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E Boudinot

Publications and source records attributed to E Boudinot.

17 recordsLinked to original sources
PubMed2004

Increased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice.

To investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control.

Acetylcholinesterase↗
PubMed2001

Effects of the potent analgesic enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan on respiration.

We investigated whether the enkephalin-catabolizing enzyme inhibitors RB101 and kelatorphan, which have been shown to be potent analgesics, depress respiration as do opioid analgesics. Ventilation was measured in cats and rodents by the barometric method, in the awake state and during anesthesia. Tissue distribution of the inhibitors was either generalized (RB101, 40-160 mg/kg i.p.), largely restricted by the blood-brain barrier to the periphery (kelatorphan, 0.7-20 mg/kg i.v.), or restricted to the brainstem (i.c.v. injection of RB101 in the fourth ventricle). RB101 did not affect ventilation in any condition tested, and large doses of kelatorphan produced a naloxone-reversible increase in ventilation and breathing frequency. Thus endogenous opioids released during conditions of normal ventilation do not exert any depressant neuromodulatory effect on this function, even when their extracellular concentrations are increased by peptidase inhibitors. The differential effect of these inhibitors on ventilation and nociception is discussed. We conclude that kelatorphan and RB101 are devoid of respiratory-depressant effects and might be interesting pharmacological alternatives to morphine and other opioid agonists.

Analgesics↗
PubMed2001

Respiratory function in adult mice lacking the mu-opioid receptor: role of delta-receptors.

Mice lacking the mu-opioid receptor (MOR) provide a unique model to determine whether opioid receptors are functionally interactive. Recent results have shown that respiratory depression produced by delta-opioid receptor agonists is suppressed in mice lacking the mu-opioid receptor. Here we investigated the involvement of mu- and delta-opioid receptors in the control of ventilation and mu/delta receptor interactions in brainstem rhythm-generating structures. Unrestrained MOR-/- and wild-type mice showed similar ventilatory patterns at rest and similar chemosensory responses to hyperoxia (100% O2), hypoxia (10% O2) or hypercapnia (5%CO2-95%O2). Blockade of delta-opioid receptors with naltrindole affected neither the ventilatory patterns nor the ventilatory responses to hypoxia in MOR-/- and wild-type mice. In-vitro, respiratory neurons were recorded in the pre-Bötzinger complex of thick brainstem slices of MOR-/- and wild-type young adult mice. Respiratory frequency was not significantly different between these two groups. The delta2 receptor agonist deltorphin II (0.1-1.0 microM) decreased respiratory frequency in both groups whereas doses of the delta1 receptor agonist enkephalin[D-Pen2,5] (0.1-1.0 microM) which were ineffective in wild-type mice significantly decreased respiratory frequency in MOR-/- mice. We conclude that deletion of the mu-opioid receptor gene has no significant effect on ensuing respiratory rhythm generation, ventilatory pattern, or chemosensory control. In MOR-/- mice, the loss of respiratory-depressant effects of delta2-opioid receptor agonists previously observed in vivo does not result from a blunted response of delta receptors in brainstem rhythm-generating structures. These structures show an unaltered response to delta2-receptor agonists and an augmented response to delta1-receptor agonists.

Analgesics, Opioid↗
PubMed1998

Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor.

Previous pharmacological studies have indicated the possible existence of functional interactions between mu-, delta- and kappa-opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of delta- and kappa-opioid receptors in mice lacking the mu-opioid receptor (MOR). Measurements of agonist-induced [35S]GTPgammaS binding and adenylyl cyclase inhibition showed that functional coupling of delta- and kappa-receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine2, D-penicillamine5] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR -/- mice. delta-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR -/- mice. Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of delta- and kappa-receptor signaling properties in mice lacking mu-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the kappa-agonist further suggest that the kappa-receptor mainly acts independently from the mu-receptor in vivo. Reduced delta-analgesia and the absence of delta-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between mu-receptors and central delta-receptors in specific neuronal pathways.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Localization of chemosensitive structures in the isolated brainstem of adult guinea-pig.

