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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 1  |  Page : 27-34

Modulation of glycinergic inhibition on respiratory rhythmic hypoglossal bursting in the rat


1 Department of Biological Sciences, College of Science, National Sun Yat-sen University; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, Taiwan
2 Department of Life Science, College of Science, National Taiwan Normal University, Taipei, Taiwan

Date of Submission28-Dec-2018
Date of Decision27-Jan-2019
Date of Acceptance28-Jan-2019
Date of Web Publication22-Feb-2019

Correspondence Address:
Dr. Kun-Ze Lee
Department of Biological Sciences, College of Science, National Sun Yat-sen University, Kaohsiung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_10_18

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  Abstract 

The hypoglossal nerve displays respiratory rhythmic bursting and is composed of preinspiratory and inspiratory activity which is important in maintaining upper airway patency. The present study was designed to examine the modulatory role of glycinergic inhibition in respiratory rhythmic hypoglossal bursting. The activity of the phrenic nerve, as well as the medial and lateral branches of the hypoglossal nerve, was recorded simultaneously in urethane-anesthetized and mechanically ventilated adult rats in response to moderate and high levels of sustained lung inflation. The results demonstrated that inspiratory activity of the phrenic nerve gradually reduced with increasing lung inflation. The burst amplitude and discharge onset of the hypoglossal nerve branches were enhanced during moderate lung inflation but inhibited by high levels of lung inflation. These lung volume-mediated respiratory reflexes were abolished following a bilateral cervical vagotomy. In addition, intravenous administration of a glycine receptor antagonist (strychnine, 1 μmole/kg) attenuated preceding onset of rhythmic hypoglossal bursting but enhanced inspiratory hypoglossal burst amplitude during the baseline. Moreover, both excitatory and inhibitory effects of lung inflation on hypoglossal nerve activity were attenuated following a glycine transmission blockade. These results suggest that glycinergic inhibition modulated rhythmic hypoglossal bursting and was involved in mediating lung volume-induced respiratory reflexes.

Keywords: Glycinergic inhibition, hypoglossal, lung inflation


How to cite this article:
Lee KZ, Hwang JC. Modulation of glycinergic inhibition on respiratory rhythmic hypoglossal bursting in the rat. Chin J Physiol 2019;62:27-34

How to cite this URL:
Lee KZ, Hwang JC. Modulation of glycinergic inhibition on respiratory rhythmic hypoglossal bursting in the rat. Chin J Physiol [serial online] 2019 [cited 2019 Nov 12];62:27-34. Available from: http://www.cjphysiology.org/text.asp?2019/62/1/27/252833


  Introduction Top


Temporal coordination between the respiratory activity of the spinal pump muscles (i.e., diaphragm and intercostal muscles) and the cranial nerve-innervated upper airway muscles (i.e., laryngeal and tongue muscles) is critical for the maintenance of upper airway patency.[1],[2] The hypoglossal nerve usually displays respiratory rhythmic bursting with earlier onset before inspiratory phrenic activity.[3],[4],[5] This earlier onset of hypoglossal activity, termed preinspiratory activity, may stabilize the upper airway before inspiratory airflow begins streaming into the lungs.[6],[7] Discharge onset of rhythmic hypoglossal bursting or preinspiratory activity of the hypoglossal nerve could be modulated by activation of central/peripheral chemoreceptors and lung mechanical/chemical afferents.[4],[8],[9],[10] The differential discharge onset between rhythmic hypoglossal and phrenic bursting has been proposed to be a stronger inspiratory drive to hypoglossal motoneurons. It may also be due to the lower activation threshold of hypoglossal motoneurons.[10],[11] Moreover, the hypoglossal nerve is composed of the medial and lateral branch, which innervated the tongue protrudor and retractor muscles, respectively. Previous studies have shown that activation of the medial hypoglossal branch can protrude the tongue and increase the upper airway patency, while independent stimulation of lateral hypoglossal branch retracted the tongue and reduced the airflow.[12],[13] From a functional aspect, it is critical to understand the mechanism responsible for the preceding onset of rhythmic hypoglossal bursting and examine whether there is a differential regulation of medial versus lateral hypoglossal branch.

