Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons

2006 ◽  
Vol 290 (5) ◽  
pp. R1387-R1396 ◽  
Author(s):  
Peter M. Lalley
Keyword(s):  
Action Potential ◽  
Respiratory Rhythm ◽  
Input Resistance ◽  
Membrane Depolarization ◽  
Respiratory Neurons ◽  
Response Analysis ◽  
Inspiratory Neurons ◽  
Potential Shape ◽  
Expiratory Neurons

Opiates have effects on respiratory neurons that depress tidal volume and air exchange, reduce chest wall compliance, and slow rhythm. The most dose-sensitive opioid effect is slowing of the respiratory rhythm through mechanisms that have not been thoroughly investigated. An in vivo dose-response analysis was performed on medullary respiratory neurons of adult cats to investigate two untested hypotheses related to mechanisms of opioid-mediated rhythm slowing: 1) Opiates suppress intrinsic conductances that limit discharge duration in medullary inspiratory and expiratory neurons, and 2) opiates delay the onset and lengthen the duration of discharges postsynaptically in phase-regulating postinspiratory and late-inspiratory neurons. In anesthetized and unanesthetized decerebrate cats, a threshold dose (3 μg/kg) of the μ-opioid receptor agonist fentanyl slowed respiratory rhythm by prolonging discharges of inspiratory and expiratory bulbospinal neurons. Additional doses (2–4 μg/kg) of fentanyl also lengthened the interburst silent periods in each type of neuron and delayed the rate of membrane depolarization to firing threshold without altering synaptic drive potential amplitude, input resistance, peak action potential frequency, action potential shape, or afterhyperpolarization. Fentanyl also prolonged discharges of postinspiratory and late-inspiratory neurons in doses that slowed the rhythm of inspiratory and expiratory neurons without altering peak membrane depolarization and hyperpolarization, input resistance, or action potential properties. The temporal changes evoked in the tested neurons can explain the slowing of network respiratory rhythm, but the lack of significant, direct opioid-mediated membrane effects suggests that actions emanating from other types of upstream bulbar respiratory neurons account for rhythm slowing.

Pre-Botzinger complex in the cat

1995 ◽  
Vol 73 (4) ◽  
pp. 1452-1461 ◽  
Author(s):  
S. W. Schwarzacher ◽  
J. C. Smith ◽  
D. W. Richter
Keyword(s):  
Spinal Cord ◽  
Neuronal Activity ◽  
Membrane Depolarization ◽  
Neonatal Rat ◽  
Respiratory Neurons ◽  
Spike Discharge ◽  
Inspiratory Phase ◽  
Inspiratory Neurons ◽  
Bötzinger Complex ◽  
Expiratory Neurons

1. Patterns of respiratory neuronal activity were examined in pentobarbitone anesthetized adult cats in a circumscribed area of the ventrolateral medulla, which has previously been defined as the pre-Botzinger complex (pre-BOTC) from electrophysiological and morphological criteria in the brain stem-spinal cord preparation of the neonatal rat. The pre-BOTC has been proposed to play a critical role in respiratory rhythm generation in mammals, but electrophysiological properties of the region have not been thoroughly characterized in the adult brain stem in vivo. 2. From intra- and extracellular recordings, we verified the existence of a well-defined zone with a distinct profile of neuronal activity between the rostral Botzinger complex containing expiratory neurons and the more caudal medullary pool of inspiratory neurons of the ventral respiratory group (VRG) in the para-ambigual region. This zone corresponds to the pre-BOTC. It was characterized by a concentration of the various types of respiratory neurons, particularly those proposed to be involved in respiratory phase transitions, including neurons discharging immediately before the onset of inspiratory phase activity (pre-inspiratory neurons), early-inspiratory, and postinspiratory neurons. The majority of these neurons were presumed interneurons because they were not antidromically activated by spinal cord or cranial nerve stimulation. 3. The locus of the pre-BOTC corresponded histologically to the rostral part of the nucleus ambiguus and ventrolateral reticular formation. It was located caudal to the retrofacial nucleus and rostral to the lateral reticular nucleus, extending 3.0-3.5 mm rostral to the obex, and 3.2-4.0 mm lateral from the midline. This location was homologous to that established in the neonatal rat. 4. Pre-inspiratory neurons (pre-I neurons) were specifically found in the pre-BOTC. Intracellular recordings from these neurons revealed two types of activity patterns. Type 1 of pre-I neurons exhibited a steady membrane depolarization during expiration and a steep membrane depolarization with a high-frequency burst of action-potential discharge during the phase transition from expiration to inspiration. This was followed by a decline of depolarization and spike discharge during the remainder of the inspiratory phase. A second type of pre-I neurons exhibited a secondary graded membrane depolarization and burst discharge during the late-inspiratory period. 5. Synaptic events were examined in other respiratory neurons during the 40-160 ms preceding the onset of phrenic nerve activity when pre-I neurons exhibited peak spike discharge. Early-inspiratory, throughout-respiratory, and postinspiratory neurons were disinhibited during this period, whereas stage-2 expiratory neurons exhibited a decrease in spike activity and repolarization.(ABSTRACT TRUNCATED AT 400 WORDS)