1. Central respiratory chemosensitivity has been intensively examined but some questions remain unsolved; namely, what is the nature of the stimulus (fixed acid and/or CO2) and where is the site of brainstem chemosensitivity (near the ventral medullary surface or structures deeper within the brainstem)? To examine these questions, we used the in vitro isolated brainstem of adult guinea-pig perfused independently through the basilar artery and the bath. 2. Respiratory motor output was recorded with a suction electrode from cranial hypoglossal (XII) roots. Changes in pH and CO2 in the Krebs perfusate were made by changing either the bicarbonate concentration or the PCO2 saturating the Krebs solution. 3. Changes in basilar artery perfusate consisting of (i) an acidifying increase in PCO2 (hypercapnic acidic Krebs solution), (ii) an increase in PCO2 with no change in pH (hypercapnic Krebs solution), or (iii) a decrease in pH with no change in PCO2 (acidic Krebs solution) evoked increases in respiratory frequency and a concomitant decrease in inspiratory burst amplitude. 4. Bath superfusion with hypercapnic acidic Krebs solution increased the inspiratory burst amplitude with no effect on respiratory burst frequency. 5. Bath superfusion with hypercapnic non-acidic Krebs solution increased the inspiratory burst amplitude and decreased the respiratory frequency, while normocapnic acidic Krebs solution increased the respiratory frequency with no change in burst amplitude. 6. These results show that respiratory responses to changes in CO2 and pH depend upon the sites of action. While a CO2 increase or a pH decrease affected the respiratory frequency in the deep brainstem structures (perfused through the basilar artery), CO2 respiratory chemosensitivity at the ventral surface could be differentiated from the hydrogen ion chemosensitivity. This suggests that different mechanisms mediated respiratory responses when deep versus superficial brainstem structures were stimulated.

Animals↗
PubMed1995

Involvement of NMDA receptors in the respiratory phase transition is different in the adult guinea pig in vivo and in the isolated brain stem preparation.

1. We investigated the involvement of N-methyl-D-aspartate (NMDA) receptors in the respiratory pattern in an in vitro preparation of adult brain stem compared with in vivo conditions in the guinea pig. 2. In vivo, combining administration of the NMDA channel blocker dizocilpine (MK-801) (3 mg/kg) with a surgical section of the vagus nerves induced an apneustic type of respiration characterized by long inspiratory "holds," as has been shown in other species. The same effect was observed in hypothermic animals (30 degrees C). 3. The isolated in vitro brain stems from these apneustic animals did not present a prolonged inspiratory phase. A second dose of dizocilpine (100 microM perfused vascularly did not induce apneusis, even after increasing brain stem temperature to 35.5 degrees C. 4. In another group of isolated brain stems of adult guinea pigs anesthetized with pentobarbital sodium before decapitation, we perfused dizocilpine and NMDA through the basilar artery. The duration of periodic inspiratory motor activity recorded from the hypoglossal nerve was unaffected by dizocilpine (1-100 microM) or the competitive NMDA antagonist D- or DL-2-amino-5-phosphonopentanoic acid (100 microM and 1 mM), although respiratory frequency decreased. The increase in respiratory activity produced by vascularly perfused NMDA (25-100 microM) was blocked by dizocilpine (100 microM). 5. We conclude that the central mechanism of inspiratory termination in the vagotomized adult guinea pig requires the activation of NMDA receptors in vivo but not in vitro. This difference is not due to the hypothermic environment in vitro. Possible mechanisms for phase switching in vitro are discussed.

Animals↗
PubMed1994

Brain stem chemosensitivity: its implication in central respiratory regulation.

Central brain stem chemosensitivity plays an essential role in acid-base regulation. The site of the chemosensitive neuronal elements has not yet been clearly established. To address this question, we used an in vitro adult guinea pig isolated brain stem preparation, maintained in survival conditions by intrabasilar and bath perfusions of Krebs solution saturated with 95% O2 and 5% CO2. Hypercapnic stimulation, produced by modifying the CO2 concentration of the medium perfusing brain stem structures via the basilar perfusion system, increased the respiratory burst frequency recorded from the hypoglossal nerve. Hypercapnia evoked by ventral surface superfusion increased the respiratory burst amplitude. These data suggest that chemosensitive neuronal elements could be located at the ventral surface as well as in the deeper brainstem structures. However, their characteristics may be different.

