scholarly journals Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist

2017 ◽  
Vol 312 (5) ◽  
pp. R727-R738 ◽  
Author(s):  
Peter M. Lalley ◽  
Steve W. Mifflin
Keyword(s):  
Spike Train ◽  
Brain Stem ◽  
Opioid Receptor ◽  
Respiratory Rhythm ◽  
Opioid Receptor Agonist ◽  
Respiratory Network ◽  
Three Phase ◽  
Μ Opioid Receptor ◽  
Effective Doses ◽  
The Brain

μ-Opioid receptors are distributed widely in the brain stem respiratory network, and opioids with selectivity for μ-type receptors slow in vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed. Doses of fentanyl that were just sufficient for prolongation of discharges and slowing of the three-phase respiratory rhythm also produced pronounced enhancement of spike train properties. Oscillation and burst patterns detected by autocorrelation measurements were greatly enhanced, and interspike intervals were prolonged. Spike train properties under control conditions and after fentanyl were uniform within each experiment, but varied considerably between experiments, which might be related to variability in acid-base balance in the brain stem extracellular fluid. Discharge threshold was shifted to more negative levels of membrane potential. The effects on threshold are postulated to result from opioid-mediated disinhibition and postsynaptic enhancement of N-methyl-d- aspartate receptor current. Lowering of firing threshold, enhancement of spike train oscillations and bursts and prolongation of discharges by lowest effective doses of fentanyl could represent compensatory adjustments in the brain stem respiratory network to override opioid blunting of CO2/pH chemosensitivity.

scholarly journals Spatial and Functional Architecture of the Mammalian Brain Stem Respiratory Network: A Hierarchy of Three Oscillatory Mechanisms

2007 ◽  
Vol 98 (6) ◽  
pp. 3370-3387 ◽  
Author(s):  
J. C. Smith ◽  
A. P. L. Abdala ◽  
H. Koizumi ◽  
I. A. Rybak ◽  
J. F. R. Paton
Keyword(s):  
Brain Stem ◽  
Sodium Current ◽  
Respiratory Rhythm ◽  
Central Pattern Generators ◽  
Respiratory Neurons ◽  
Mammalian Brain ◽  
Two Phase ◽  
Respiratory Network ◽  
Three Phase ◽  
The One

Mammalian central pattern generators (CPGs) producing rhythmic movements exhibit extremely robust and flexible behavior. Network architectures that enable these features are not well understood. Here we studied organization of the brain stem respiratory CPG. By sequential rostral to caudal transections through the pontine-medullary respiratory network within an in situ perfused rat brain stem–spinal cord preparation, we showed that network dynamics reorganized and new rhythmogenic mechanisms emerged. The normal three-phase respiratory rhythm transformed to a two-phase and then to a one-phase rhythm as the network was reduced. Expression of the three-phase rhythm required the presence of the pons, generation of the two-phase rhythm depended on the integrity of Bötzinger and pre-Bötzinger complexes and interactions between them, and the one-phase rhythm was generated within the pre-Bötzinger complex. Transformation from the three-phase to a two-phase pattern also occurred in intact preparations when chloride-mediated synaptic inhibition was reduced. In contrast to the three-phase and two-phase rhythms, the one-phase rhythm was abolished by blockade of persistent sodium current ( INaP). A model of the respiratory network was developed to reproduce and explain these observations. The model incorporated interacting populations of respiratory neurons within spatially organized brain stem compartments. Our simulations reproduced the respiratory patterns recorded from intact and sequentially reduced preparations. Our results suggest that the three-phase and two-phase rhythms involve inhibitory network interactions, whereas the one-phase rhythm depends on INaP. We conclude that the respiratory network has rhythmogenic capabilities at multiple levels of network organization, allowing expression of motor patterns specific for various physiological and pathophysiological respiratory behaviors.