Glycine is an inhibitory neurotransmitter in the central nervous system and is involved in regulating respiratory rhythm and/or pattern.[14],[15],[16] Several studies have demonstrated that loss of glycinergic inhibition disturbs respiratory rhythm.[16],[17],[18] In addition, expiratory bursting of the thoracic ventral root commences earlier during inspiration after application of a glycine receptor antagonist (i.e., strychnine) to the brainstem.[19] Similarly, Dutschmann and Paton observed that postinspiratory activity of the recurrent laryngeal nerve shifted forward to the inspiratory period after blockade of glycinergic inhibition.[20] This phasic shifting of respiratory activity was also observed in response to trigeminal stimulation and capsaicin-induced pulmonary C-fiber activation.[21],[22] Thus, the activation of peripheral sensory inputs may produce a response similar to the loss of central glycinergic transmission. Notably, intra-jugular capsaicin injection not only shifted postinspiratory activity of the recurrent laryngeal nerve but also delayed the preceding onset of preinspiratory activity of the hypoglossal nerve and abducens branch of the recurrent laryngeal nerve.[22],[23] Collectively, these observations indicated that glycinergic transmission in the central nervous system may be temporally coordinated with respiratory activity during preinspiratory, inspiratory, and expiratory periods. Accordingly, the present study was designed to examine the modulatory role of glycinergic inhibition on the discharge onset and burst amplitude of rhythmic activity in the medial and lateral hypoglossal nerve branch.


  Materials and Methods Top


Animal preparation

A total of 15 adult male Wistar rats (2–4 months of age), purchased from the Animal Center of National Taiwan University, were housed in an animal room with water and food ad libitum. Experimental protocols were approved by the Animal Care and Use Committee of National Taiwan Normal University.

Animals were anesthetized with urethane (1.2 g/kg, i.p., Sigma) 30 min after atropine pretreatment (0.5 mg/kg, i.m., Sigma) and were then placed in a supine position. The trachea was cannulated with a PE-240 tube (Clay Adams), and two additional catheters (PE-50, Clay Adams) were inserted into the femoral artery and vein for blood pressure measurement and drug administration, respectively. The rat was then paralyzed with gallamine triethiodide (5 mg/kg, i.v., Sigma) and artificially ventilated with oxygen by a ventilator (NEMI, 7–10 ml/kg, 60–70 breaths/min). A positive end-expired pressure of 3 cmH2O was applied by inserting the outlet tube of the ventilator into a beaker of water. The tracheal pressure was detected through an arm of the tracheal tube and a transducer connected to a preamplifier (7P1, Grass Instrument). The end-tidal fractional concentration of CO2 was measured with a CO2 analyzer (Electrochemistry CD3A, Ametek) by inserting a 25-gauge needle into the tracheal tube. It was maintained at 5% by adjusting the frequency and volume of the ventilator.

Nerve recording

The phrenic nerve was ventrally identified at the cervical region and cut peripherally.[24] The medial and lateral hypoglossal nerve branch was dissected from the digastric muscle and cut distally on the left side.[23] The phrenic nerve and hypoglossal nerve branches were placed on bipolar stainless electrodes. Neural signals were amplified and filtered (0.3–3 kHz, P511, Grass Instrument), and integrated (time constant: 50 ms). All signals were recorded onto a hard disc through the PowerLab system (ADInstruments Pty Ltd, Australia) for off-line analyses.

Lung inflation

Two levels of sustained lung volume (i.e., moderate and high inflation) were applied for 10 s to evoke a respiratory reflex, which modulated rhythmic hypoglossal activity, as previously described.[10],[25] Moderate and high lung inflation were randomly produced by switching the connection of the tracheal tube from the ventilator to a water trapping system,[26] which generated a positive static pressure (5 and 10 cmH2O for moderate and high levels of lung inflation, respectively) to the rat lung through an air compressor.