Animals↗
PubMed1992

Respiratory network remains functional in a mature guinea pig brainstem isolated in vitro.

We previously developed a perfused isolated brainstem preparation in the adult guinea pig (Morin-Surun and Denavit-Saubie 1989a) which permitted us to describe several types of rhythmic neuronal discharge. In the present study, we demonstrate that nearly all the periodic neuronal activity we recorded in the ventral respiratory areas were directly related to the respiratory-like periodic output of the hypoglossal nerve. This respiratory-like activity lasted several hours only when the brainstem was perfused by the basilar artery. This shows the necessity of the intraarterial perfusion to preserve a functional respiratory network. Analysis of the characteristics of hypoglossal respiratory-like activity shows that (1) two types of respiratory rhythms can be recorded; one with long respiratory phases (inspiratory and expiratory) and one with short respiratory phases. Depending on the preparation, either type occurs alone or intermingled with the other. (2) The shape of the inspiratory-like activity can change throughout the recording period while the periodicity remains stable. This preparation generates a respiratory rhythm and enables us to dissociate the different mechanisms involved in respiratory neurogenesis.

Animals↗
PubMed1992

Control of breathing by endogenous opioid peptides: possible involvement in sudden infant death syndrome.

Experiments have been performed in order to evaluate the respiratory consequences of a suppression or accumulation of endogenous opioid peptides, in the neuronal network which generates the motor respiratory activity. Iontophoretic application of naloxone onto respiratory neurons increases their firing activity and increases their respiratory modulation. On the other hand the local injection of kelatorphan (an enkephalinase inhibitor) decreases the firing of respiratory neurons and thus reduces the respiratory modulation. This effect of kelatorphan mimics the effect on respiratory neuron of an iontophoretic application of met-enkephalin. Furthermore the local injection of kelatorphan reduces the frequency of the respiratory output recorded from the phrenic nerve. This effect is reversed by systemic administration of naloxone. The results demonstrate the involvement of endogenous opioid peptides in the control of breathing suggesting that in Sudden Infant Death Syndrome a possible dysregulation in opioidergic system could occur.

Animals↗
PubMed1987

Central respiratory depression induced by acetylcholinesterase inhibition: involvement of anaesthesia.

We have studied the effects of anaesthesia on the changes in central respiratory activity following the inhibition of acetylcholinesterase in chronically implanted cats. The organophosphate paraoxon was administered to the brainstem respiratory centres by intracerebroventricular (i.c.v.) injection (3 mg) into the IVth ventricle, thus avoiding peripheral effects such as paralysis of respiratory muscles. Paraoxon had opposite effects on respiratory activity depending on whether the cats were anaesthetized or not: it induced respiratory depression and sometimes respiratory arrest during pentobarbital (30 mg/kg i.v.) or halothane anaesthesia, but in the same animals in the waking state, the same dose of paraoxon always stimulated respiration. These results show a strong interaction between anaesthetics and the effects of acetylcholine (ACh) accumulation on central respiratory activity. This study extends previous results showing an interaction between ACh and pentobarbital on single respiratory neurons and stresses the importance of a 'wakefulness stimulus' for sustaining respiratory activity after organophosphate poisoning.

Anesthesia↗
PubMed1987

Excitability of 'silent' respiratory neurons during sleep-waking states: an iontophoretic study in undrugged chronic cats.

An iontophoretic study of respiratory-related neurons (RN) was conducted in the medullary ventral respiratory area of chronically implanted, undrugged cats during states of sleep and wakefulness. Most RN recorded were unaffected by sleep-wake states but a few RN decreased their firing rate during sleep (sleep sensitive cells). The excitability of RN was assessed in the different states by local application of L-glutamate. Glutamate iontophoresis revealed the presence of 5 cells which were silent during sleep and completely or mostly silent during undisturbed wakefulness but always discharged with a respiratory-modulated pattern of the expiratory type in response to glutamate application. Arousing stimuli induced spontaneous firing of these cells and REM sleep reduced glutamate effectiveness. It was concluded that silent RN and RN which become inactive during sleep permanently receive subthreshold respiratory-modulated inputs which are amplified or depressed by state-dependent tonic inputs.

Animals↗
PubMed1987

Effects of pentobarbital and flurazepam on respiratory neurons in undrugged cats.