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

2009 ◽  
Vol 107 (5) ◽  
pp. 1591-1599 ◽  
Author(s):  
K. L. Krause ◽  
S. E. Neumueller ◽  
B. D. Marshall ◽  
T. Kiner ◽  
J. M. Bonis ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
Minute Ventilation ◽  
Pulmonary Ventilation ◽  
Respiratory Rhythm ◽  
Blood Gases ◽  
Arterial Blood ◽  
Opioid Receptor Agonist ◽  
Bötzinger Complex ◽  
Μ Opioid Receptor

Opioids are clinically important in the alleviation of pain. An undesirable side effect of opioids is depression of breathing. Data from isolated preparations suggest this effect is due to attenuation of discharge activity of neurons in the pre-Bötzinger complex (preBötzC), a medullary area with respiratory rhythmogenic properties. The purpose of this study was to examine how [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), a μ-opioid receptor agonist, affected breathing after injection into the presumed preBötzC of the adult awake goat. We hypothesized that DAMGO would cause breathing to decrease and become irregular when injected into the presumed preBötzC and the surrounding region of the conscious animal. We further hypothesized that ventilatory sensitivity to CO2 and hypoxia would be blunted after the injection of DAMGO. Microtubules were bilaterally implanted into the presumed preBötzC of 10 adult female goats. After recovery from the surgery, DAMGO (0.5–10 μl, 1 nM–10 μM) was injected into the presumed preBötzC during the awake state. DAMGO had no effect on pulmonary ventilation [inspiratory minute ventilation (V̇i)], respiratory rhythm and pattern, the activation pattern of inspiratory and expiratory muscles, or arterial blood gases during eupneic breathing conditions ( P > 0.10). However, DAMGO attenuated ( P < 0.05) the evoked increase in breathing frequency when inspired CO2 was increased, and DAMGO attenuated the V̇i response to reduction of inspired O2 to 10.8% ( P < 0.05). We conclude that our data do not provide support for the concept that in awake mammals opioid depression of breathing is due to a directed action of opioids on preBötzC neurons.

scholarly journals The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time

2018 ◽  
Vol 41 (1) ◽  
pp. 475-499 ◽  
Author(s):  
Jan-Marino Ramirez ◽  
Nathan A. Baertsch
Keyword(s):  
Coupled Oscillators ◽  
Respiratory Rhythm ◽  
Control Of Breathing ◽  
Lessons Learned ◽  
Rhythm Generation ◽  
Glutamatergic Transmission ◽  
Neuronal Control ◽  
Respiratory Network ◽  
Three Phase ◽  
The Brain

Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time.

scholarly journals Neurogenic hypertension and the secrets of respiration

2017 ◽  
Vol 312 (6) ◽  
pp. R864-R872 ◽  
Author(s):  
Benedito H. Machado ◽  
Daniel B. Zoccal ◽  
Davi J. A. Moraes
Keyword(s):  
Brain Stem ◽  
Neural Control ◽  
Respiratory Rhythm ◽  
Sympathetic Outflow ◽  
Neurogenic Hypertension ◽  
Electrophysiological Properties ◽  
Respiratory Network ◽  
Rhythm Pattern ◽  
Contraction And Relaxation ◽  
The Brain

Despite recent advances in the knowledge of the neural control of cardiovascular function, the cause of sympathetic overactivity in neurogenic hypertension remains unknown. Studies from our laboratory point out that rats submitted to chronic intermittent hypoxia (CIH), an experimental model of neurogenic hypertension, present changes in the central respiratory network that impact the pattern of sympathetic discharge and the levels of arterial pressure. In addition to the fine coordination of respiratory muscle contraction and relaxation, which is essential for O2 and CO2 pulmonary exchanges, neurons of the respiratory network are connected precisely to the neurons controlling the sympathetic activity in the brain stem. This respiratory-sympathetic neuronal interaction provides adjustments in the sympathetic outflow to the heart and vasculature during each respiratory phase according to the metabolic demands. Herein, we report that CIH-induced sympathetic over activity and mild hypertension are associated with increased frequency discharge of ventral medullary presympathetic neurons. We also describe that their increased frequency discharge is dependent on synaptic inputs, mostly from neurons of the brain stem respiratory network, rather than changes in their intrinsic electrophysiological properties. In perspective, we are taking into consideration the possibility that changes in the central respiratory rhythm/pattern generator contribute to increased sympathetic outflow and the development of neurogenic hypertension. Our experimental evidence provides support for the hypothesis that changes in the coupling of respiratory and sympathetic networks might be one of the unrevealed secrets of neurogenic hypertension in rats.