Experimental protocols

In the first protocol, moderate and high lung inflation was applied to the rat lung in a random order after a stable recording of phrenic and hypoglossal nerve activity before and after the bilateral cervical vagotomy (n = 5). In the second protocol, alterations in the respiratory activity of the phrenic and hypoglossal nerves induced by sustained lung inflation were examined before and after a bolus venous injection of a glycine receptor antagonist (strychnine, 1.0 μmole/kg, Sigma) (n = 10).

Data analysis

Data stored on the hard disc were retrieved and analyzed with software written in Visual C++ 6.0. Data from 10 respiratory cycles before treatment were averaged as the baseline value. The activity of the phrenic and hypoglossal nerve branches was defined as the amplitude of the neurogram signals and was normalized into a percentage of the baseline (i.e., % BL). Inspiratory duration was defined as the period of a phrenic burst, and expiratory duration was calculated as an interval period between two successive phrenic bursts. The discharge onset of rhythmic hypoglossal bursting relative to the commencement of inspiratory phrenic activity was calculated.[23] The blood pressure, heart rate, and tracheal pressure data were calculated using the data pad module of the PowerLab system.

A two-way repeated measurement analysis of variance (factor one: levels of lung inflation [baseline, moderate, and high lung inflation]; factor two: vagal intact vs. vagotomy or before vs. after strychnine treatment) followed by a post hoc Student–Newman–Keuls test were used to analyze physiological parameters. Data were expressed as the mean ± the standard error of the mean. P < 0.05 was considered statistically significant.


  Results Top


Effects of lung inflation on respiratory activity before and after vagotomy

Moderate lung inflation did not significantly modulate the phrenic activity but instead produced an excitation on rhythmic hypoglossal activity [Figure 1]. Specifically, inspiratory burst amplitude of the medial and lateral hypoglossal branch was significantly increased to 172% ± 20% BL and 170% ± 13% BL during moderate lung inflation, respectively [P < 0.01, [Figure 2]a and [Figure 2]c. In addition, discharge onset of rhythmic hypoglossal bursting significantly increased from 0.09 ± 0.01 s to 0.36 ± 0.06 s in the medial hypoglossal branch and from 0.10 ± 0.01 s to 0.34 ± 0.06 s in the lateral hypoglossal branch [P < 0.01, [Figure 2]b and [Figure 2]d. Thus, rhythmic hypoglossal bursting discharged earlier than the phrenic activity during moderate lung inflation.
Figure 1: Effects of lung inflation on the respiratory activity of the phrenic nerve and medial and lateral branches of the hypoglossal nerve (XIIMED and XIILAT) before and after strychnine administration (Panel A). Moderate lung inflation increased the hypoglossal burst amplitude and advanced the onset of hypoglossal branches. High lung inflation caused a cessation of respiratory rhythmic bursting in the phrenic nerve and hypoglossal nerve branches. Strychnine administration attenuated both excitatory effects of moderate lung inflation and inhibitory effects of high lung inflation. (Panel B) represents the temporal enlargement of phrenic and hypoglossal neurograms in a single respiratory cycle labeled a-f in Panel A. TP: tracheal pressure, MI: moderate lung inflation, HI: high lung inflation, Int.: integrated neurogram

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Figure 2: Rhythmic hypoglossal bursting in response to lung inflation before and after bilateral vagotomy. Moderate lung inflation caused excitation of both burst amplitude (Panel a and c) and discharge onset (Panel b and d) of hypoglossal nerve branches, However, rhythmic hypoglossal activity was significantly reduced during high lung inflation. Both excitatory and inhibitory hypoglossal responses were attenuated following a vagotomy. *: P<0.05; **:P <0.01 versus the baseline. #: P <0.05; ##: P <0.01 significant difference between vagal-intact versus vagotomized. XIIMED: Medial hypoglossal branch. XIILAT: Lateral hypoglossal branch