Differing activities of medullary respiratory neurons in eupnea and gasping

1991 ◽  
Vol 70 (3) ◽  
pp. 1265-1270 ◽  
Author(s):  
D. Zhou ◽  
M. J. Wasicko ◽  
J. M. Hu ◽  
W. M. St John
Keyword(s):  
Carbon Monoxide ◽  
Brain Stem ◽  
Phrenic Nerve ◽  
Peak Discharge ◽  
Discharge Frequency ◽  
Respiratory Neurons ◽  
Ventilatory Pattern ◽  
Medullary Respiratory Neurons ◽  
Inspiratory Neurons ◽  
Expiratory Neurons

Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate, paralyzed, and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal, laryngeal, or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea, activities of inspiratory neurons commenced at various times during inspiration, and for most the discharge frequency gradually increased. In gasping, the peak discharge frequency of inspiratory neurons was unaltered. However, all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping, with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.

scholarly journals An In Vitro Protocol for Recording From Spinal Motoneurons of Adult Rats

2008 ◽  
Vol 100 (1) ◽  
pp. 474-481 ◽  
Author(s):  
Jonathan S. Carp ◽  
Ann M. Tennissen ◽  
Donna L. Mongeluzi ◽  
Christopher J. Dudek ◽  
Xiang Yang Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Mechanical Stability ◽  
Pharmacological Study ◽  
Input Resistance ◽  
Spinal Motoneurons ◽  
Adult Rats ◽  
Precise Control

In vitro slice preparations of CNS tissue are invaluable for studying neuronal function. However, up to now, slice protocols for adult mammal spinal motoneurons—the final common pathway for motor behaviors—have been available for only limited portions of the spinal cord. In most cases, these preparations have not been productive due to the poor viability of motoneurons in vitro. This report describes and validates a new slice protocol that for the first time provides reliable intracellular recordings from lumbar motoneurons of adult rats. The key features of this protocol are: preexposure to 100% oxygen; laminectomy prior to perfusion; anesthesia with ketamine/xylazine; embedding the spinal cord in agar prior to slicing; and, most important, brief incubation of spinal cord slices in a 30% solution of polyethylene glycol to promote resealing of the many motoneuron dendrites cut during sectioning. Together, these new features produce successful recordings in 76% of the experiments and an average action potential amplitude of 76 mV. Motoneuron properties measured in this new slice preparation (i.e., voltage and current thresholds for action potential initiation, input resistance, afterhyperpolarization size and duration, and onset and offset firing rates during current ramps) are comparable to those recorded in vivo. Given the mechanical stability and precise control over the extracellular environment afforded by an in vitro preparation, this new protocol can greatly facilitate electrophysiological and pharmacological study of these uniquely important neurons and other delicate neuronal populations in adult mammals.