scholarly journals Tracheal occlusion-evoked respiratory load compensation and inhibitory neurotransmitter expression in rats

2014 ◽  
Vol 116 (8) ◽  
pp. 1006-1016 ◽  
Author(s):  
Hsiu-Wen Tsai ◽  
Paul W. Davenport
Keyword(s):  
Neural Network ◽  
Brain Stem ◽  
Breathing Pattern ◽  
Respiratory Rhythm ◽  
Inhibitory Neurotransmitter ◽  
Load Compensation ◽  
Efferent Projections ◽  
Motor Reflex ◽  
Sensory Pathway ◽  
The Brain

Respiratory load compensation is a sensory-motor reflex generated in the brain stem respiratory neural network. The nucleus of the solitary tract (NTS) is thought to be the primary structure to process the respiratory load-related afferent activity and contribute to the modification of the breathing pattern by sending efferent projections to other structures in the brain stem respiratory neural network. The sensory pathway and motor responses of respiratory load compensation have been studied extensively; however, the mechanism of neurogenesis of load compensation is still unknown. A variety of studies has shown that inhibitory interconnections among the brain stem respiratory groups play critical roles for the genesis of respiratory rhythm and pattern. The purpose of this study was to examine whether inhibitory glycinergic neurons in the NTS were activated by external and transient tracheal occlusions (ETTO) in anesthetized animals. The results showed that ETTO produced load compensation responses with increased inspiratory, expiratory, and total breath time, as well as elevated activation of inhibitory glycinergic neurons in the caudal NTS (cNTS) and intermediate NTS (iNTS). Vagotomized animals receiving transient respiratory loads did not exhibit these load compensation responses. In addition, vagotomy significantly reduced the activation of inhibitory glycinergic neurons in the cNTS and iNTS. The results suggest that these activated inhibitory glycinergic neurons in the NTS might be essential for the neurogenesis of load compensation responses in anesthetized animals.

scholarly journals Four stereoisomers of the novel μ-opioid receptor agonist tapentadol hydrochloride

2011 ◽  
Vol 67 (2) ◽  
pp. o71-o76 ◽  
Author(s):  
Krishnan Ravikumar ◽  
Balasubramanian Sridhar ◽  
Nitin Pradhan ◽  
Mayur Khunt
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
The Novel ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor

scholarly journals Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain

Pain ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 2277-2284 ◽  
Author(s):  
Antonio Rodriguez-Gaztelumendi ◽  
Viola Spahn ◽  
Dominika Labuz ◽  
Halina Machelska ◽  
Christoph Stein
Keyword(s):  
Abdominal Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Analgesic Effects ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor ◽  
Ph Dependent

Genesis of rhythmic respiratory activity in pons independent of medulla

1985 ◽  
Vol 59 (3) ◽  
pp. 684-690 ◽  
Author(s):  
W. M. St John ◽  
T. A. Bledsoe
Keyword(s):  
Brain Stem ◽  
Phrenic Nerve ◽  
Respiratory Activity ◽  
Respiratory Rhythm ◽  
Related Activity ◽  
Pharmacological Agents ◽  
Pneumotaxic Center ◽  
Trigeminal Nerves ◽  
The Brain ◽  
Pontomedullary Junction

We hypothesized that rhythmic respiratory-related activity could be generated in pons independent of medullary mechanisms. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, we recorded efferent activities of the phrenic nerve and mylohyoid branch of the trigeminal nerve. Following transections of the brain stem at the pontomedullary junction, the phrenic and trigeminal nerves discharged with independent rhythms. Spontaneous trigeminal discharges eventually ceased but were reestablished after strychnine, doxapram, and/or protriptyline were administered. In some animals having no spontaneous trigeminal discharges after transection, these discharges appeared, with a rhythm different from the phrenic, following administration of these agents. In other cats having no transections between pons and medulla, these pharmacological agents induced trigeminal and phrenic discharges after kainic acid had been injected into the entire dorsal and ventral medullary respiratory nuclei. Phrenic and trigeminal discharges were linked, indicating survival of bulbospinal neurons or presence of pontospinal units. We conclude that rhythms, similar to respiratory rhythm, can occur by mechanisms in isolated pons. Such mechanisms are hypothesized to be within the pneumotaxic center and may underlie the neurogenesis of eupnea.

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