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High lung inflation significantly reduced the respiratory activity of the phrenic nerve and hypoglossal nerve branches [Figure 1]. Three of five animals ceased respiratory rhythmic bursting, while two exhibited weaker respiratory activity, during high lung inflation. In the grouped data, the inspiratory duration was significantly reduced, and the expiratory duration was significantly prolonged during high lung inflation [P < 0.01, [Figure 3]a and [Figure 3]b. Moreover, inspiratory burst amplitude of the phrenic nerve decreased to 35% ± 21% BL [P < 0.01, [Figure 3]c, and hypoglossal burst amplitude reduced to ~ 20%–25% BL [P < 0.01, [Figure 2]a and [Figure 2]c. Since respiratory rhythmic activity was significantly eliminated by high lung inflation, discharge onset of rhythmic hypoglossal bursting was also significantly attenuated [P < 0.05, [Figure 2]b and [Figure 2]d.
Figure 3: Inspiratory duration (Panel a) and phrenic burst amplitude (Panel c), while prolonging the expiratory duration (Panel b) before vagotomy. High lung inflation induced a significant reduction in the inspiratory duration and phrenic burst amplitude, while prolonging the expiratory duration before vagotomy. These inhibitory responses of the phrenic activity were abolished after the bilateral vagotomy. **: P <0.01 versus the baseline. ##: P <0.01 significant difference between vagal-intact versus vagotomized animals

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A bilateral cervical vagotomy did not significantly influence the respiratory cycle duration and phrenic burst amplitude but significantly augmented the rhythmic hypoglossal bursting. Specifically, the hypoglossal burst amplitude was increased to 170% ± 19% BL in the medial hypoglossal branch and to 159% ± 16% BL in the lateral hypoglossal branch [P < 0.05, [Figure 2]a and [Figure 2]c. Moreover, the preceding onset of hypoglossal bursting was significantly enhanced following the vagotomy [P < 0.01, [Figure 2]b and [Figure 2]d. Notably, the inhibitory effect of high lung inflation and the excitatory effect of moderate lung inflation were abolished after the bilateral vagotomy, suggesting that lung volume-mediated respiratory reflexes were primarily mediated by vagal afferent inputs.

Effects of strychnine on lung volume-mediated respiratory reflexes

IV administration of strychnine did not significantly modulate the respiratory frequency and the phrenic burst amplitude [Figure 4]b and [Figure 4]c, but it did reduce the inspiratory duration [P < 0.05, [Figure 4]a. Inspiratory burst amplitude of the hypoglossal nerve branches was significantly enhanced following strychnine [P < 0.05, [Figure 5]a and [Figure 5]c; however, the preceding onset of hypoglossal bursting was reduced to 0.04–0.05 s in the hypoglossal nerve branches [Figure 5]b and [Figure 5]d.
Figure 4: The inspiratory duration (Panel a), expiratory duration (Panel b) and phrenic burst amplitude (Panel c) in response to lung inflation before and after strychnine. Intravenous administration of strychnine reduced the inspiratory duration and attenuated the phrenic response during high levels of lung inflation. **: P < 0.01 versus the baseline. #: P < 0.05; ##: P < 0.01 significant difference between before versus after strychnine treatment

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Figure 5: Rhythmic hypoglossal bursting in response to lung inflation before and after strychnine. Strychnine significantly enhanced the inspiratory burst amplitude of hypoglossal nerve branches (Panel a and c), but slightly reduced the preceding onset of hypoglossal bursting (Panel b and d). Both excitatory and inhibitory hypoglossal responses were attenuated by the administration of strychnine. *: P <0.05; **: P <0.01 versus the baseline. #: P <0.05; ##: P <0.01 significant difference between before versus after strychnine treatment. XIIMED: Medial hypoglossal branch, XIILAT: Lateral hypoglossal branch