The Effects of Nasal Flow Stimulation on Central Respiratory Pattern

1995 ◽  
Vol 9 (4) ◽  
pp. 203-208 ◽  
Author(s):  
Satoshi Nonaka ◽  
Akihiro Katada ◽  
Kizuku Nakajima ◽  
Takashi Ohsaki ◽  
Tokuji Unno
Keyword(s):  
Cycle Time ◽  
Suppressive Effect ◽  
Respiratory Cycle ◽  
Respiratory Pattern ◽  
Respiratory Neurons ◽  
Electromyographic Activity ◽  
Inspiratory Neurons ◽  
Expiratory Neurons ◽  
Flow Stimulation ◽  
Nasal Flow

The purpose of this study was to analyze the functional role of nasal afferents on central respiratory mechanisms. The electromyographic activity of the diaphragm and the neuronal activities of respiratory neurons within the brainstem were recorded during nasal flow stimulation, using decerebrate cats. Flow stimulation delivered to the nose prolonged the respiratory cycle time and decreased the amplitude of diaphragmatic activity. The respiratory cycle time was prolonged due to prolongation of expiratory phase. Cool air flow stimulation was more effective for changing the respiratory pattern than was warm air. All recorded inspiratory neurons of the dorsal respiratory group decreased their firing rate during stimulation, but more than half of expiratory neurons of the ventral respiratory group did not change. These results suggest that nasal afferents which respond to temperature can modulate the central respiratory pattern and have a stronger suppressive effect on the activity of inspiratory neurons than that of expiratory neurons.

Neural mechanisms of sneeze

1975 ◽  
Vol 229 (3) ◽  
pp. 770-776 ◽  
Author(s):  
HL Batsel ◽  
AJ Lines
Keyword(s):  
High Frequency ◽  
Neural Mechanisms ◽  
Nucleus Ambiguus ◽  
Respiratory Neurons ◽  
Similar Response ◽  
Response Patterns ◽  
Nerve Activity ◽  
Inspiratory Neurons ◽  
Expiratory Neurons ◽  
Stimulation Of

Sneezes were induced in anestized cats by repetitive stimulation of the ethmoidal nerve. Activity of bulbar respiratory neurons during sneezing was recorded extracellularly through tungsten microelectrodes. Most expiratory neurons could be locked onto the stimulus pulses so that they responded either throughout inspiration as well as expiration or so that they began responding at some time during inspiration. As inspiration approached termination, multiple spiking occurred, finally to result in high-frequency bursts which just preceded active expiration. A fraction of expiratory neurons were activated only in bursts. Latent expiratory neurons were recruited in sneezing. Inspiratory neurons near nucleus ambiguus and most of those near fasciculus solitarius displayed similar response patterns consisting of silent periods followed by delayed smooth activations. Temporal characteristics of the silent periods, "inhibitory gaps," suggested that they resulted from inhibition whose source was the expiratory neurons which were driven throughout inspriation. Some inspiratory neurons in the area of fasciculus solitarius failed to exhibit inhibitory gaps.

Evidence that glycine and GABA mediate postsynaptic inhibition of bulbar respiratory neurons in the cat

1992 ◽  
Vol 73 (6) ◽  
pp. 2333-2342 ◽  
Author(s):  
A. Haji ◽  
R. Takeda ◽  
J. E. Remmers
Keyword(s):  
Input Resistance ◽  
Respiratory Neurons ◽  
Gamma Aminobutyric Acid ◽  
Somatic Membrane ◽  
Postsynaptic Inhibition ◽  
Gaba A ◽  
Axonal Conduction ◽  
Inspiratory Neurons ◽  
Presynaptic Release ◽  
Decerebrate Cats

