold of any of the nerves studied. Naloxone did, however, increase respiratory frequency (P less than 0.01) mainly by causing a significant (P less than 0.01) shortening of TE as it had no significant effect on TI. Naloxone also significantly increased the rate at which peak nerve activity increased with CO2 in the HG (P less than 0.01) and the GP (P less than 0.01) nerves, but not in the phrenic and RL nerves. Instead, the maximum activity produced by hypercapnia and the PETCO2 level at which maximum activity occurred in the phrenic, but not the RL, increased after naloxone. The result of these effects was that naloxone extended the range over which the HG and GP behaved proportionally with the phrenic, but it did not change the curvilinear nature of these relationships.

Topics: Animals; Cats; Cranial Nerves; Glossopharyngeal Nerve; Hypercapnia; Hypoglossal Nerve; Naloxone; Phrenic Nerve; Recurrent Laryngeal Nerve; Respiration; Respiratory Muscles; Spinal Nerves

The role of endogenous opioids in systemic and renal circulatory changes during combined acute hypoxemia and hypercapnic acidosis was evaluated in seven conscious female mongrel dogs in rigid sodium balance. Animals were studied 2 wk apart in separate protocols of combined acute hypoxemia (arterial O2 tension = 33 +/- 1 mmHg) and hypercapnic acidosis (arterial CO2 tension = 56 +/- 1 mmHg, pH = 7.19 +/- 0.01) of 40 min duration during 1) naloxone, 5 mg/kg iv bolus followed by an intravenous infusion of 5 mg.kg-1.h-1, and 2) vehicle (5% dextrose in water) alone. Systemic circulatory changes during the combined acute blood-gas derangement including increased mean arterial pressure, heart rate, and cardiac output and decreased total peripheral resistance were comparable between naloxone and vehicle treatments. However, in striking contrast to the brief fall in renal hemodynamic function during combined acute hypoxemia and hypercapnic acidosis with vehicle, naloxone administration during the combined acute blood-gas derangement resulted in a sustained decrease in effective renal plasma flow, glomerular filtration rate, and filtered sodium load and enhanced rise in circulating norepinephrine and epinephrine. Changes in plasma renin activity were comparable between vehicle and naloxone protocols except that plasma renin activity increased from the first to the second 20-min periods of combined hypoxemia and hypercapnic acidosis with naloxone. These observations suggest that endogenous opioids may contribute to preservation of renal hemodynamic function during acute blood-gas derangements, possibly through attenuation of sympathetic nervous system and renin-angiotension activation.

Topics: Animals; Blood Gas Analysis; Catecholamines; Dogs; Endorphins; Hemodynamics; Hypercapnia; Hypoxia; Kidney; Naloxone; Reference Values; Renin; Sympathetic Nervous System

To determine whether endogenous opioids influence the fetal breathing response to CO2 we have investigated the effect of the opiate antagonist, naloxone on the incidence, rate, and amplitude of breathing movements during hypercapnia in fetal lambs in utero. In 20 experiments in six pregnant sheep (130-145 days gestation) hypercapnia was induced by giving the ewe 4-6% CO2-18% O2 in N2 to breathe for 60 min. After 30 min of hypercapnia either naloxone (13 experiments) or saline (7 experiments) was infused intravenously for the remaining 30 min. During hypercapnia breath amplitude increased from 5.8 +/- 0.5 to 9.1 +/- 1.2 mmHg (P less than 0.001), and infusion of naloxone was associated with a further significant increase to 15.7 +/- 1.2 mmHg (P less than 0.001). Naloxone had no effect on the incidence or rate of breathing movements during hypercapnia. After hypercapnia there was a significant decrease in the incidence of fetal breathing movements in the naloxone group (14.7 +/- 3.2%). Infusion of saline during hypercapnia had no effect on incidence, rate, or amplitude of fetal breathing movements. These results suggest that endogenous opioids act to suppress or limit breath amplitude during hypercapnia but do not affect rate or incidence of breathing movements.