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The excitatory effect of moderate lung inflation on rhythmic hypoglossal bursting was significantly attenuated by strychnine [Figure 1] and [Figure 5]. For example, the hypoglossal burst amplitude was no longer enhanced by moderate lung inflation [Figure 5]a and [Figure 5]c. In addition, the more-advanced onset of rhythmic hypoglossal bursting during moderate lung inflation was substantially decreased by strychnine. Specifically, the preceding onset of the medial hypoglossal branch reduced from 0.39 ± 0.07 s to 0.12 ± 0.01 s after strychnine administration [P < 0.01, [Figure 5]b. Similarly, strychnine significantly reduced the response of the lateral hypoglossal branch during moderate lung inflation.

The administration of strychnine also attenuated the inhibitory effect of high lung inflation on respiratory activity. High lung inflation levels caused a complete cessation of respiratory rhythmic bursting in nine of 10 animals before strychnine treatment. However, 50% (5 of 10) of animals regained respiratory rhythmic activity after strychnine during the same level of lung inflation. In addition, the attenuated burst amplitude of the phrenic and hypoglossal nerve branches was reversed due to the administration of strychnine [Figure 4]c, [Figure 5]a and [Figure 5]c.

Cardiovascular response to lung inflation and strychnine

The mean arterial blood pressure and heart rate in response to lung inflation and strychnine are shown in [Table 1]. High levels of lung inflation caused a significant reduction in the blood pressure, but this hypotensive response was not influenced by the vagotomy and the strychnine treatment.
Table 1: The effect of lung inflation on the mean arterial blood pressure and heart rate before and after vagotomy or strychnine treatment

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  Discussion Top


There were four findings in the present study. First, moderate lung inflation induced an excitatory effect on the rhythmic hypoglossal bursting, as reflected by increases in the burst amplitude and discharge onset of rhythmic hypoglossal bursting relative to the inspiratory phrenic activity. Second, the administration of strychnine (1 μmole/kg) abolished the advanced discharge onset and the increased amplitudes of rhythmic hypoglossal bursting during moderate lung inflation. Third, strychnine reversed the inhibitory response of the phrenic nerve and hypoglossal branches during high lung inflation. Fourth, medial and lateral hypoglossal branch responded similarly to lung inflation, vagotomy, and strychnine administration. These results suggested that glycinergic inhibition participated in modulating the rhythmic hypoglossal bursting during the baseline and lung volume-mediated respiratory reflexes.

Modulation of lung volume on rhythmic hypoglossal bursting

The present data are compatible with previous observations indicating that the discharge onset of rhythmic hypoglossal bursting precedes the inspiratory phrenic activity and even discharged earlier during moderate lung inflation.[9],[25] The alteration of discharge onset and amplitude of hypoglossal bursting during lung inflation were abolished following a bilateral cervical vagotomy. This suggested that respiratory reflexes induced by lung inflation were mediated by vagal afferents. Notably, discharge onset of rhythmic hypoglossal bursting after a vagotomy was earlier than that in vagal-intact animals. This phenomenon indicated that vagal afferent inputs may produce a tonic inhibition on the rhythmic hypoglossal bursting during the baseline. Interestingly, advanced discharge onset of hypoglossal bursting during moderate lung inflation was greater than that in vagotomized animals. This finding suggested that vagal afferent inputs also provoked the excitatory reflex of the discharge onset of hypoglossal bursting. Thus, the activation of vagal afferents may produce tonic inhibition and/or excitation of rhythmic hypoglossal bursting dependent on the level of lung inflation.