Experiments were carried out on decerebrate cats to identify transsynaptic mediators of spontaneous postsynaptic inhibition of bulbar inspiratory and postinspiratory neurons. Somatic membrane potentials were recorded through the central micropipette of a coaxial multibarreled electrode. Blockers of type A gamma-aminobutyric acid (GABA-A) and glycine receptors were iontophoresed extracellularly from peripheral micropipettes surrounding the central pipette. Effective antagonism was demonstrated by iontophoresis of agonists with antagonists; application of strychnine antagonized the action of glycine but not GABA, and application of bicuculline antagonized the action of GABA but not glycine. In both types of neurons, iontophoresis of either antagonist depolarized the somatic membrane and increased input resistance throughout the respiratory cycle. Bicuculline preferentially depolarized the somatic membrane in both types of neurons during inactive phases. Strychnine increased the firing rate of inspiratory neurons during inspiration despite maintenance of somatic membrane potential at preiontophoresis levels. Tetrodotoxin reduced the effects of iontophoresed bicuculline and strychnine, suggesting that the action of the antagonists required presynaptic axonal conduction. The present results suggest that presynaptic release of both GABA and glycine contributes to tonic postsynaptic inhibition of bulbar respiratory neurons. GABA-A receptors appear to contribute to inhibition during inactive phases in inspiratory and postinspiratory neurons, whereas glycinergic mechanisms appear to contribute to inspiratory inhibition in inspiratory neurons.

scholarly journals Inspiratory Off-Switch Mediated by Optogenetic Activation of Inhibitory Neurons in the preBötzinger Complex In Vivo

2021 ◽  
Vol 22 (4) ◽  
pp. 2019
Author(s):  
Swen Hülsmann ◽  
Liya Hagos ◽  
Volker Eulenburg ◽  
Johannes Hirrlinger
Keyword(s):  
Respiratory Rate ◽  
Respiratory Rhythm ◽  
Inhibitory Neurons ◽  
Respiratory Neurons ◽  
Ventrolateral Medulla ◽  
Transgenic Mouse Line ◽  
Respiratory Network ◽  
Prebotzinger Complex ◽  
Prebötzinger Complex

The role of inhibitory neurons in the respiratory network is a matter of ongoing debate. Conflicting and contradicting results are manifold and the question whether inhibitory neurons are essential for the generation of the respiratory rhythm as such is controversial. Inhibitory neurons are required in pulmonary reflexes for adapting the activity of the central respiratory network to the status of the lung and it is hypothesized that glycinergic neurons mediate the inspiratory off-switch. Over the years, optogenetic tools have been developed that allow for cell-specific activation of subsets of neurons in vitro and in vivo. In this study, we aimed to identify the effect of activation of inhibitory neurons in vivo. Here, we used a conditional transgenic mouse line that expresses Channelrhodopsin 2 in inhibitory neurons. A 200 µm multimode optical fiber ferrule was implanted in adult mice using stereotaxic surgery, allowing us to stimulate inhibitory, respiratory neurons within the core excitatory network in the preBötzinger complex of the ventrolateral medulla. We show that, in anesthetized mice, activation of inhibitory neurons by blue light (470 nm) continuously or with stimulation frequencies above 10 Hz results in a significant reduction of the respiratory rate, in some cases leading to complete cessation of breathing. However, a lower stimulation frequency (4–5 Hz) could induce a significant increase in the respiratory rate. This phenomenon can be explained by the resetting of the respiratory cycle, since stimulation during inspiration shortened the associated breath and thereby increased the respiratory rate, while stimulation during the expiratory interval reduced the respiratory rate. Taken together, these results support the concept that activation of inhibitory neurons mediates phase-switching by inhibiting excitatory rhythmogenic neurons in the preBötzinger complex.