Two hypnotic drugs known to enhance GABAergic transmission, a barbiturate (pentobarbital) and a benzodiazepine (flurazepam), were applied locally to respiratory-related neurons (RN) located in the ventral respiratory area in the medulla of non-anaesthetized cats which were either decerebrated or chronically implanted. Pentobarbital applied iontophoretically depressed the spontaneous discharge rate of most RN tested as well as the increase in firing of RN discharge induced by iontophoretic application of glutamate; pentobarbital also potentiated inhibition induced by iontophoresed GABA. Flurazepam applied by iontophoresis or pressure pulses depressed a minority of RN tested and did not enhance GABA-induced inhibition. These results suggest: that inhibition of RN activity through GABAergic mechanisms can be affected by drugs which act at the chloride ionophore but not those acting indirectly through the benzodiazepine binding site, and the effects of the agents on medullary neuronal activity are independent of an effect on the states of consciousness or on structures rostral to the medulla.

Animals↗
PubMed1985

Different targets involved in the effect of cholecystokinin on respiration.

Respiratory and cardiovascular effects of intravenous administration of cholecystokinin octapeptide (CCK-8) (0.3 to 20 micrograms/kg) were compared in different cat preparations: chronically implanted and decerebrate vagotomized or decerebrate non-vagotomized. In all preparations CCK-8 induced an immediate drop in blood pressure (between 44.0 and 58.1%) and heart rate (between 25.1 and 62.5%) which had completely recovered 5 min after the end of the injection. During cardiovascular modifications tidal volume decreased in non-vagotomized cats and was associated with a decrease in respiratory frequency in decerebrate cats and with an increase in respiratory frequency in chronically implanted animals. Only an increase of tidal volume occurred in vagotomized cats. After cardiovascular conditions had returned to normal, tidal volume remained significantly modified: decreased in chronically implanted (-39%), in decerebrate non-vagotomized (-34%) and increased in vagotomized cats (+27.7%). However, modifications of frequency persisted only in chronically implanted preparations (+69.2%). Recovery from respiratory modifications occurred 30 min after injection. These effects were not produced by systemic administration of non-sulfated CCK-8. The cardiorespiratory modifications induced by CCK-8 are discussed in relation to the different targets which can be reached by the octapeptide in each preparation.

Animals↗
PubMed1984

Different effects of mu and delta opiate agonists on respiration.

The involvement of different opiate receptor subtypes in opiate-induced respiratory depression was studied in the unanaesthetized rat. Synthetic opioid agonists, specific for mu or delta receptors, were administered intraperitoneally in freely moving rats while respiratory parameters were recorded by means of the whole body plethysmographic method. TRIMU-4 (Tyr-D-Ala-Gly-NH-CH(CH3)-CH2-CH(CH3)2), a specific agonist of the mu receptor, reduced the tidal volume and did not change the respiratory frequency. DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr), a relatively specific agonist of the delta receptor subtype, reduced respiratory frequency and was significantly less effective on tidal volume than was TRIMU-4. It is concluded that the respiratory depression occurring after the administration of opiates in clinical practice is a dual complementary effect involving mu and delta receptors.

Animals↗
PubMed1984

Differentiation of two respiratory areas in the cat medulla using kainic acid.

Kainic acid (KA) was used to destroy neuronal perikarya in different areas of the brainstem. Single KA microinjections were performed in 30 anaesthetized, vagotomized, artificially ventilated cats. Consequences were studied on the phrenic nerve activity (PNA) and blood pressure. We observed changes of the PNA unrelated to blood pressure alteration. Destruction of the dorsal respiratory area (DRA) including the nucleus tractus solitarius at the obex level produced a 40% decrease of the PNA frequency. Destruction restricted to the lateral part of the ventral respiratory area (VRA1) including the ambiguus nucleus induced a 60% decrease of the integrated PNA amplitude followed by a 40% increase of PNA frequency. These latter effects were also observed after destruction inside the infra solitary reticular formation (ISRF). No effect was observed after destruction in other brain structures. We concluded that ISRF and VRA1 form a single ventral bulbar respiratory area. This area controls respiration in a way different from that of the dorsal respiratory area (DRA).

Action Potentials↗