The pulmonary vagal afferents are mainly composed of slowly adapting pulmonary stretch receptors, rapidly adapting receptors and unmyelinated pulmonary C-fibers.[27] Previous studies have shown that activation of pulmonary C-fibers can evoke pulmonary chemoreflexes, which delay discharge onset of rhythmic hypoglossal bursting and tongue movement.[7],[23],[28] Moreover, excitation of rapidly adapting receptors has been demonstrated to produce augmented breathing and shortened expiratory duration.[29],[30] These responses were not observed during moderate lung inflation in this study. Accordingly, excitatory effects of moderate lung inflation on rhythmic hypoglossal bursting were proposed to be primarily mediated by slowly adapting pulmonary stretch receptors. These receptors can be categorized into different types depending on the response to different levels of lung volume change.[31],[32] Although phrenic activity was gradually inhibited with increasing lung inflation levels, the data indicated that different lung volumes produced opposite effects on rhythmic hypoglossal bursting. Moderate lung inflation evoked earlier onset of preinspiratory hypoglossal activity, while high lung inflation ceased rhythmic hypoglossal bursting. In this regard, excitatory and inhibitory effects of lung inflation may be mediated by different types of slowly adapting pulmonary stretch receptors. In addition, both excitatory and inhibitory second order neurons of slowly adapting pulmonary stretch receptors existed within the nucleus of the solitary tract.[33] Thus, the differential activation of excitatory and inhibitory second-order neurons in the brainstem could have also contributed to the opposed rhythmic hypoglossal bursting in response to moderate versus high lung inflation.

Effect of modulation of glycinergic inhibition on rhythmic hypoglossal bursting

The present data showed that onset of rhythmic hypoglossal bursting depended on glycinergic inhibition, due to significant attenuation after intravenous administration of a glycine receptor antagonist (i.e., strychnine). However, glycine receptors are widely distributed in the central and peripheral nervous system,[34] thus, the systemic administration of a glycine receptor antagonist cannot specifically indicate which region is involved in the modulation of rhythmic hypoglossal bursting. Smith et al. demonstrated that preceding discharge onset of hypoglossal bursting was eliminated after transection at the pontine-medullary junction. Thus, the pontine may be the potential source of preinspiratory drives to the hypoglossal motoneurons.[35] This concept was proven by two studies showing that modulation of the pontine Kölliker-Fuse nucleus influenced preinspiratory activity of the hypoglossal nerve.[3],[36] Future studies are warranted to determine whether glycinergic inhibition within the Kölliker-Fuse nucleus plays a role in regulating discharge onset of rhythmic hypoglossal bursting.

The blockade of glycine receptors not only decreased the onset of preinspiratory activity but increased the inspiratory burst amplitude of hypoglossal branches. This result could be explained by an inhibitory glycinergic signal impinging on the hypoglossal motoneurons during inspiration.[37],[38] Alternatively, there may be a shift in preinspiratory bursting from the late-expiratory period to the inspiratory period, which could reduce the preinspiratory burst amplitude but augment inspiratory burst amplitude. Results from a power spectral analysis suggested that the controlling mechanisms of preinspiratory versus inspiratory hypoglossal activity may be distinct.[39] This viewpoint was supported by a separation of the preinspiratory and inspiratory components of the hypoglossal bursting during hypocapnia, hypothermia, and increased positive end-expired pressure.[9],[10],[40] In addition to modulation of rhythmic hypoglossal bursting during the baseline, strychnine also attenuated excitatory and inhibitory responses of hypoglossal activity during moderate and high lung inflation, respectively. Hence, there is a possibility that strychnine administration modulated the putative regions involved in signal processing of slowly adapting pulmonary stretch receptors, such as the nucleus of the solitary tract, the Bötzinger complex, and the ventral respiratory group.[41],[42],[43]


  Conclusion Top


The results demonstrated that the glycinergic mechanism may be involved in the modulation of rhythmic hypoglossal bursting and is critical to the maintenance of upper airway patency.[44]

Financial support and sponsorship

  • The Ministry of Science and Technology (105-2628-B-110-002-MY3 & 108-2636-B-110-001)
  • Higher Education Sprout Project (07C030111)
  • NSYSU-KMU Joint Research Project (107-I001).


Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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