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

1996 ◽  
Vol 75 (2) ◽  
pp. 811-819 ◽  
Author(s):  
J. C. Rekling ◽  
J. Champagnat ◽  
M. Denavit-Saubie
Keyword(s):  
Membrane Potential ◽  
Brain Stem ◽  
Respiratory Rhythm ◽  
Input Resistance ◽  
Newborn Mouse ◽  
Hypoglossal Motoneurons ◽  
Inspiratory Neurons ◽  
Type 3

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. Cellular responses to TRH were investigated using whole cell recordings from hypoglossal motoneurons and three types of inspiratory neurons located in the rostral ventrolateral part of the slice. 2. Bath-applied TRH (1 microM) decreased the time between inspiratory discharges recorded on the XII nerve from 12.3 +/- 3.3 s to 4.9 +/- 1.1 s (n = 28; means +/- SD), i.e., caused an approximate threefold increase in the respiratory frequency. The coefficient of variation of the time between the inspiratory discharges decreased by one-half. Thus the respiratory output became more stable in response to TRH. The duration of the inspiratory discharges increased from 474 +/- 108 ms to 679 +/- 114 ms, and the amplitude decreased by 24%. An increase in the interdischarge noise on the XII nerve was recorded in the early phase of the TRH application. 3. Anatomically identified hypoglossal motoneurons (7 cells) responded to bath applied TRH with a depolarization eliciting spikes between the inspiratory potentials. The depolarization was accompanied by an increase in spontaneous excitatory synaptic activity that disappeared late during the TRH application. The duration of the inspiratory potentials was increased, indicating that the hypoglossal motoneurons received a longer duration synaptic input from the respiratory rhythm generator. 4. Type-1 inspiratory neurons showed a prolonged depolarization (3 cells), a transient depolarization (2 cells), or no change in membrane potential (2 cells) during 10 min of continued superfusion with a TRH-containing solution. The duration of the inspiratory potentials was increased during the TRH superfusion. With tetrodoxin (TTX, 1 microM) present in the superfusing solution TRH induced a prolonged depolarization (3 cells) or a transient depolarization (1 cell), demonstrating that type-1 inspiratory neurons are depolarized postsynaptically by TRH. The input resistance was not changed during the depolarizing response to TRH. 5. Type-2 inspiratory neurons showed a transient depolarization (7 cells) in response to bath-applied TRH. The duration of the inspiratory potentials was increased markedly during TRH. The transient depolarization was not the result of a postsynaptic action of TRH, because type-2 neurons (9 cells) showed no depolarization to TRH with TTX present in the superfusing solution. 6. Type-3 inspiratory neurons showed a transient depolarization (4 cells) with a partial recovery of the membrane potential late during the TRH application. The duration of the inspiratory potentials increased markedly during TRH. Four cells showed a transient depolarization with an increase in input resistance during TRH with TTX present in the superfusing solution. Thus type-3 neurons are depolarized postsynaptically by TRH. 7. We conclude that TRH increases the frequency of the respiratory rhythm in newborn mice through an action at the level of the brain stem.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory neuronal activity during apnea and poststimulatory effects of laryngeal origin in the cat

2000 ◽  
Vol 89 (3) ◽  
pp. 917-925 ◽  
Author(s):  
Fulvia Bongianni ◽  
Donatella Mutolo ◽  
Marco Carfì ◽  
Giovanni A. Fontana ◽  
Tito Pantaleo
Keyword(s):  
Respiratory Depression ◽  
Superior Laryngeal Nerve ◽  
Respiratory Neurons ◽  
Inhibitory Input ◽  
Phase Theory ◽  
Inspiratory Neurons ◽  
Three Phase ◽  
Expiratory Neurons ◽  
Inspiratory Activity ◽  
Respiratory Reflexes

