Glial vascular endothelial growth factor overexpression in rat brainstem under tolerable hypoxia: evidence for a central chemosensitivity.

The ventilatory response to hypoxia is mediated by peripheral inputs arising from the arterial chemoreceptors. In their absence, hypoxic adaptation can be achieved, possibly as a result of central cellular reorganization. To study this reorganization, we used chemodenervated rats to investigate the expression and localization of vascular endothelial growth factor (VEGF) in the brainstem.

Desferrioxamine enhances hypoxic ventilatory response and induces tyrosine hydroxylase gene expression in the rat brainstem in vivo.

The iron chelator desferrioxamine (DFO) induces accumulation of the hypoxia-inducible factor (HIF-1), a transcription factor that up-regulates genes involved in adaptative responses to hypoxia. This property makes DFO a potential neuroprotector against hypoxic stress. We investigated in rats the effects of DFO on the ventilatory response to mild hypoxic tests and the expression of tyrosine hydroxylase (TH), a target gene of HIF-1.

Progesterone reverses the neuronal responses to hypoxia in rat nucleus tractus solitarius in vitro.

The nucleus tractus solitarius (NTS) is a relay nucleus that integrates peripheral chemoreceptor input in response to hypoxia and hence influences the generation of respiratory rhythm. Several studies have shown that administration of progesterone stimulates ventilatory responses to hypoxia. There is some evidence that this steroid hormone can act at the level of the arterial peripheral chemoreceptors, whereas its action in the central nervous system remains unclear.

Selective cardiorespiratory and catecholaminergic areas express the hypoxia-inducible factor-1alpha (HIF-1alpha) under in vivo hypoxia in rat brainstem.

Under severe oxygen deprivation, all cells are able to express the transcription factor HIF-1, which activates a wide range of genes. Under tolerable hypoxia, chemosensory inputs are integrated in brainstem areas, which control cardiorespiratory responses. However, the molecular mechanisms of this functional acclimatization are unknown.

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.

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.

O2-sensing after carotid chemodenervation: hypoxic ventilatory responsiveness and upregulation of tyrosine hydroxylase mRNA in brainstem catecholaminergic cells.

Ventilatory responses to acute and long-term hypoxia are classically triggered by carotid chemoreceptors. The chemosensory inputs are carried within the carotid sinus nerve to the nucleus tractus solitarius and the brainstem respiratory centres. To investigate whether hypoxia acts directly on brainstem neurons or secondarily via carotid body inputs, we tested the ventilatory responses to acute and long-term hypoxia in rats with bilaterally transected carotid sinus nerves and in sham-operated rats.

Genetic and developmental models for the neural control of breathing in vertebrates.

The present paper reviews some of the possible mechanisms that may link gene function in the brainstem and breathing patterns in vertebrates. On one hand, adaptation and acclimatisation of mature breathing to environmental constraints such as hypoxia, involves complex regulation of the gene expression in precise cardiorespiratory sites of the brainstem. On the other hand, targeted inactivation of different genes suggests that postnatal respiratory variables at rest depend on genes controlling the prenatal development of the brainstem.

Intracellular sigma1 receptor modulates phospholipase C and protein kinase C activities in the brainstem.

Most physiological effects of sigma1 receptor ligands are sensitive to pertussis toxin, suggesting a coupling with cell membrane-bound G proteins. However, the cloning of the sigma1 receptor has allowed the identification of an intracellular protein anchored on the endoplasmic reticulum. Here, we show, using the isolated adult guinea pig brainstem preparation, that activation of the sigma1 receptor results in its translocation from the cytosol to the vicinity of the cell membrane and induces a robust and rapid decrease in hypoglossal activity, which is mediated by phospholipase C.

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).

Respiratory effects of glutamate receptor antagonists in neonate and adult mammals.

We determined the conditions (immaturity, species, anesthesia, receptor blockade selectivity) under which glutamate receptor blockade produces respiratory depression in mammals. In unrestrained 0- to 2-day-old neonate and adult mice and cats, ventilation was measured by the barometric method, before and after separate or sequential administration of a non-NMDA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline, 2-200 mg kg(-1) in mice, 10-40 mg kg(-1) in cats), and a NMDA receptor antagonist, dizocilpine (3 mg kg(-1) in mice, 0.15-1.

Synaptic potentials in respiratory neurones during evoked phase switching after NMDA receptor blockade in the cat.

1. Blockade of NMDA receptors by dizocilpine impairs the inspiratory off-switch (IOS) of central origin but not the IOS evoked by stimulation of sensory afferents. To investigate whether this difference was due to the effects of different patterns of synaptic interactions on respiratory neurones, we stimulated electrically the superior laryngeal nerve (SLN) or vagus nerve in decerebrate cats before and after i.