Topics: Animals; Carbon Dioxide; Electrocardiography; Electromyography; Female; Fetal Movement; Hydrogen-Ion Concentration; Hypercapnia; Naloxone; Oxygen; Pregnancy; Respiration; Sheep

Though administration of opioid peptides depresses ventilation and ventilatory responsiveness, the role of endogenous opioid peptides in modulating ventilatory responsiveness is not clear. We studied the interaction of endogenous opioids and ventilatory responses in 12 adult male volunteers by relating hypercapnic responsiveness to plasma levels of immunoactive beta-endorphin and by administering the opiate antagonist naloxone. Ventilatory responsiveness to hypercapnia was not altered by pretreatment with naloxone, and this by itself suggests that endogenous opioids have no role in modulating this response. However, there was an inverse relationship between basal levels of immunoactive beta-endorphin in plasma and ventilatory responsiveness to CO2. Furthermore, plasma beta-endorphin levels rose after short-term hypercapnia but only when subjects had been pretreated with naloxone. We conclude that measurement of plasma endorphin levels suggests relationships between endogenous opioid peptides and ventilatory responses to CO2 that are not apparent in studies limited to assessing the effect of naloxone.

Topics: Adult; beta-Endorphin; Depression, Chemical; Endorphins; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Premedication; Respiration

Two female patients revived from fulminant attacks of asthma are described. Ventilatory responses to asphyxia in these patients were 0.70 +/- 0.10 l min-1 % SaO2-1 and 0.64 +/- 0.21 l min-1 % SaO2-1 (mean +/- SEM), respectively. These values were significantly less than the responses of seven normal female subjects (1.54 +/- 0.11 l min-1 % SaO2-1 mean +/- SEM; p less than 0.01). Ventilatory responses to hypercapnia of the two patients were in the low normal range. Dopamine-receptor blockade with prochlorperazine significantly increased the ventilatory response to asphyxia in normal subjects (p less than 0.05 or less for each subject) but did not alter the depressed responses in the asthmatic patients. In one patient, naloxone in a dose of 400 micrograms reversed the decreased ventilatory responsiveness; the response to asphyxia was increased from 0.72 l min-1 % SaO-1 to 1.80 l min-1 % SaO2-1 (p less than 0.01) and the response to hypercapnia was increased from 0.90 l min-1 mmHg-1 to 4.80 l min-1 mmHg-1 (p less than 0.01). Naloxone had no effect in the second asthmatic patient nor in five normal subjects. Defective chemoreceptor responses to chemical stimuli may play a role in sudden death from asthma; endogenous opioids may mediate this disorder of ventilatory control.

Topics: Adult; Asphyxia; Asthma; Bronchodilator Agents; Endorphins; Female; Heart Rate; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Prochlorperazine; Pulmonary Ventilation; Receptors, Dopamine; Respiratory Insufficiency; Resuscitation; Spirometry

The respiratory depressant effects of ethanol and their potential reversibility by naloxone were studied in 10 normal subjects. Ventilatory and mouth occlusion pressure (P0.1) responses to hypercapnia and hypoxia without and with an inspiratory resistive load (13 cmH2O X 1(-1) X S) were measured. The resistive load detected with 50% probability (delta R50) and the exponent (n) in Stevens' psychophysical law for magnitude estimation of resistive loads were studied using standard psychophysical techniques. Each of these studies was performed before ethanol ingestion, after ethanol ingestion (1.5 ml/kg, by mouth), and then again after naloxone (0.8 mg iv). Ethanol increased delta R50 (P less than 0.05) and decreased n (P less than 0.05). Naloxone caused no further change in these parameters. The load compensation (Lc), defined as the ratio of loaded to unloaded response slopes, was not significantly changed after ethanol and naloxone. No correlation was found between the Lc and delta R50 or n. The ventilatory and P0.1 responses to hypercapnia and hypoxia with and without inspiratory resistive loading decreased after ethanol (P less than 0.05, hypercapnia; NS, hypoxia). After naloxone the hypercapnic ventilatory responses increased (P less than 0.05). This suggests that the respiratory depressant effects of ethanol may be mediated via endorphins.

Topics: Adult; Ethanol; Humans; Hypercapnia; Hypoxia; Male; Naloxone; Perception; Respiration; Work of Breathing

Topics: Endorphins; Hypercapnia; Lung Diseases, Obstructive; Naloxone; Respiration

Intratracheal pressure (ITPmax) and respiratory drive (dITP/dt) from the occluded, liquid-filled trachea of term fetal lambs in utero were measured for each breath at the onset of fetal breathing (1) during spontaneous breathing, (2) during sciatic nerve stimulation, (3) during induced hypercapnia, and (4) following naloxone administration. These responses were characterized by linear increase of ITPmax and dITP/dt following which these parameters became stable. The rate of rise of ITPmax and dITP/dt was lowest and similar during spontaneous breathing and sciatic stimulation, but increased incrementally with hypercapnia and naloxone. Mechanical factors could not account for these responses in the liquid-filled lung, nor did appreciable chemical changes occur during this period. These results suggest that progressive breathing responses at the onset of fetal breathing may stem from gradual recruitment of central respiratory neurons, and that the rate of rise of such recruitment depends on facilitation by natural arousal, somatosensory stimulation and hypercapnia as well as on release from natural endorphin inhibition.