We investigated the behavior of medullary respiratory neurons in cats under pentobarbitone anesthesia, vagotomized, paralysed, and artificially ventilated to elucidate neural mechanisms underlying apnea and poststimulatory respiratory depression induced by superior laryngeal nerve (SLN) stimulation. Inspiratory neurons were completely inhibited during SLN stimulation and poststimulatory apnea. During recovery of inspiratory activity, augmenting inspiratory neurons were depressed, decrementing inspiratory neurons were excited, and late inspiratory neurons displayed unchanged bursts closely locked to the end of the inspiratory phase. Augmenting expiratory neurons were either silenced or displayed different levels of tonic activity during SLN stimulation; some of them were clearly activated. These expiratory neurons displayed activity during poststimulatory apnea, before the onset of the first recovery phrenic burst. Postinspiratory or decrementing expiratory neurons were activated during SLN stimulation; their discharge continued with a decreasing trend during poststimulatory apnea. The results support the three-phase theory of rhythm generation and the view that SLN stimulation provokes a postinspiratory apnea that could represent the inhibitory component of respiratory reflexes of laryngeal origin, such as swallowing. In addition, because a subpopulation of augmenting expiratory neurons displays activation during SLN stimulation, the hypothesis can be advanced that not only postinspiratory, or decrementing expiratory neurons, but also augmenting expiratory neurons may be involved in the genesis of apnea and poststimulatory phenomena. Finally, the increase in the activity of decrementing inspiratory neurons after the end of SLN stimulation may contribute to the generation of poststimulatory respiratory depression by providing an inhibitory input to bulbospinal augmenting inspiratory neurons.

scholarly journals cAMP-Dependent Protein Kinase Modulates Expiratory Neurons In Vivo

1997 ◽  
Vol 77 (3) ◽  
pp. 1119-1131 ◽  
Author(s):  
Peter M. Lalley ◽  
Olivier Pierrefiche ◽  
Anne M. Bischoff ◽  
Diethelm W. Richter
Keyword(s):  
Protein Kinase ◽  
Input Resistance ◽  
Inhibitory Peptide ◽  
Synaptic Currents ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Expiratory Neurons ◽  
Messenger System

Lalley, Peter M., Olivier Pierrefiche, Anne M. Bischoff, and Diethelm W. Richter. cAMP-dependent protein kinase modulates expiratory neurons in vivo. J. Neurophysiol. 77: 1119–1131, 1997. The adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) second-messenger system influences neuronal excitability by modulating voltage-regulated and transmitter-activated channels. In this study we investigated the influence of the cAMP-PKA system on the excitability of expiratory (E) neurons in the caudal medulla of anesthetized, paralyzed, and artificially ventilated adult cats. We intracellularly injected the PKA inhibitors cAMP-dependent PKA inhibitor 5-22 amide (Walsh inhibitory peptide) and Rp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (Rp-cAMPS), the PKA activator Sp-adenosine 3′,5′-cyclic monophosphothioate triethylamine (Sp-cAMPS), and the adenylyl cyclase activator forskolin and measured membrane potential, neuronal input resistance, and synaptic membrane currents. Inhibition of cAMP-PKA activity by Walsh inhibitory peptide or Rp-cAMPS injections hyperpolarized neurons, decreased input resistance, and depressed spontaneous bursts of action potentials. Action potential duration was shortened and afterhyperpolarizations were increased. Inhibitory synaptic currents increased significantly. Stimulation of cAMP-PKA activity by Sp-cAMPS or forskolin depolarized neurons and increased input resistance. Spontaneous inhibitory synaptic currents were reduced and excitatory synaptic currents were increased. Rp-cAMPS depressed stimulus-evoked excitatory postsynaptic potentials and currents, whereas Sp-cAMPS increased them. Sp-cAMPS also blocked postsynaptic inhibition of E neurons by 8-hydroxy-dipropylaminotetralin, a serotonin-1A (5-HT-1A) receptor agonist that depresses neuronal cAMP-PKA activity. To determine the predominant effect of G protein-mediated neuromodulation of E neurons, we injected guanosine-5′-O-(3-thiotriphosphate) tetralithium salt (GTP-γ-S), an activator of both stimulatory and inhibitory G proteins. GTP-γ-S hyperpolarized E neurons, reduced input resistance, and increased action potential afterhyperpolarization. We conclude that the intracellular cAMP-PKA messenger system plays an important role in the activity-dependent modulation of excitability in E neurons of the caudal medulla. In addition, the cAMP-PKA pathway itself is downregulated during activation of 5-HT-1A receptors.

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