Brainstem neurons projecting to the rostral ventral respiratory group (VRG) in the medulla oblongata of the rat revealed by co-application of NMDA and biocytin.

Groups of neurons in the medulla and pons are essential for the rhythm generation, pattern formation and modulation of respiration. The rostral Ventral Respiratory Group (rVRG) is thought to be a crucial area for rhythm generation. Here we co-applied biocytin and NMDA in the rVRG to label retrogradely brainstem neurons reciprocally connected to a population of inspiratory neurons in the rat rVRG.

K+ channels of expiratory neurones in the brain stem preparation of the newborn rat.

Single channel activity of expiratory neurones was studied in outside-out recordings. Expiratory neurones were identified in the ventrolateral region of the in vitro isolated brain stem-spinal cord preparation of newborn rats in cell-attached and whole-cell configurations by their pattern of firing related to phrenic motor output. Three potassium (K+) channels of 10, 30 and 70 pS exhibited steady-state activity during long voltage commands (up to 5 min) and could be found associated together in the same patches.

Coherent inspiratory oscillation of cranial nerve discharges in perfused neonatal cat brainstem in vitro.

1. To understand the neural organization of respiratory movement control and its developmental transformation, we studied the temporal characteristics of inspiratory activities, especially nerve-to-nerve short-term synchronization, in an in vitro preparation of the isolated, perfused brainstem of kittens aged 0-14 days (postnatal day (P) 0-14). 2.

Membrane potentials of respiratory neurones during dizocilpine-induced apneusis in adult cats.

1. In the vagotomized cat, blockade of NMDA receptors by dizocilpine (MK-801) produces an apneustic pattern of respiration characterized by a large increase in the duration of inspiration. 2.

Plasticity of tyrosine hydroxylase gene expression in the rat nucleus tractus solitarius after ventilatory acclimatization to hypoxia.

The aim of this study was to define the influence of long-term hypoxia on gene expression of tyrosine hydroxylase (TH) in the rat nucleus tractus solitarius (NTS). Animals were exposed to normobaric hypoxia (10% O2 in nitrogen) for 2 weeks. At this time, the hypoxia-induced hyperventilation reached a plateau, indicating ventilatory acclimatization.

Pharmacological properties of peripherally induced postsynaptic potentials in bulbar respiratory neurons of decerebrate cats.

Intracellular recordings of bulbar inspiratory and post-inspiratory neurons, combined with extracellular iontophoresis of antagonists of putative neurotransmitters, were performed in decerebrate cats. Inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of the superior laryngeal nerve or vagus nerve were depressed by bicuculline in all 22 neurons tested, but not modified by strychnine. The non-N-methyl-D-aspartate (NMDA) glutamate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) decreased the neurally evoked excitatory postsynaptic potentials (EPSPs) in 23 out of 26 neurons tested, while the NMDA antagonist dizocilpine had no notable effect.

A cholecystokinin-B receptor antagonist potentiates GABAergic and glycinergic inhibition in the nucleus of the solitary tract of the rat.

In both rodent and primate in vivo models, cholecystokininB (CCKB) antagonists such as PD134,308 have anxiolytic effects that may involve the potentiation of GABAergic transmission. We have investigated this interaction using exogenous application of GABA and whole cell patch recording techniques in neurons of the nucleus of the solitary tract (NTS) in brainstem slice preparations. In the presence of PD143,308 the magnitude of the GABA-evoked decrease in membrane input resistance was enhanced by 41.

Inhibitions mediated by glycine and GABAA receptors shape the discharge pattern of bulbar respiratory neurons.

Experiments were performed to identify the glycinergic or GABAergic nature, and the timing of discharge, of the neurons which produce chloride-dependent inhibitions on other bulbar respiratory neurons (RNs) during their silent and active phases. RNs recorded extracellularly in pentobarbital-anesthetized or decerebrate cats, were subjected to iontophoretic applications of glutamate, of the glycine antagonist strychnine, and of the GABAA receptor antagonist bicuculline. Both antagonists induced discharge or increased discharge frequency in restricted parts of the respiratory cycle without affecting the discharge frequency in other parts of the cycle.

Thyrotropin-releasing hormone (TRH) depolarizes a subset of inspiratory neurons in the newborn mouse brain stem in vitro.

1. To extend the classification of respiratory neurons based on active membrane properties and discharge patterns to include responses to respiratory modulators, we have studied the effect of thyrotropin-releasing hormone (TRH, 1-5 microM) on the spontaneous respiratory-related neural activity in a thick brain stem slice preparation from the newborn mouse. The action of TRH on the respiratory output from the slice was investigated by recordings from the XII nerve.