Topics: Animals; Electric Stimulation; Female; Fetus; Hypercapnia; Naloxone; Pregnancy; Respiration; Sciatic Nerve; Sheep; Trachea

In anaesthesiology of today, due to the increased use of strong analgetics, it is necessary to have an effective antagonist for mini- mizing the danger of respiratory depression in postoperative period. Naloxone, ( Narcan , R-Endo Laboratories Inc., Subsidiary of E. J. du Pont de Nemours and Co., (Inc.), USA), a new narcotic antagonist was investigated in this study. It has been applied to 58 patients in cases of respiratory depression at the end of anaesthesia in which fentanyl was given, (these cases constituted 14% of all anaesthesias). Fentanyl was given intravenously in fractional doses, (fig 1), during NLA, and other general anaesthesias, for operation and diagnostic examination ( exeption of cardiosurgery), in children and adolescents from two month-to nineteen years of age, (tab. 1.). Naloxone was given intravenously, in fractional doses from 1 microgram to 5 micrograms/kg body weight. As a criterium of an antidepressive effect of Naloxone--in addition to clinical evaluation, blood gases analyses and continuous capnographic recording has been accepted. In all 58 cases diminition of respiratory depression was observed 2-3 min. after injected each dose of Naloxone. Respiratory rate increased from 15 to 22/min. concentration of CO2 in expired gases decreased from 5-6% to 4,5%, (fig. 2 and 3), and regain of consciousness, and return of intensive reaction to endotracheal tube stimulation was observed. Naloxone produced neither changes in the cardiovascular system, nor side effects. Based on these results Naloxone has been suggested as an effective narcotic antagonist. It increase of the possibility of applying strong analgetics in children--allowing to keep a steady level of anaesthesia with easy elimination respiratory depression in the desired period of time.

Topics: Adolescent; Anesthesia, Intravenous; Child; Child, Preschool; Depression, Chemical; Female; Fentanyl; Humans; Hypercapnia; Infant; Male; Naloxone; Pulmonary Gas Exchange; Respiration; Respiratory Insufficiency

To study the significance of normalization of ventilatory or thermal homeostasis during naloxone reversal, 95 patients were given naloxone after thiopental-N2O-O2-relaxant anaesthesia supplemented with fentanyl (6 microgram/kg/h). If naloxone 0.16 mg was given to combat postoperative apnoea during hypercapnia (end tidal carbon dioxide concentration (ETco2)8%), minute ventilation and respiratory rate were significantly higher during the first minutes as compared to the normocapnic patients. Shivering occurred in 44% in the hypercapnic group, as compared to about 30% if naloxone was given during normocapnia (ETco2 5%). Postoperative pain and restlessness were significantly increased in the hypercapnic group. During normocapnia, untoward reactions were less frequent (40%) if naloxone was given in smaller increments (0.08 + 0.08 mg) rather than in one dose (0.16 mg) (72%). This was mainly due to nausea (8% compared to 32%). The incidence and severity of shivering showed a positive correlation to the duration of anaesthesia (r = 0.42) and to the total amount of fentanyl (r = 0.32), but not to the actual postoperative oesophageal temperature (r = -0.13). The results indicate that though untoward reactions after naloxone reversal are aggravated by naloxone-induced normalization of deranged homeostatic mechanisms, their aetiology probably should be sought in an acute abstinence syndrome.

Topics: Adult; Aged; Akathisia, Drug-Induced; Anesthesia, General; Body Temperature; Female; Fentanyl; Homeostasis; Humans; Hypercapnia; Male; Middle Aged; Naloxone; Nitrous Oxide; Respiration; Shivering; Thiopental

Topics: Adolescent; Adult; Arteries; Blood Pressure; Carbon Dioxide; Forearm; Humans; Hypercapnia; Morphine; Naloxone; Reflex; Vascular Resistance; Vasomotor System